223

Salmonella Species, Including Salmonella Typhi

DAVID A. PEGUES | SAMUEL I. MILLER

Salmonella choleraesuis from porcine intestine.1 Salmonella are effective commensals and pathogens that cause a spectrum of diseases in humans and animals, including domesticated and wild mammals, reptiles, birds, and insects. Some Salmonella serotypes, such as Salmonella Typhi, Salmonella Paratyphi, and Salmonella Sendai, are highly adapted to humans and have no other known natural hosts, whereas others, such as Salmonella Typhimurium, have a broad host range and can infect a wide variety of animal hosts and humans. Some Salmonella serotypes, such as Dublin (cattle) and Arizonae (reptiles), are mostly adapted to an animal species and only occasionally infect humans. The widespread distribution of Salmonella in the environment, their increasing prevalence in the global food chain, and their virulence and adaptability have an enormous medical, public health, and economic impact worldwide.

Salmonellae are named for the pathologist Salmon, who first isolated

Classification and Taxonomy

Salmonella is a genus of the family of Enterobacteriaceae. Before 1983, the existence of multiple Salmonella species was taxonomically accepted. Currently, as a result of experiments indicating a high degree of DNA similarity, the genus Salmonella is separated into two species: Salmonella enterica, which contains six subspecies (I, II, IIIa, IIIb, IV, and VI), and Salmonella bongori, which was formerly subspecies V.13 S. enterica subspecies I contains almost all the serotypes pathogenic for humans, except for rare human infections with subspecies IIIa and IIIb that were formerly designated by the genus Arizonae. Members of the seven Salmonella subspecies can be serotyped into one of more than 2500 serotypes (serovars) according to antigenically diverse surface structures: somatic O antigens, the carbohydrate component of lipopolysaccharide, and flagellar (H) antigens (Table 2231).13 The name usually refers to the location where the Salmonella serotype was first isolated. According to the current Salmonella nomenclature system in use at the U.S. Centers for Disease Control and Prevention (CDC) and World Health Organization laboratories, the full taxonomic designation Salmonella enterica subspecies enterica serotype Typhimurium can be shortened to Salmonella serotype Typhimurium or Salmonella Typhimurium.14 The authors have chosen to use the abbreviated form in this chapter and will omit the serotype, for example, designating Salmonella serotype Typhimurium as Salmonella Typhimurium.

History
Before the 19th century, typhus and typhoid fever were confused. Though various clinical distinctions were proposed, none reliably distinguished these syndromes. In 1829 in Paris, P. Ch. A. Louis separated typhoid from other fevers on the basis of intestinal lymph node and spleen pathology.2 He also described the clinical phenomena of rose spots, intestinal perforation, and hemorrhage. In the English literature, William Jenner in 1850 settled the question of whether typhus and typhoid were different diseases.3 He distinguished typhoid based on the pathologic evidence of enlargement of the Peyers patches and mesenteric lymph nodes. Jenner also noted that prior attacks of typhoid protected against subsequent attacks; this was not the case for typhus. In 1869, Wilson proposed the term enteric fever as an alternative to typhoid fever, given the anatomic site of infection.4 Though enteric fever remains a more accurate term, the use of the term typhoid persists today. In 1873 Budd demonstrated that food, water, and fomites could transmit typhoid fever.5 Gaffkey in Germany isolated the typhoid bacillus in 1884 from the spleens of infected patients.6 In 1896, Pfeiffer and Kalle made the first typhoid vaccine with heat-killed organisms.7 In the same year Widal and others demonstrated that convalescent sera from typhoid patients caused the organisms to stick together in large balls and lose their motility.8 Widal coined the term agglutinin to describe this observation. The antigenic classification or serotyping of Salmonella used today is a result of years of study of antibody interactions with bacterial surface antigens by Kauffman and White during the 1920s to 1940s.9 In 1948, Theodore Woodward and colleagues reported the successful treatment of Malaysian typhoid patients with chloromycetin,10 and the modern age of antimicrobial therapy for typhoid fever began. In 1952, Zinder and Lederberg, using S. Typhimurium, discovered genetic transduction, the transfer of genetic information from one cell to another by a virus particle (bacteriophage P22).11 Ames and coworkers in 1973 reported the development of the Ames test, which uses S. Typhimurium auxotrophic mutants to test the mutagenic activity of chemical compounds.12 At present Salmonella pathogenesis is studied widely in animal and tissue culture models of mammalian infection as an important model of host-parasite interactions.

The Genome
The genome sequences of 15 complete salmonellae serotypes, including two S. Typhi strains, two S. Paratyphi A strains, and one S. Paratyphi B strain, six nontyphoidal strains, and numerous other species-specific serotypes including Arizonae, Choleraesuis, Dublin, and Gallinarum, are available in Genbank. Twenty-five other partially completed genomes using next generation sequencing technology also are available, including 15 S. Typhi sequences.15 The salmonellae genomes contain approximately 4.8 to 4.9 million base pairs with approximately 4400 to 5600 coding sequences. A characteristic phenomenon of host restriction such as that found for S. Typhi is gene loss. In S. Typhi strain CT18 there are 204 inactivated pseudogenes, which may explain its host restriction to humans, though a recent publication comparing Salmonella Gallinarum, which is host restricted to poultry, to Salmonella Enteritidis phage type 4, which infects poultry and is broad host range, found significant overlap between the defined pseudogenes in both S. Typhi and S. Gallinarum.15,16

Microbiology
Salmonellae are gram-negative, non-spore-forming, facultatively anaerobic bacilli that measure 2 to 3 by 0.4 to 0.6 m in size. Like other Enterobacteriaceae, they produce acid on glucose fermentation, reduce nitrates, and do not produce cytochrome oxidase.17 All organisms except S. Gallinarum-Pullorum are motile as a result of peritrichous flagella, and most do not ferment lactose. However, approximately 1% of organisms are able to ferment lactose and therefore may not be

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223-1

taBLE

Salmonella Species, Subspecies, and Serotypes and Their Usual Habitats No. of Serotypes Within Subspecies 1504 502 95 333 72 13 22 2541

Salmonella Species and Subspecies S. enterica subsp. enterica (I) S. enterica subsp. salmae (II) S. enterica subsp. arizonae (IIIa) S. enterica subsp. diarizonae (IIIb) S. enterica subsp. houtenae (IV) S. enterica subsp. indica (VI) S. bongori (V) Total

Usual Habitat Warm-blooded animals Cold-blooded animals and the environment* Cold-blooded animals and the environment* Cold-blooded animals and the environment* Cold-blooded animals and the environment* Cold-blooded animals and the environment* Cold-blooded animals and the environment*

*Isolates of all species and subspecies have occurred in humans. Adapted from Popoff MY, Bockemhl J, Gheesling LL. Supplement 2002 (No. 46) to the Kauffmann-White scheme. Res Microbiol. 2004;155:568-570.

Although serotyping of all surface antigens can be used for formal identification, most laboratories perform a few simple agglutination reactions that define specific O antigens into serogroups, designated as groups A, B, C1, C2, D, and E Salmonella. Strains in these six serogroups cause approximately 99% of Salmonella infections in humans and warm-blooded animals. Although this grouping is useful in epidemiologic studies and can be used to confirm genus identification, it cannot identify whether the organism is likely to cause enteric fever, because considerable cross-reactivity occurs among serogroups. For example, S. Enteritidis, which typically causes gastroenteritis, and S. Typhi, which causes enteric fever, are both group D. Similarly, another frequent cause of gastroenteritis, S. Typhimurium, and some S. Paratyphi, another cause of enteric fever, are both group B. Subtyping methods frequently are used for epidemiologic purposes to differentiate strains of common Salmonella serotypes. Phenotyping methods may be useful for characterizing outbreak-associated strains and sporadic multidrug-resistant isolates, and include bacteriophage typing, plasmid profile analysis, antimicrobial susceptibility, and biotyping. More discriminative genotyping techniques, including ribotyping, pulsed-field gel electrophoresis, insertion sequences analysis, PCR-based fingerprinting, multilocus sequence typing, and genomic DNA analysis using microarrays have been used in epidemiologic studies to differentiate strains within a given serotype.

detected if only MacConkey agar or other semiselective media are used to identify Salmonella based on colorimetric assay for fermentation of lactose. The differential metabolism of sugars can be used to distinguish many Salmonella serotypes; serotype Typhi is the only organism that does not produce gas on sugar fermentation.17 Freshly passed stool is preferred for the isolation of Salmonella and should be plated directly onto agar plates. Low-selective media, such as MacConkey agar and deoxycholate agar, and intermediate-selective media, such as Salmonella-Shigella, xylose-lysine-deoxycholate, or Hektoen agar, are widely used to screen for both Salmonella and Shigella species. Selective chromogenic media, such as CHROMagar, are more specific than other selective media, reduce the need for confirmatory testing and time to identification, and increasingly are used for the primary isolation and presumptive identification of Salmonella from clinical stool specimens.18 In addition to plating stool onto primary media, tetrathionate- and selenite-based enrichment broths are often used to facilitate the recovery of low numbers of organisms.18 Highly Salmonella-selective media, such as selenite with brilliant green, should be reserved for use in stool cultures of suspected carriers and under special circumstances, such as outbreaks. Bismuth sulfite agar, which contains an indicator of hydrogen sulfite production and does not contain lactose, is preferred for the isolation of S. Typhi and can be used for the detection of the 1% of Salmonella strains (including most Salmonella serogroup C strains) that ferment lactose.19 After primary isolation, possible Salmonella isolates can be tested in commercial identification systems or inoculated into screening media such as triple-sugariron and lysine-iron agar. Direct detection of Salmonella from stool and food specimens using polymerase chain reaction (PCR) and rapid serologic diagnosis using anti-Salmonella 09 IgM antibodies are under development.20-22 Isolates with typical biochemical profiles for Salmonella should be serogrouped with commercially available polyvalent antisera or sent to a reference or public health laboratory for complete serogrouping. Salmonellae are serogrouped according to their polysaccharide O (somatic) antigens, Vi (capsular) antigens, and H (flagellar) antigens according to the Kauffman-White scheme.23 The Vi antigen is a heatlabile capsular homopolymer of N-acetylgalactosaminouronic acid that is used for the identification of S. Typhi strains and occasionally other Salmonella serotypes by slide agglutination.24 In S. Typhi and S. Paratyphi C, the polysaccharide Vi antigen can inhibit O antigen agglutination because it is so abundant, and boiling is required to inactive Vi antigen and to detect O antigen. Most antigenic variability occurs in the O antigen, which is composed of chains of oligosaccharide attached to a core oligosaccharide linked covalently to lipid A.

Epidemiology
SALMONELLA tYPHI aND SALMONELLA ParatYPHI In contrast to other Salmonella serotypes, the etiologic agents of enteric feverS. Typhi and S. Paratyphi serotypes A, B, and Chave no known hosts other than humans. Most commonly, foodborne or waterborne transmission occurs as a result of fecal contamination by ill or asymptomatic chronic carriers. Usually, waterborne transmission involves the ingestion of fewer microorganisms and, as a result, has a longer incubation period and lower attack rate compared with foodborne transmission. Although direct person-to-person transmission is uncommon, S. Typhi can be transmitted sexually, including by anal and oral sex.25 Health care workers can acquire the disease from infected patients as a result of poor hand hygiene or handling laboratory specimens.26 Enteric fever continues to be a global health problem, with an estimated 21.6 million cases caused by S. Typhi and 5.5 million cases caused by S. Paratyphi A, B, or C annually and an incidence ranging from 25 to 1000 cases per 100,000 population in endemic regions.27,28 An estimated 200,000 to 600,000 deaths occur annually, based on extrapolation from endemic regions.27 Regions with a high incidence of typhoid fever (>100/100,000 cases/year) include south-central Asia and southeast Asia. Regions of medium incidence (10-100/100,000 cases/year) include the rest of Asia, Africa, Latin America and the Caribbean, and Oceania, except for Australia and New Zealand (Fig. 223-1).27 The incidence of enteric fever correlates with poor sanitation and lack of access to clean drinking water. In endemic regions, typhoid fever is more common in urban than rural areas and among young children and adolescents (aged 1 to 15 years). Reported risk factors include contaminated water or ice, flooding, food and drinks purchased from street vendors, raw fruits and vegetables grown in fields fertilized with sewage, ill contacts in the household, lack of handwashing and toilets, and evidence of prior Helicobacter pylori infection, likely related to chronic reduced gastric acidity. Outbreaks of typhoid fever in developing countries can result in high morbidity and mortality, especially among children less than 5 years of age and when caused by antimicrobial-resistant strains.29,30 Between 1970 and 1989, many strains of S. Typhi developed plasmid-mediated multidrug resistance to the common first-line antimicrobials chloramphenicol, ampicillin, and trimethoprim in many regions of the world, especially in the Indian subcontinent and south Asia.31 Although these multidrugresistant strains belonged to different Vi phage types, they typically contain a self-transferable 120-MDa plasmid of the H1 incompatibility

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High (>100/100,000/year) Medium (10-100/100,000/year) Low (<10/100,000/year) Figure 223-1 annual incidence of typhoid fever per 100,000 population. (Adapted from Crump JA, Luby SP, Mintz ED. The global burden of typhoid fever. Bull World Health Organ. 2004;82:346-353.)

type that often also encodes resistance to streptomycin, sulfonamides, and tetracyclines.31 In the 1990s, with the increased use fluoroquinolones for treatment of multidrug-resistant typhoid fever, chromosomal and plasmid-encoded resistance to ciprofloxacin emerged among S. Typhi and S. Paratyphi A isolates from the Indian subcontinent and south Asia.32 In 2003, in Katmandu, Nepal, 73.3% and 94.9% of S. Typhi and S. Paratyphi A strains contained gyrA gene mutation, were resistant to nalidixic acid, and had decreased susceptibility to fluoroquinolones (ciprofloxacin minimum inhibitory concentration [MIC] 0.25-1.0 g/mL), a phenotype associated with an increased risk of fluoroquinolone treatment failure.33,34 Even more alarmingly, in 2005, 22% of S. Typhi strains from New Delhi, India, were resistant to ciprofloxacin and 16% were resistant to ceftriaxone.35 Although multidrug-resistant strains remain common in many areas of Asia, in some areas antimicrobial-susceptible strains have reemerged and are genetically unrelated to the previous multidrug-resistant clones.36 With improvements in food handling and water/sewage treatment, enteric fever has become a rare occurrence in developed nations. In 2006, a total of 353 cases of typhoid fever were reported in the United States compared with 35,994 cases in 1920.37 From 25% to 30% of reported cases of enteric fever in the United States are domestically acquired. Although the majority of these cases are sporadic, 7% of total cases were part of recognized outbreaks linked to contaminated food products and previously unrecognized chronic carriers.38 The incidence of typhoid among U.S. travelers is estimated to be 3 to 30 cases per 100,000.38 Of 1393 cases of typhoid fever reported to the CDC between 1994 and 1999, 74% were associated with recent international travel, most commonly to India (30%), Pakistan (13%), Mexico (12%), Bangladesh (8%), the Philippines (8%), and Haiti (5%). An increased proportion of cases are associated with foreignborn U.S. residents visiting friends and relatives (~80%). Only 4% of travelers diagnosed with enteric fever gave a history of S. Typhi vaccination within the previous 5 years. Increased rates of multidrugresistant S. Typhi and S. Paratyphi have been reported among travelers returning to the United States and United Kingdom.39,40 In the United States, 42% of recent S. Typhi isolates and 87% of S. Paratyphi isolates were resistant to nalidixic acid and had a decreased susceptibility to ciprofloxacin (MIC 0.12 g/mL).39,41

NONtYPHOIDaL SaLMONELLaE In many countries the incidence of human Salmonella infections has increased markedly, although good population-based surveillance data are mostly lacking. In the United States, the incidence rate of nontyphoidal Salmonella infection has doubled in the last two decades, with an estimated 1.4 million cases occurring annually (Fig. 223-2).42 In 2007, the incidence rate of salmonellosis (14.9 per 100,000 population) was highest among 11 potentially foodborne diseases under active

30 Reported cases per 100,000 population Outbreak caused by contaminated pasteurized milk, IL

25

20

15

10 5

0 1968 1970 1975 1980 1985 1990 1995 2000 Year 2005 2006

Figure 223-2 Incidence rate per 100,000 population of nontyphoidal salmonellosis by year, United States, 1968 through 2006. (Adapted from McNabb SJ, Jajosky RA, Hall-Baker PA, et al. Summary of notifiable diseasesUnited States, 2006. MMWR Morb Mortal Wkly Rep. 2008;55:75).

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35 Rate per 100,000 population 30 25 20 15 10 5 0 Georgia Maryland Minnesota New Mexico Connecticut Tennessee California Colorado New York
Oregon

Campylobacter Salmonella Shigella STEC 0157

Figure 223-3 Incidence rate per 100,000 population of laboratory-confirmed Salmonella, Campylobacter, Shigella, and Shiga toxin producing E. coli O157 (StEC 1057) infections by selected sites in the United States, compared with national health objectives (Foodborne Diseases Active Surveillance Network, 2007). (From Centers for Disease Control and Prevention (CDC). Preliminary FoodNet data on the incidence of foodborne illnesses selected sites, United States, 2007. MMWR Morb Mortal Wkly Rep. 2008;57:366-370.)

Overall

surveillance, ranging from 8.65 to 21.78 per 100,000 population (Fig 223-3).43 Compared to 1996 to 1998, relative rates of Salmonella decreased only 8% in 2007. During this period, five Salmonella serotypes accounted for one-half of all human isolates reported in the United StatesTyphimurium (19%), Enteritidis (14%), Newport (9%), Javiana (5%), and Heidelberg (4%).43 The incidence of nontyphoidal Salmonella infection is highest during the rainy season in tropical climates and during the warmer months in temperate climates, coinciding with the peak in foodborne outbreaks.44 Unlike S. Typhi and S. Paratyphi, whose only reservoir is humans, nontyphoidal Salmonella can be acquired from multiple animal reservoirs. Transmission of Salmonella to humans can occur by many routes, including consumption of food animal products, especially eggs, poultry, undercooked ground meat and dairy products, fresh produce contaminated with animal waste, contact with animals or their environment, and contaminated water.45-47 During the 1980s and 1990s, S. Enteritidis associated with shell eggs emerged as the predominant Salmonella serotype and source of foodborne disease in the United States and some other countries.48,49 In the United States, the rate of reported S. Enteritidis isolates increased from 0.6 per 100,000 population in 1976 to a high of 3.9 per 100,000 in 1994.50 As a result of intensive surveillance and control effort, including egg qualityassurance programs on farms, egg refrigeration, and consumer education, the incidence of S. Enteritidis infection declined to 1.7 per 100,000 in 2003, although S. Enteritidis remains the second most common Salmonella serotype reported.50 Between 1985 and 2003, there was a total of 997 reported outbreaks of S. Enteritidis infection in the United States, with 33,687 illnesses, 3281 hospitalizations, and 82 deaths.50 Of the 44% of these outbreaks with a confirmed food vehicle, 75% were associated with eggs or egg-containing ingredients.50 Outbreaks of S. Enteritidis infection also have been associated with inadequately cooked poultry and a variety of other foods 50 Sporadic S. Enteritidis infection has been associated with egg and poultry consumption as well as international travel and exposure to birds and reptiles in the home.51 Although S. Enteritidis has been identified from a substantial fraction of U.S. egg-laying flocks, only a small proportion of eggs are contaminated with S. Enteritidis.52 Even with this low frequency of contamination, an estimated 2.2 million of the 65 billion shell eggs produced in the United States were estimated to be contaminated with S. Enteritidis in the mid-1990s.52 Infection localizes to the ovaries and upper oviduct tissue and is transmitted to the forming egg before shell deposition, resulting in contamination of the albumen and yolk. Although cooking eggs until all liquid yolk is solidified kills S. Enteritidis, the use of pasteurized egg products remains the safest alternative for institutions and the general public.

Transmission of S. Enteritidis from farm to farm may be facilitated by contaminated chicken manure, insects, and rodents and by ingestion of feed contaminated with mouse droppings, because S. Enteritidis strains cultured from the spleens of mice caught on farms have enhanced ability to contaminate eggs.53 The loss of cross-immunity resulting from culling chickens infected with S. Gallinarum and S. Pullorum in the United States and United Kingdom also may have contributed to the emergence of S. Enteritidis.54 Salmonella live in the intestines of most food animals, and contamination of raw poultry and meat products can occur during slaughter and processing. Retail ground poultry and meat are at high risk of contamination with Salmonella, including with antimicrobial resistant strains.55 In a 2007 survey of food products, 26.3% of ground chicken, 17.9% of ground turkey, and 2.7% of ground beef specimens tested positive for Salmonella.56 Although raw chicken carcasses and other meats are less commonly contaminated with Salmonella than is ground poultry, cross-contamination of food items from handling of raw chicken and inadequate hand hygiene are risks for sporadic salmonellosis in the home.57 There is considerable mismatch between animal and human Salmonella serotypes, suggesting that the risk of transmission is not equal for all food products and serotypes.58 Changes in food consumption and the rapid growth of international trade in agricultural food products have facilitated the dissemination of new Salmonella serotypes associated with fresh fruits and vegetables. Human or animal feces may contaminate the surface of fruits and vegetables and may not be removed by washing. Recent foodborne outbreaks of salmonellosis associated with fresh produce include tomatoes (S. Newport), cantaloupe (multiple serotypes), unpasteurized orange juice (multiple serotypes), cilantro (S. Thompson), and raw seed sprouts (S. Muenchen and S. Stanley). Tomatoes can internalize Salmonella when imersed in water, and contamination on the tomato or melon surface can be transferred to the interior when it is cut.59 Sprout seeds can become contaminated before sprouting, and soaking seeds with 20,000 ppm calcium hypochlorite or other disinfectant can reduce, but does not eliminate, the risk of sproutassociated illness.60 Manufactured food items pose an enormous potential hazard of foodborne salmonellosis in developed countries because of their centralized production and wide-scale distribution. Both pasteurized and unpasteurized milk and milk products, including powdered infant formula, have increasingly been recognized as a source of Salmonella infections.61 In 1994, an estimated 224,000 cases of S. Enteritidis gastroenteritis developed among persons in the United States who ate a nationally distributed ice cream product. The source of the S. Enteritidis was most likely pasteurized ice cream premix that was contami-

National Health Objective

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nated during transport in tanker trailers that previously carried nonpasteurized liquid eggs.62 In 2008 to 2009, a large multistate outbreak of S. Typhimurium infection was associated with peanut butter and peanut paste used in more than 180 different food products. Salmonellosis associated with exotic pets is a resurgent public health problem, especially from exposure to reptiles, including turtles, iguanas, lizards, and snakes.63,64 Of all Salmonella serotypes, 40% have been cultured predominantly from reptiles and are rarely found in other animals or humans. The recognition of pet turtleassociated salmonellosis led to the banning of shipment of small pet turtles in several countries but not to elimination of the problem.65 Based on extrapolation from population-based surveillance, 6% of all sporadic Salmonella infections and 11% among persons less than 21 years old are attributable to contact with reptiles or amphibians.64 Exposure to pet birds, pet rodents, dogs, and cats and to pet food and pet treats made from animal parts are other potential sources of human salmonellosis, including infection with multidrug-resistant strains.66-68 Multidrug resistance among human nontyphoidal Salmonella isolates is increasing in both developing and developed countries (Fig. 223-4).41,69,70 A diversity of transferable resistance plasmids have been identified from multidrug-resistant nontyphoidal Salmonella strains and contribute to the conjugative transfer of resistance between enteric bacterial species.71 Of particular concern is the worldwide emergence in the 1990s of a distinct strain of multidrug-resistant S. Typhimurium characterized as definitive phage type 104 (DT104) that is resistant to at least five antimicrobialsampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracyclines (R-type ACSSuT).72 All DT104 strains contain a chromosome- and integron-encoded -lactamase (PSE-1) that appears to have been acquired from plasmids in Pseudomonas species.73 The DT104 strain has broad host reservoirs, and its widespread clonal dissemination in domestic livestock, especially among beef and dairy cattle, likely was promoted by use of antimicrobials on farms for therapeutic uses and for growth enhancement.74,75 In the United States, the proportion of human S. Typhimurium R-type ACSSuT increased from 0.6% in 1979 to 34% in 1996. In 2005, resistance to at least ACSSuT was among the most common multidrugresistant phenotypes (6.9%) among non-Typhi Salmonella, including 22.2% of S. Typhimurium and 12.6% of S. Newport isolates (see Fig. 223-4).41 Acquisition of S. Typhimurium DT104 is associated with exposure to ill farm animals and to a variety of meat products, including raw or undercooked ground beef.76 Although likely no more virulent than susceptible S. Typhimurium strains, infection with DT104 is

ACSSuT 12 MDR-AmpC 11 Nalidixic acid 10 9 8 7 6 5 4 3 2 1 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Year

Figure 223-4 resistance patterns of non-typhi Salmonella isolates, United States, 1996 to 2005. ACSSuT, resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline; MDR-AMPC, resistance to ACSSuT + amoxicillin/clavulanic acid + ceftiofur and decreased susceptibility to ceftriaxone (MIC 2 g/mL); Nalidixic acid, MIC 32 g/mL. (From Centers for Disease Control and Prevention. National Antimicrobial Resistance Monitoring System [NARMS] 2005 Annual Report. Available at: http://www.cdc.gov/narms/reports.htm.)

associated with increased risk of bloodstream infection and hospitalization, likely reflecting inadequate empirical antimicrobial therapy.77,78 Outbreaks and sporadic cases of nontyphoidal Salmonella resistant to third-generation cephalosporins increasingly have been reported.79-81 Resistance is mediated by a transferable plasmid containing ampC (blaCMY) probably acquired by horizontal genetic transfer from Escherichia coli strains in food-producing animals and linked to the widespread use of the veterinary cephalosporin ceftiofur.82 In 1998, the first reported case of ceftriaxone-resistant Salmonella infection acquired in the United States occurred in a child in Nebraska and was associated with exposure to cattle on his familys ranch that harbored S. Typhimurium with a 160-kb plasmid encoding CMY-2 AmpC -lactamase.79 Recent U.S. surveys found that 5.1% of Salmonella isolates from cattle and pigs and 1.6% of isolates from humans were ceftriaxone resistant (MIC 16 g/mL).41 A multidrug-resistant strain of S. Newport (MDR-AmpC), with decreased susceptibility to ceftriaxone (MIC > 2 g/mL) and resistance to eight other human antimicrobials and ceftiofur, has emerged in the United States (see Fig. 223-4).83 In 2005, MDR-AmpC was detected in 2.0% of all non-Typhi Salmonella and 12.6% of S. Newport isolates.41 Risk factors for infection with MDR-AmpC S. Newport include consumption of uncooked ground beef, runny eggs or omelets, and recent exposure to an antimicrobial to which the strain is resistant.81 Multidrug-resistant Salmonella strains expressing carbapenemase genes have been reported rarely.84,85 Nalidixic acid and fluoroquinolone-resistant Salmonella strains have been emerging among humans and animals, and resistance is due to chromosomal mutations of the intracellular targets DNA gyrase (gyrA or gyrB) or topoisomerase IV, to overproduction of efflux pumps, and more recently to acquisition of the plasmid-mediated quinolone resistance determinant qnr.86-89 From 1996 to 2005, the proportion of non-Typhi Salmonella isolates in the United States that were nalidixic acid resistant (MIC 32 g/mL) increased fivefold (from 0.4% to 2.4%), although ciprofloxacin resistance remained rare (see Fig. 223-4).41 In comparison, in the United Kingdom, the incidence of ciprofloxacin resistance increased from 0% in 1993 to 14% in 1996 following the licensing of the enrofloxacin for veterinary use in 1993.90 In Taiwan in 2000, a strain of ciprofloxacin-resistant (MIC 4 g/mL) S. Choleraesuis caused a large outbreak of invasive infections that was linked to the use of enrofloxacin in swine feed.69 On the basis of increased prevalence of nalidixic acidresistant Salmonella and fluoroquinolone-resistant Campylobacter species in humans, the U.S. FDA withdrew approval of the use of fluoroquinolones in poultry in 2005. Although health careassociated salmonellosis is infrequent, such infections have been associated with multidrug-resistant strains, sustained transmission, and substantial morbidity and mortality.91-95 Nosocomial transmission of Salmonella from patients to health care workers has been associated with handling soiled linen, noncompliance with barrier precautions, and fecally incontinent residents.96 However, the risk of transmission from health care workers to patients appears to be low if infection control measures are observed carefully.97 In contrast, the risk of nosocomial transmission to neonates and infants from acutely or chronically infected family members appears higher.98 Neonates are at high risk for fecal-oral transmission of Salmonella because of relative gastric achlorhydria and the buffering capacity of ingested breast milk and formula. High-iron infant formula may further increase the risk of infant salmonellosis compared with breast-feeding.99 Contaminated enteral feeding and crowding also have been associated with nosocomial transmission among pediatric patients.100 Control of outbreaks in daycare centers may be difficult because of the need for frequent diaper changing and the higher rate and longer duration of convalescent carriage seen in the preschool age group.101 Residents of nursing homes are at increased risk of foodborne salmonellosis and more severe morbidity and mortality because of poor infection control compliance and presence of comorbid illnesses, acidsuppressing medications, and waning immunity.91,102,103

Percent with resistance pattern

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Pathogenesis
Salmonella infections begin with the ingestion of bacteria in contaminated food or water. Estimates of the infectious dose vary substantially and depend on the method of determination. In studies involving administration of laboratory Salmonella strains to healthy human volunteers, the median dose required to produce disease was approximately 106 bacteria.104 In contrast, investigations of point source outbreaks suggest that as few as 200 bacteria may produce nontyphoidal gastroenteritis in many of those exposed, and that the ingested dose is an important determinant of incubation period and disease severity.104,105 Discrepancies in these results may stem from use of attenuated strains in the challenge experiments and from variation in disease susceptibility in the general population. Gastric acidity represents the initial barrier to Salmonella colonization, and conditions that increase gastric pH significantly increase susceptibility to infection. On exposure to acid in vitro, salmonellae display an adaptive acid tolerance response that probably facilitates bacterial survival in the stomach and passage to the small intestine.106 INtEraCtIONS WItH INtEStINaL EPItHELIUM aND INDUCtION OF ENtErItIS Salmonellae must evade host antimicrobial factors secreted into the intestinal lumen, including antimicrobial peptides, bile salts, and secretory immunoglobulin A, and traverse a protective mucous barrier before encountering intestinal epithelial cells.107,108 Salmonellae express an array of distinct fimbriae that contribute to tight adherence to intestinal epithelial cells in culture. It is necessary to delete multiple fimbriae synthesis genes to prevent infection in animal models, suggesting that functional redundancy exists.109 Microscopy reveals that salmonellae invade intestinal epithelial cells by a morphologically distinct process termed bacteria-mediated endocytosis (Fig. 223-5).110 Shortly after bacteria adhere to the apical epithelial surface, profound cytoskeletal rearrangements occur in the host cell, disrupting the normal epithelial brush border and inducing formation of membrane ruffles that reach out and enclose adherent bacteria in large vesicles. This process resembles the membrane ruffling and macropinocytosis induced in many cell types by growth factors and is functionally distinct from receptor-mediated endocytosis, the mechanism by which

Figure 223-5 Scanning electron micrograph showing Salmonella typhimurium entering an HEp-2 cell through bacteria-mediated endocytosis. Membrane ruffles extend from the cell surface, enclosing and internalizing adherent bacteria. (From Ohl ME, Miller SI. Salmonella: A model for bacterial pathogenesis. Annu Rev Med. 2001;52: 259-274.)

many other pathogens enter nonphagocytic cells. Following bacteria internalization, a fraction of the Salmonella-containing vesicles transcytose to the basolateral membrane, and the apical epithelial brush border reconstitutes. The epithelial cell type that serves as the principal portal for Salmonella invasion remains uncertain. In the mouse enteric fever model, salmonellae preferentially adhere to and enter the specialized microfold cells (M cells) that overlie lymphoid tissue within Peyers patches.111 In bovine and rabbit models of enteritis, however, salmonellae do not appear to interact preferentially with M cells, but instead adhere to and invade intestinal enterocytes diffusely.112 It is possible that M cells are the principal portal of entry in the enteric fever syndrome, and that generalized invasion of enterocytes plays a greater role in the enteritis induced by nontyphoidal Salmonella serotypes. Salmonellae encode a type III secretion system (T3SS) within Salmonella pathogenicity island 1 (the SPI-1 T3SS), which is required for bacteria-mediated endocytosis and intestinal epithelial invasion. T3SSs are complex macromolecular machines that have evolved to subvert host cell function through the translocation of virulence proteins directly from the bacterial cytoplasm into the host cell (see Chapters 1 and 3 for overview). Salmonella mutants lacking a functional SPI-1 T3SS do not invade epithelial cells in tissue culture and are severely attenuated in animal models of infection following oral administration.112 In the past decade considerable attention has focused on identifying the virulence proteins translocated into epithelial cells by the SPI-1 T3SS and delineating the host cell processes these proteins target. At least five translocated proteins are essential for efficient invasion of cultured epithelial cells, though invasion in animal tissues may be more complicated and diverse.113 Two SPI-1 translocated proteins, SipC and SipA, promote membrane ruffling and Salmonella invasion through direct interactions with the actin cytoskeleton. The SipC protein inserts into the host cell plasma membrane and forms part of a protein complex that allows translocation of additional SPI-1 virulence proteins directly into the host cell cytoplasm.114 SipC also directly nucleates actin polymerization at the site of Salmonella attachment and stimulates actin filament bundling.115 The SipA protein further enhances actin polymerization through stabilization of actin filaments and reduction of the critical concentration for polymerization.116 SipA mutants invade epithelial cells less efficiently than wild-type bacteria and induce disorganized, diffuse ruffling in host cells, in contrast to the localized ruffling induced around wild-type bacteria. Additional SPI-1 translocated proteins contribute to Salmonella invasion by targeting members of the Rho family of monomeric GTP binding proteins (G proteins). Rho family members, including cdc42, rac, and rho, regulate the structure and dynamics of the actin cytoskeleton and are required for formation of the membrane ruffles that mediate Salmonella internalization. The SPI-1 translocated proteins SopE and SopE2 directly activate Rac1 and Cdc42 in vitro by acting as GDP/GTP exchange factors (GEFs), and induce membrane ruffling and macropinocytosis following microinjection into epithelial cells.117 SopB is an additional SPI-1 translocated protein that targets inositol phosphate signaling within the host cell by acting as an inositol polyphosphatase.118 Among other effects, this activity indirectly stimulates Rho GTPases and promotes membrane ruffling.119 Recent data suggest that only Rac1 and RhoG are essential for the effects of SopE, SopE2, and SopB.120 Although mutation of SopB, SopE, or SopE2 alone does not impact invasion, combined deletion of these three genes leads to a severe reduction in epithelial cell invasion.119 Such functional redundancy among translocated proteins is an emerging theme in a variety of T3SSs. Overall, available data indicate that SipA and SipC act in concert with downstream cellular effectors of activated Rho GTPases to initiate and spatially direct the actin rearrangements that lead to Salmonella internalization. Recent studies in mice indicate that salmonellae may also cross the intestinal epithelial border by an SPI-1independent process involving host dendritic cells.121,122 These cells express tight junction proteins and can intercalate between intestinal epithelial cells and access the intes-

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tinal lumen without disrupting epithelial integrity. In this manner dendritic cells may internalize bacteria in the intestinal lumen, and subsequently carry these bacteria to distant sites as they undergo their physiologic migration to lymphoid tissues. The diversity of mechanisms utilized by salmonellae to cross the intestinal barrier indicates the importance of this mechanism to its lifestyle within mammals. In addition to invasion of intestinal epithelial cells, Salmonella serotypes clinically associated with gastroenteritis induce a secretory response in intestinal epithelium and initiate recruitment and transmigration of neutrophils into the intestinal lumen. The SPI-1 T3SS is also required for these responses in tissue culture and animal models of enteritis. Specifically, Salmonella strains unable to deliver any SPI-1 virulence proteins as a result of mutations in the secretion apparatus fail to induce fluid secretion or neutrophil accumulation in ligated bovine ileal loops, and do not cause gastroenteritis in calves.123 In tissue culture models of enteritis, translocation of SPI-1 proteins into intestinal epithelial cells leads to synthesis and polarized secretion of inflammatory mediators and neutrophil chemoattractants, including interleukin-8 (IL-8).124 Several SPI-1 translocated proteins that contribute to intestinal inflammation and fluid secretion have been identified. Stimulation of Rho GTPase signaling by SopE and SopE2 also leads to activation of microtubule-associated protein kinase pathways and movement of the proinflammatory transcription factor nuclear factorB (NF-B) to its site of action in the nucleus.117 In addition to its role in invasion, the inositol polyphosphatase activity of SopB leads to accumulation of d-myo-inositol-1,4,5,6-tetrakisphosphate in epithelial cells.125 The increased concentration of this compound ultimately leads to an increase in cellular basal chloride secretion, with associated fluid flux. The SPI-1 translocated proteins SopA and SopD also contribute to intestinal secretory and inflammatory responses in ligated ileal loops, but the molecular basis of these effects remains unclear. Many other effector proteins that are delivered by the T3SS apparatus may also effect these or similar pathways with different targets. Individual nontyphoidal salmonellae have a diverse complement of effector proteins, for instance, many strains do not have SopE2. The association of specific effector proteins could alter the pathogenicity of specific strains and their emergence in humans from animal reservoirs.126 Following Salmonella invasion, intestinal inflammation may also result from activation of the innate immune system through stimulation of proinflammatory receptors present on phagocytes and the basolateral surface of intestinal epithelia. This includes activation of Toll-like receptor 4 (Tlr4) by lipopolysaccharide and Toll-like receptor 5 (Tlr5) by bacterial flagellin.127 The cytosolic surveillance pathway is also activated by the translocation of flagellin into the cytoplasm by the type III secretion system and its recognition by the inflammasome through the Ipaf pathway. This pathway results in the secretion of IL-1-, an important pro-inflammatory cytokine.128,129 Intestinal inflammation probably contributes to fluid secretion and diarrhea through disruption of the epithelial barrier and increased water flux by an exudative mechanism. In contrast to the neutrophilic inflammation and gastroenteritis induced by nontyphoidal Salmonella strains, S. Typhi induces monocytic inflammation in the human intestine and produces significantly less, if any, diarrhea.130 The molecular basis of this difference in the host response remains unknown. One possibility is the presence of the Vi-polysaccharide capsule in most strains of S. Typhi that can prevent recognition of LPS by TLR4.131 Several studies demonstrate that salmonellae also utilize the SPI-1 T3SS to deliver proteins that downregulate the host inflammatory response associated with Salmonella invasion. The SptP protein inactivates Rho GTPase signaling by acting as a GTPase-activating protein (Rho GAP).132 This directly opposes the activity of SopE and SopE2 and reduces membrane ruffling and proinflammatory signaling following bacterial invasion. In addition, the SspH1 and AvrA proteins inhibit NF-B activation and related host cell cytokine synthesis.133,134 These SPI-1 translocated proteins may promote bacterial persistence in the host by maintaining host cell integrity and allowing evasion of the host immune response. The presence of SPI-1 translocated pro-

teins with opposing molecular actions (e.g., SopE and SptP) suggests that there may be temporal ordering of protein function, with initial activity of SPI-1 proteins associated with invasion and proinflammatory signaling and subsequent activity of anti-inflammatory proteins. This dampening of the inflammatory response attributed to multiple bacterial effector proteins may contribute to the long period of relative asymptomatic colonization of the intestinal tract typical of nontyphoidal Salmonella infection. INtEraCtIONS WItH MaCrOPHaGES aND SYStEMIC INFECtION After crossing the epithelial barrier, salmonellae encounter and enter macrophages present in the submucosal space and Peyers patches. Macrophage invasion may occur through bacteria-mediated macropinocytosis or through phagocytosis directed by several receptors present on the macrophage. Available data in both human infection and animal models of disease indicate that the ability of Salmonella to survive and replicate within macrophages is essential for dissemination within the host and induction of systemic disease. In persons with enteric fever and positive blood cultures, the majority of organisms are contained within the mononuclear fraction.135 Furthermore, the ability of Salmonella mutants to replicate within macrophages in tissue culture correlates with ability to produce systemic disease in the mouse typhoid model, and microscopic examination of infected mouse liver and spleen demonstrates that the majority of organisms are located within macrophages.136,137 Although residence within the macrophage shields the bacterium from effectors of humoral immunity, it also exposes the bacterium to the microbicidal and nutrient-poor environment of the phagosome. Within the host, salmonellae induce the expression of numerous genes that allow evasion of these antimicrobial defenses. Once in the intracellular environment the bacteria persist within a vacuolar compartment that endures for hours to days. Salmonellae can survive within a compartment that fuses with lysosomes, and hence inhibition of phagosome fusion with lysosomes is unlikely to be a major pathogenic strategy of salmonellae. The vacuole acidifies, though its acidification may be delayed. Resistance to a variety of vacuolar bactericidal activities is essential to pathogenesis including resistance to antimicrobial peptides, nitric oxide, and oxidative killing. This is supported by experiments demonstrating that S. Typhimurium mutants sensitive to these compounds are less virulent for mice and that mice deficient in these activities are more susceptible to S. Typhimurium.138 Salmonella sense the acidic environment of the Salmonella-containing vacuole (SCV) and activate a variety of regulatory proteins required for Salmonella adaptation to the intracellular environment for replication within host cells. The best studied of these is the PhoP/PhoQ two-component regulatory system. The PhoP/PhoQ system senses the intracellular environment and regulates transcription of over 200 genes some of which are required for survival within macrophages. PhoQ is the sensor protein for the phagosome environment by sensing acidic pH and antimicrobial peptides to activate gene expression.139-141 Activation of the PhoP/PhoQ and other regulons leads to widespread modifications in the protein and lipopolysaccharide components of the bacterial inner and outer membranes.142 As many as 900 to 1000 genes are induced in response to the phagosome environment including many involved in remodeling of the cell surface to resist host cell killing mechanisms.143 These surface modifications confer resistance to antimicrobial factors within the phagosome, including antimicrobial peptides, oxygen, and nitrogen radicals. PhoP/PhoQ-regulated lipopolysaccharide modifications include addition of aminoarabinose, ethanolamine, palmitate, and 2-hydroxymryistate to lipid A, thus altering the charge density and fluidity of the outer membrane and discouraging antimicrobial peptide insertion in the membrane.142 Cell surface polysaccharide is also dramatically altered.142 In addition, PhoP/PhoQ-regulated modifications in lipid A structure produce a lipopolysaccharide molecule with significantly less proinflammatory

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signaling activity and repress flagellin synthesis, which may facilitate bacterial survival within host tissues.142 PhoP/PhoQ mutants of S. Typhi are avirulent in humans and are promising live typhoid vaccine candidates.144 S. Typhi also modifies its surface through synthesis of the Vi capsule, a polysaccharide structure that confers resistance to phagocytosis by neutrophils and killing by complement, reduces recognition of lipopolysaccharide, and promotes survival within human macrophages.145 Salmonella have a second T3SS that is necessary for survival in the macrophage and for establishment of systemic infection.146 Proteins delivered by both type III secretion systems are important for intracellular survival. SipA delivered by SPI1 persists on the phagosome membrane, where it promotes intracellular survival.147 Encoded on Salmonella pathogenicity island 2 (SPI-2) is an additional T3SS that is adapted to be expressed by intracellular bacteria and translocates proteins across the membrane of the SCV into the macrophage cytosol. SPI-2 translocated proteins are hypothesized to alter trafficking to the SCV to promote bacterial growth such that useful nutrients are routed to the SCV. Most remarkably, salmonellae alter the phagosome to tubulate in a mechanism that requires SPI-2 translocated proteins. Such tubulation has been correlated with virulence, as SPI-2 translocated proteins implicated in this process are required for phagosome tubulation to occur. Phagosome tubulation is dynamic and rapid and appears to be dependent on the recruitment of microtubule motors, the activation of small GTPases, and membrane lipid alteration. The mechanism by which tubulation of the phagosome promotes virulence is unknown, but it could allow bacteria or their products to specifically traffic within the phagosome to different cellular localizations to promote nutrient acquisition or cell-to-cell spread. Several SPI-2 translocated proteins, including SifA, SifB, SseJ, SopD2, PipB, and PipB2, localize to the surface of the SCV. Other SPI-2 translocated proteins interact with the actin cytoskeleton surrounding the SCV and probably contribute to remodeling of vacuole-associated actin networks.148,149 SpvB is a Salmonella virulence protein that is secreted into the macrophage cytoplasm, possibly by the SPI-2 T3SS, and ADPribosylates monomeric actin (G-actin), thus promoting disassembly of actin networks around the vacuole.149,150 Other proteins appear to localize to the Golgi apparatus possibly to promote secretory traffic to the SCV.138,151 Many other bacterial factors are required for full virulence including those required for synthesis of essential nutrients and iron acquisition, and the virulence plasmids found in many nontyphoidal Salmonella serotypes. The virulence plasmids of S. Typhimurium, S. Dublin, S. Choleraesuis, and S. Enteritidis all contain an 8-kb region that promotes dissemination beyond the intestine in animal models and bacteremia in humans.152 This region encodes the SpvB protein, as well as several other proteins of unknown function. HOSt rESPONSE aND IMMUNItY The innate immune system senses invasive Salmonella infections using receptors that recognize conserved elements of bacterial structure. This includes recognition by plasma membrane and phagosomal membrane Toll-like receptors (Tlr) and cytoplasmic recognition receptors or the nucleotide-oligomerization domain-like receptors (Nod),117 lipopolysaccharide by Tlr4, bacterial lipoproteins by Toll-like receptor 2 (Tlr2), and flagellin by Tlr5 flagellin by a signaling system that includes Ipaf and peptidoglycan by Nod1 and Nod2.127 Activation of these receptors on phagocytes and epithelia leads to synthesis of cytokines that orchestrate the inflammatory response and instruct the subsequent antigen-specific immune response. Mice lacking a functional Tlr4 response are highly susceptible to Salmonella infection, confirming the importance of this initial response to infection.153 Other studies indicate that caspase-1, a protease important for secretion of IL-1 and IL-18 as well as inflammatory cell death in host cells, is important for infection in mice by the oral route, indicating that recognition and activation of the cytoplasmic sensing components by Nod family members are important for control of infection in the

intestinal mucosa.154 Studies in mice further demonstrate that the initial control of S. Typhimurium replication in host tissue requires recruitment and activation of macrophages. In both mice and humans, macrophage activation and efficient killing of Salmonella are associated with production of interferon-, IL-12, and tumor necrosis factor .155-157 Mice with targeted disruptions in these genes are highly susceptible to infection. Rheumatoid arthritis patients treated with tumor necrosis factor antagonists have developed severe and fatal septicemias.158 In addition, humans with mutations in the interferon- and IL-12 receptor genes develop severe infections with nontyphoidal Salmonella serotypes.159 Although the innate immune system is able to suppress initial Salmonella replication, final clearance of infection and immunity to rechallenge requires a Th1-type CD4 T-cell response and production of specific antibodies by B cells.157 This is supported by the observation that mice lacking mature CD4 cells (H2I;AB mice) or B cells (lgh-6 mice) are unable to control Salmonella infection.157,160,161 The importance of cellular immunity in controlling Salmonella infection in humans is made apparent by the extreme susceptibility of individuals with human immunodeficiency virus (HIV) infection, lymphoproliferative diseases, or immune suppression following transplant.162-165 A variety of other immunodeficiences have been associated with Salmonella infection including common variable immunodeficiency.166 Furthermore, vaccine studies in humans demonstrate that protection against S. Typhi infection correlates with development of cellmediated immunity.167 In accord with the importance of CD4 T cell mediated immunity, recent population-based studies in humans have found an association between specific major histocompatibility complex class II alleles and susceptibility to typhoid fever.168 CD8 T cells with cytolytic activity against Salmonella-infected host cells are also present in infected mice, but the importance of this activity in immunity remains unclear. Little is known about the antigen specificity of protective immune responses to Salmonella infection in humans, though antibodies against the Vi polysaccharide, lipopolysaccharide O antigen, and flagella are present in previously vaccinated or infected individuals.

Clinical Manifestations
Specific Salmonella serotypes most often produce characteristic clinical syndromes, including gastroenteritis, enteric fever, bacteremia and vascular infection, localized infections, and the chronic carrier state, and outcomes of infection differ subtantially by serotype.169 GaStrOENtErItIS Infection with nontyphoidal Salmonella most often results in selflimited acute gastroenteritis that is indistinguishable from that caused by many other enteric bacterial pathogens. Within 6 to 48 hours after ingestion of contaminated food or water, nausea, vomiting, and diarrhea occur.170 In most cases, stools are loose, of moderate volume, and without blood. In rare cases, stool may be watery and of large volume (cholera-like) or of small volume associated with tenesmus (dysentery-like). Fever (38 to 39 C), abdominal cramping, nausea, vomiting, and chills frequently are reported. Headache, myalgias, and other systemic symptoms also may occur. Microscopic examination of stools shows neutrophils and, less frequently, red blood cells. Infrequently, Salmonella can cause a syndrome of pseudoappendicitis or can mimic the intestinal changes of inflammatory bowel disease.170 Toxic megacolon is a rare but potentially life-threatening complication.171 Diarrhea is usually self-limited, typically lasting for 3 to 7 days.170 Diarrhea that persists for more than 10 days should suggest another diagnosis. If fever is present, it usually resolves within 48 to 72 hours. Occasionally, patients require hospitalization because of dehydration, and death occurs infrequently. In the United States, nontyphoidal Salmonella infections result in an estimated rate of hospitalization of 2.2 per 1 million population and in 582 deaths per year.172 A disproportionate number of these deaths occur among the elderly, especially

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those residing in long-term care facilities, and among immunocompromised patients, including persons with HIV/AIDS, lupus flares, or rheumatologic illness who are receiving antitumor necrosis factor antibody therapy.46,103,158,173,174 After resolution of gastroenteritis, the mean duration of carriage of nontyphoidal Salmonella in the stool is 4 to 5 weeks and varies by Salmonella serotype.101 Antimicrobial therapy may increase the duration of carriage.101 In addition, a higher proportion of neonates have prolonged carriage; in one study, 50% of neonates were still excreting Salmonella at 6 months.175 However, the delayed clearance of infection in neonates does not result in permanent carriage, because almost all chronic carriers are adults.101 ENtErIC FEVEr Enteric fever is a severe systemic illness characterized by fever and abdominal pain that is caused by dissemination of S. Typhi and S. Paratyphi. Recent studies in Asia suggest that the incidence of enteric fever is highest in children less than 5 years of age and that young children experience similar rates of fever, signs and symptoms, and need for hospital admission compared with older people.29 These findings contrast with earlier studies which suggested that S. Typhi infection caused a mild disease in young children.176 Patients with immunosuppression, biliary and urinary tract abnormalities, hemoglobinopathies, malaria, schistosomiasis, bartonellosis, histoplasmosis, and Helicobacter co-infection are at increased risk of severe disease.130,177-179 Although enteric fever classically is described as an acute illness with fever and abdominal tenderness, the symptoms are nonspecific and may be insidious in onset. The diagnosis of enteric fever should be considered strongly in the evaluation of any traveler who returns from tropical and subtropical areas with fever. In the preantibiotic era, approximately 15% of patients with typhoid fever died.180 Today the average case-fatality rate of enteric fever in the developing world is less than 1% and is 0.4% in the United States; increased mortality is associated with multidrug-resistant strains and delayed antimicrobial therapy.37,181 The incubation period for S. Typhi averages 10 to 14 days but ranges from 5 to 21 days depending on the inoculum ingested and the health and immune status of the person. Following ingestion of the organism, persons may develop enterocolitis with diarrhea lasting several days; these symptoms usually resolve before the onset of fever. Diarrhea is more common in certain geographic areas, among patients with HIV/AIDS, and among children under 1 year of age.176 Typically, fecal leukocytes are detected and stool protein is increased.176 Constipation is present in 10 to 38% of patients. Although fever and abdominal pain are the classic signs of enteric fever, fever is documented on presentation in only approximately 75% of cases, and abdominal pain is reported in only 30 to 40%.176,180 The presentation of enteric fever may be altered by comorbidities and early administration of antimicrobials. Nonspecific symptoms, such as chills, diaphoresis, dull frontal headache, anorexia, cough, weakness, sore throat, dizziness, and muscle pains, are frequent before the onset of fever.182 Initially, fever is low grade, rises by the second week of illness to 39 to 40 C, and usually resolves by 4 weeks without antimicrobial therapy. Patients with enteric fever usually appear acutely ill, although those previously exposed to S. Typhi or S. Paratyphi or who seek early medical attention can present with a milder illness. Relative bradycardia is neither a sensitive nor a specific sign of typhoid fever, occurring in fewer than 50% of patients.130 Approximately 30% of patients will have rose spotsa faint salmon-colored maculopapular rash on the trunkat the end of the first week (Fig. 223-6).130 Organisms can be cultured from punch biopsies of these lesions, and the pathology is characterized by a perivascular mononuclear cell infiltrate. The rash can be very faint in highly pigmented patients and typically resolves after 2 to 5 days. Some patients develop cervical lymphadenopathy. Crackles on auscultation are uncommon, and chest radiographs are almost always normal.130 Frequently, abdominal examination reveals pain on deep palpation and increased peristalsis. From 20% to 50% of patients have hepatosplenomegaly. In the preanFigure 223-6 rose spotsthe rash of enteric fever due to S. typhi or S. Paratyphi.

tibiotic era, two thirds of pregnancies complicated by typhoid fever resulted in fetal demise and miscarriage. Recent evidence does not suggest that enteric fever results in significant complications of pregnancy or neonatal outcomes.183 The development of severe disease (which occurs in ~10% to 15% of patients) depends on host factors (immunosuppression, antacid therapy, previous exposure, and vaccination), strain virulence and inoculum, and choice of antibimicrobial therapy. Gastrointestinal bleeding (10 to 20%) and intestinal perforation (1 to 3%) most commonly occur in the third and fourth weeks of illness and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyers patches at the initial site of Salmonella infiltration. Both complications are life threatening and require immediate fluid resuscitation and surgical interventions, with broad-spectrum antibimicrobial coverage for polymicrobial peritonitis.130 Surgical repair may include resection and primary anastomosis, oversewing of the ulcer, and ostomy. Neurologic manifestations occur in 2% to 40% of patients, and include meningitis, Guillain-Barr syndrome, neuritis, and neuropsychiatric symptoms such as picking at bedclothes or imaginary objects, described as muttering delirium or coma vigil.184 Rare complications whose incidences are reduced by prompt antibiotic treatment include disseminated intravascular coagulation; hematophagocytic syndrome; pancreatitis; hepatic and splenic abscesses and granulomas; endocarditis, pericarditis, and myocarditis; orchitis; hepatitis; glomerulonephritis; pyelonephritis and hemolytic uremic syndrome; severe pneumonia; arthritis; osteomyelitis; and parotitis. Following resolution of the fever, weakness, weight loss, and debilitation may persist for months. Up to 10% of patients have a mild relapse, usually within 2 to 3 weeks of fever resolution and associated with the same strain type and susceptibility profile. Laboratory abnormalities associated with enteric fever are nonspecific and include leukopenia, anemia, subclinical disseminated intravascular coagulopathy, and elevated creatinine kinase and liver function tests (e.g., aspartate transaminase and alanine transaminase; 300 to 500 U/dL),185 and liver biopsies demonstrate focal Kupffer cell hyperplasia and mononuclear cell infiltration of the portal space.186 Creatinine clearance is usually normal. Patients rarely develop proteinuria and immune complex glomerulonephritis, and irreversible loss of renal function has not been reported. Nonspecific ST- and T-wave electrocardiographic abnormalities are uncommon. Enteric Fever Diagnosis The definitive diagnosis of enteric fever requires the isolation of S. Typhi or S. Paratyphi from blood, bone marrow, another sterile site, rose spots, stool, or intestinal secretions. The sensitivity of blood culture is only 40% to 80%, probably because of high rates of antibimicrobial use in endemic areas and the small quantities of S. Typhi (i.e., <15 organisms/mL) typically present in the blood of patients with typhoid fever.187

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Because almost all S. Typhi in blood are associated with the mononuclear cellplatelet fraction, blood clot culture, centrifugation of blood and culture of the buffy-coat fraction, or the lysis direct platinglysis centrifugation method can substantially reduce the time to isolation of the organism and variably improve sensitivity.188,189 Enteric fever is the only bacterial infection of humans for which bone marrow examination is recommended routinely, but the sensitivity is variable (55% to 90%). Higher colony counts are present in the bone marrow compared with blood and, unlike blood culture, are not reduced by up to 5 days of prior antimicrobial therapy.190 The duodenal string test is a useful noninvasive technique to sample duodenal secretions, with a sensitivity of up to 58%.191 Children have a higher incidence of positive stool cultures compared with adults (60% vs. 27%), and stool cultures may become positive during the third week of illness in untreated patients.192 Thus, the optimal diagnostic approach in both children and adults is to culture blood, bone marrow, and intestinal secretions (gastric and/or stool). With this approach, the diagnosis can be established in more than 90% of patients.193 A number of serologic tests, including the classic Widal test that is more than 100 years old, have been developed to detect S. Typhi antigen or antibody. The Widal test is neither sensitive (47% to 77%) nor specific (50% to 92%) and may lead to overdiagnosis of enteric fever in endemic areas. Newer commercially available kits for the rapid serologic diagnosis of enteric fever typically detect IgM antibody to lipopolysaccharide or outer membrane proteins of S. Typhi. These kits perform better among hospitalized patients than among those evaluated in the community setting for enteric fever.194,195 However, in countries where resources are limited, rapid and simple tests to detect antiS. Typhi antibody against lipopolysaccharide or outer membrane protein may replace the less accurate Widal test. DNA probe and PCR assays have been developed for detection of S. Typhi and S. Paratyphi in blood and are more rapid and sensitive than standard culture but are not yet commercially available and are impractical in many areas where typhoid is endemic.196,197 BaCtErEMIa aND VaSCULar INFECtION Up to 8% of patients with nontyphoidal Salmonella gastroenteritis develop bacteremia; of these, 5% to 10% develop localized infections.198 Bacteremia and metastatic infection are more common with S. Choleraesuis and S. Dublin and among infants, the elderly, and those who are immunocompromised.162,177,199-203 Among children, nontyphoidal Salmonella bacteremia usually is associated with gastroenteritis and prolonged fever, infrequently causes focal infections, and is fatal in less than 10% of cases.200 In contrast, adults are more likely to have primary bacteremia and have a high incidence of secondary focal infections and death.200 The mortality of nontyphoidal Salmonella bacteremia increases with the magnitude of bacteremia and in the presence of coma or septic shock.204,205 Salmonella have a propensity for infection of vascular sites, including vascular grafts, and high-grade or persistent bacteremia suggests an endovascular infection.206 The risk of endovascular infection complicating Salmonella bacteremia is estimated to be 9% to 25% in persons over 50 years of age, usually involves the aorta, and most commonly results from seeding atherosclerotic plaques or aneurysms.207-209 Mortality rates range from 14% to 60% and are lower with prompt diagnosis and combined medical and surgical therapy.200-201 Venous septic thrombophlebitis also has been reported.210 SaLMONELLOSIS aND HIV INFECtION Nontyphoidal Salmonella are the leading cause of community-acquired bacteremia in HIV-infected persons in both developing and developed countries.211,212 In the pre-HAART (highly active antiretroviral therapy) era, nontyphoidal Salmonella bacteremia occurred 20 to 100 times more commonly among those with HIV infection compared with the general population.164,213 Among HIV-infected patients, nontyphoidal Salmonella bacteremia is associated with lower CD4 lymphocyte

counts and a higher risk of metastatic complications, recurrent bacteremia, and mortality despite antimicrobial therapy, especially in Africa.212,214 Recurrent nontyphoidal Salmonella bacteremia is an AIDS-defining illness that apparently results from incomplete clearance of the primary infection owing to impaired cell-mediated immunity and dysregulation of proinflammatory cytokines release.215 In the pre-HAART era, as many as 43% of patients with nontyphoidal Salmonella bacteremia had one or more recurrent episodes.215 Among patients receiving HAART, the incidence of recurrent nontyphoidal Salmonella bacteremia has declined up to 96% compared with the pre-HAART era.203 The risk reduction is likely due to the impact of HAART on virologic suppression and immune reconstitution, a direct bactericidal activity of some antiretrovirals on Salmonella species, the prophylactic use of trimethoprim-sulfamethoxazole, and the therapeutic use of ciprofloxacin.203,216,217 LOCaLIZED INFECtIONS Extraintestinal focal infections develop in approximately 5% to 10% of persons with Salmonella bacteremia, and their diagnosis and management are summarized in Table 223-2.198 CHrONIC CarrIEr StatE The chronic carrier state is defined as the persistence of Salmonella in stool or urine for periods greater than 1 year. From 0.2% to 0.6% of patients with nontyphoidal Salmonella infection develop chronic carriage.218 Up to 10% of untreated patients with typhoid fever excrete S. Typhi in the feces for up to 3 months, and 1% to 4% develop chronic carriage.180,207 The frequency of chronic carriage is higher in women; in persons with biliary abnormalities, gallstones, or concurrent bladder infection with Schistosoma haematobium; and in infants.219,220 Chronic carriage of S. Typhi and S. Paratyphi A has been associated with an increased incidence of carcinoma of the gallbladder and of other gastrointestinal malignancies.221 Serology for the Vi antigen may be useful in distinguishing chronic carriage from acute infection with S. Typhi because chronic carriers will often have a high antibody titer to this antigen.222

Immunization Against S. Typhi

Theoretically, it is possible to eliminate Salmonella that cause enteric fever, as the bacteria survive only in human hosts and are spread by contaminated food and water. However, given the high prevalence of the disease in developing countries that lack adequate sewage disposal and water treatment, this goal currently is unrealistic. Thus, travelers to at-risk countries should be advised to monitor their food and water intake carefully and to strongly consider vaccination. Two typhoid vaccines currently are commercially available: (1) Ty21a, an oral, live attenuated S. Typhi vaccine (given on days 1, 3, 5, and 7 with a booster every 5 years); and (2) a parenteral Vi capsular polysaccharide vaccine (Vi CPS), consisting of purified Vi polysaccharide from the bacterial capsule (given as a single 0.5-mL intramuscular dose with a booster every 2 years). Ty21a vaccine is contraindicated in pregnant women, those taking antimicrobial therapy, and immunocompromised patients. The minimal age for vaccination is 6 years for Ty21a and 2 years for Vi CPS. The old parenteral whole-cell typhoid-paratyphoid A and B vaccine is no longer licensed in the United States, largely because of significant side effects.223 In addition, an acetone-killed whole-cell vaccine is available only for use by the U.S. military. These vaccines have been most extensively evaluated in endemic populations, achieve approximately 50% to 80% efficacy depending on prior exposure, and confer protection that lasts only for several years.224-226 Although data on typhoid vaccines in travelers are limited, some evidence suggests that efficacy may be substantially lower than that for local populations in endemic areas. Currently, there is no licensed vaccine against paratyphoid fever. Ty21a confers

223 Salmonella Species, Including Salmonella typhi

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223-2

taBLE

Extraintestinal Infectious Complications of Salmonellosis Manifestations Valvular vegetation, infected mural thrombus Prolonged fever, pain in back, chest, or abdomen Meningitis, ventriculitis, brain abscess, subdural empyema, encephalopathy Pneumonia Complications Valve perforation, relapse (20-25%), pericarditis Mycotic aneurysm, aneurysm rupture, aortoenteric fistula, vertebral osteomyelitis Seizures, mental retardation, hydrocephalus, brain infarction, relapse Lung abscess, empyema, bronchopleural fistula Relapse, chronic osteomyelitis Mortality 70% Diagnosis Therapy* Blood culture, Early valve surgery echocardiography + 6 wk P ceph 3, P ampicillin, or P, then PO fluoroquinolone Blood culture, Early surgical intervention sonogram, MRI + 6 wk P ceph 3, P or CT ampicillin, or P, then PO fluoroquinolone CSF culture, CT or MRI 3 wk P ceph 3, P ampicillin, or a carbapenem

Site Incidence Risk Factors Endocarditis207,254 0.2-0.4% Preexisting valvular heart disease Arteritis200,255,256 Rare Atherosclerosis, aortic aneurysm, endocarditis, prosthetic graft, myelodysplasia Infants (especially neonates)

14-60%

Central nervous system257-259

0.1-0.9%

~20-60%

Pulmonary260

Rare

Bone261,262

<1%

Joint, reactive263-265

0.6%

Joint, septic266

0.1-0.2%

Muscle/soft tissue267 Hepatobiliary268

Rare

Lung malignancy, structural lung disease, sickle cell anemia Sickle cell anemia, Femur, tibia, male gender, humerus, connective tissue lumbar vertebrae disease, immunosuppression HLA-B27, Joints (3 joints) antimicrobial involved therapy (especially knee, ankle, wrist, and sacroiliac) Osteoarthritis, Knee, hip, shoulder connective tissue disease, sickle cell disease, prosthetic joint Local trauma, male Abscess, gender, diabetes, pyomyositis HIV infection Cholelithiasis, cirrhosis, amebic abscess, echinococcal cyst, hepatocellular carcinoma Sickle cell anemia, splenic cyst, splenic hematoma Hepatomegaly, cholecystitis, hepatic abscess

~25-60%

Respiratory culture, chest radiograph Bone radiograph

2 wk P/PO abx

Very low

4 wk P ceph 3, P ampicillin, or P, then PO fluoroquinolone + surgery for sequestra Nonsteroidal antiinflammatory agent

Prolonged symptoms (mean duration, 5.5 mo) Joint destruction, osteomyelitis

Negligible Joint fluid examination and culture Very low Joint fluid examination and culture Ultrasonography, aspiration Ultrasonography, aspiration

Repeated needle aspiration + 4 wk P/PO abx

Rare

Splenic269

Rare

Splenomegaly

Urinary163,270,271

0.6%

Genital207

Rare

Urolithiasis, malignancy, renal transplant, elderly female Pregnancy, renal transplant

Cystitis, pyelonephritis

Osteomyelitis, endovascular infection, frequent relapse Rupture with secondary peritonitis, subphrenic abscess, spontaneous bacterial peritonitis Left pleural empyema, subphrenic abscess, rupture with secondary peritonitis Renal abscess, interstitial nephritis, relapse

~33%

Drainage + 2 wk P abx

~10%

Drainage + 2 wk P abx

<10%

Ultrasonography, aspiration

2 wk P abx + percutaneous drainage or splenectomy

~20%

Urine culture, ultrasonography Ultrasonography, aspiration

Soft tissue272

<1%

Ovarian abscess, Abscess testicular abscess, prostatitis, epididymitis Local trauma, Pustular dermatitis, Septic immunosuppression SC abscess, thrombophlebitis, wound infection endophthalmitis

Very low

Removal of structural abnormality + 1-2 wk P abx + 6 wk PO fluoroquinolone or TMP-SMX Drainage of collection + 1-2 wk P abx + 6 wk PO fluoroquinolone or TMP-SMX 2 wk P abx + drainage of collection

~15%

Drainage culture

*P ceph 3, parenteral third-generation cephalosporin; P ampicillin, parenteral ampicillin; P/PO fluoroquinolone, parenteral or oral fluoroquinolone; P/PO abx, parenteral or oral antimicrobial (e.g., fluoroquinolone, ampicillin, TMP-SMX, or third-generation cephalosporin); TMP-SMX, trimethoprim-sulfamethoxazole. CSF, cerebrospinal fluid; CT, computed tomography; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging, PO, oral; SC, subcutaneous.

moderate protection (45%) against S. Paratyphi B infection but not against S. Paratyphi A.225,227 A meta-analysis of efficacy and toxicity vaccine trials comparing the whole-cell vaccine, Ty21a, and Vi CPS in populations in endemic areas found that, while all three vaccines have similar efficacy for the first year, the 3-year cumulative efficacy of the whole-cell vaccine (73%)

exceeds that of both Ty21a (51%) and purified Vi (55%).228 In addition, the heat-killed whole-cell vaccine maintains its efficacy for 5 years, while Ty21a and Vi CPS maintain their efficacy for 4 and 2 years, respectively. However, the whole-cell vaccine is associated with a much higher incidence of side effects than the other two vaccines: 16% of whole-cell vaccine recipients develop fever and 10% miss a day of work

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Part III Infectious Diseases and their Etiologic agents

or school, whereas only 1% to 2% of persons receiving the alternative vaccines have any fever. Vi CPS typhoid vaccine is poorly immunogenic in children less than 5 years of age because of T cellindependent properties.224 The recently developed Vi-rEPA vaccine contains Vi polysaccharide bound to a nontoxic recombinant protein that is identical to Pseudomonas aeruginosa exotoxin A. In 2- to 4-year-olds, two injections of Vi-rEPA induced higher T cell responses and higher levels of serum antibodies to Vi than did Vi CPS in 5- to 14-year olds.229 In a two-dose trial in 2- to 5-year-old children in Vietnam, Vi-rEPA provided 91% efficacy at 27 months and was very well tolerated.230 At least three new live vaccines are in clinical development. Typhoid vaccine is not required for international travel, but it is recommended for travelers to areas where there is a moderate to high risk of exposure to S. Typhi , especially those traveling to south Asia and other developing countries in Asia, Africa, the Caribbean, and Central and South America, who will have exposure to potentially contaminated food and drink.226 Typhoid vaccine should be considered even for persons planning less than 2 weeks travel to high-risk areas.38 In addition, laboratory workers who work with S. Typhi and household contacts of known S. Typhi carriers should be vaccinated. Because vaccine protective efficacy can be overcome by high inocula that are common in foodborne exposure,226,231 immunization is an adjunct and not a substitute for avoiding high-risk foods and beverages. Immunization is not recommended for adults residing in typhoid-endemic areas or in the management of persons potentially exposed to a common-source outbreak. In 2000, the World Health Organization recommended immunization of school-aged children in high-risk areas where antimicrobial-resistant S. Typhi strains are prevalent. Currently, only China and Vietnam have incorporated typhoid vaccination into routine immunization programs.232 Enteric fever is a notifiable disease in the United States. Individual health departments have their own guidelines for allowing food handlers or health care workers to return to work. The reporting system enables public health departments to identify potential source patients and to treat chronic carriers in order to prevent further outbreaks. In addition, since 1% to 4% of patients with S. Typhi infection become chronic carriers, it is important to monitor patients (especially childcare providers and food handlers) for chronic carriage and to treat this condition if indicated.

Therapy for Salmonellosis

ENtErIC (tYPHOID) FEVEr Early diagnosis and prompt administration of appropriate antimicrobial therapy prevents severe complications of enteric fever and results in case-fatality rates of less than 1%.233 The initial choice of antimicrobial therapy depends on the susceptibility of the S. Typhi and S. Paratyphi strains in the area of residence or travel (Table 223-3). For treatment of drug-susceptible typhoid fever, fluoroquinolones are the most effective class of agents with cure rates of about 98% and rates of relapse and fecal carriage of less than 2%.233 In a recent Cochrane review, fluoroquinolone therapy for multidrug-resistant enteric fever reduced rates of clinical failure but not microbiologic failure or relapse compared with ceftriaxone or cefixime.234 The greatest experience is with ciprofloxacin (500 mg orally twice a day for 5 to 7 days). Ofloxacin (400 mg orally twice a day for 5 to 7 days) is similarly successful for treatment of nalidixic acidsusceptible strains. A 3-day course of oral fluoroquinolone therapy is effective for the treatment of uncomplicated, multidrug-resistant typhoid, and may be especially useful for management of typhoid epidemics.235 However, the increased incidence of nalidixic acidresistant S. Typhi in Asia, likely related to the widespread availability of these agents over the counter, is now limiting the use of fluoroquinolones for empirical therapy. Patients infected with nalidixic acidresistant S. Typhi strains should be treated with ceftriaxone, azithromycin, or high-dose ciprofloxacin therapy (ciprofloxacin 750 mg twice a day) for 10 to 14 days. High-dose fluoroquinolone therapy for 7 days for treatment of nalidixic acidresistant enteric fever has been associated with delayed resolution of fever, higher rates of treatment failure, and high rates of fecal carriage immediately post-treatment.236 Ceftriaxone, cefotaxime, and oral cefixime are effective agents for treatment of multidrug-resistant enteric fever, including nalidixic acid and fluoroquinolone-resistant strains. Ceftriaxone (1 to 2 g daily in adults or 60 to 75 mg/kg daily in children) administered either intravenously or intramuscularly for 10 to 14 days or oral cefixime (200 mg twice daily in adults or 10 to 15 mg/kg twice daily in children) for 7 to 14 days resolves fever in an average of 4 days, and results in cure rates of 95%, relapse rates of 3% to 6%, and fecal carriage rates of less than 3%.234 Oral azithromycin (1 g once a day for

223-3

taBLE

Recommended Antimicrobial Treatment for Typhoid Fever Optimal Treatment Alternative Effective Treatment Duration (days) 5-7* 5-7 5-7* 7-14 7 10-14 10-14 Drug Chloramphenicol Amoxicillin TMP-SMX Azithromycin Typical Adult Dose 500 mg PO qid 1 g PO tid 160/800 mg PO bid 1 g PO daily Duration (days) 14-21 14 7 7

Susceptibility Drug Uncomplicated Typhoid Fever Fully sensitive Ciprofloxacin Ofloxacin Multidrug resistance

Typical Adult Dose 500 mg PO bid 400 g PO bid

Fluoroquinolone (e.g., 500 mg PO bid ciprofloxacin) Cefixime 200 mg PO bid Quinolone resistance Azithromycin 1 g PO daily Ceftriaxone 2 g IV daily Severe Typhoid Fever Requiring Parenteral Treatment Fully sensitive Fluoroquinolone (e.g., 400 mg IV q12h ciprofloxacin) Multidrug resistance Quinolone resistance Fluoroquinolone (e.g., ciprofloxacin) Ceftriaxone Cefotaxime 400 mg IV q12h 2 g IV q12h 2 g IV q8h

Cefixime

200 mg PO bid

7-14

10-14 10-14 10-14

Chloramphenicol Ampicillin TMP-SMX Ceftriaxone Cefotaxime Fluoroquinolone (e.g., ciprofloxacin)

1.5 g IV q6h 2 g IV q6h 160/800 mg IV q8-12h 2 g IV q12h 2 g IV q8h 400 mg IV q8h

14-21 14 14 10-14 10-14 14

*Three-day course also effective. bid, twice daily; qid, four times daily; tid, three times daily; IV, intravenously; PO, orally; TMP-SMX, trimethoprim-sulfamethoxazole. Adapted from Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ. 2006;333:78-82; and World Health Organization (WHO) Department of Vaccines and Biologicals. Background document: The diagnosis, prevention and treatment of typhoid fever. Geneva: WHO; 2003:19-23. Available at: http://www.who.int/vaccine_research/ documents/en/typhoid_diagnosis.pdf.

223 Salmonella Species, Including Salmonella typhi

2899

5 days or 1 g on day 1 followed by 500 mg orally for 6 days) results in fever clearance in 4 to 6 days with rates of relapse and convalescent stool carriage of less than 3%.236 In a recent Cochrane review, azithromycin significantly reduced rates of treatment failure and duration of hospital stay compared with fluoroquinolones for the management of uncomplicated S. Typhi or S. Paratyphi A infection, including multidrug-resistant or nalidixic acidresistant strains.237 Despite efficient in vitro killing of Salmonella, first- and second-generation cephalosporins as well as aminoglycosides are ineffective in treating clinical infections. Chloramphenicol (500 mg four times a day), ampicillin (1 g four times a day), amoxicillin (1 g three times a day), and trimethoprimsulfamethoxazole (1 double-strength tablet twice a day) formerly were widely used for treatment of typhoid.238 However, emergence of plasmid-encoded resistance first to chloramphenicol in the 1970s and then to chloramphenicol, ampicillin, and trimethoprim beginning in 1989 has limited the usefulness of these agents in many developing countries, except in Latin America and sub-Saharan Africa, where resistance remains relatively uncommon. The agents are inexpensive, widely available, and as effective as fluoroquinolones for the treatment of susceptible strains, resolving fever in 5 to 7 days.234 However, they require 14 to 21 days of divided daily therapy, and adherence may be low. Oral chloramphenicol is not available in the United States. Most patients with uncomplicated enteric fever can be managed at home with oral antimicrobial therapy and antipyretics. Patients with persistent vomiting, diarrhea, or abdominal distention should be hospitalized and treated with supportive therapy and a parenteral thirdgeneration cephalosporin or fluoroquinolone, depending on the susceptibility profile. Therapy should be administered for at least 10 days, or 5 days after resolution of fever. High-dose dexamethasone (initial dose 3 mg/kg followed by eight doses of 1 mg/kg every 6 hours for 48 hours) should be considered for patients with severe typhoid fever with shock, obtundation, stupor, or coma. In a randomized, prospective, double-blind study performed in Indonesia, the administration of dexamethasone with chloramphenicol was associated with a substantially lower mortality in patients with severe typhoid fever compared with those who received chloramphenicol alone (10% vs. 55%).239 Patients should be carefully monitored, as dexamethasone may mask signs of abdominal complications. Steroid treatment beyond 48 hours may increase the relapse rate.240 The 1% to 4% of patients who develop chronic carriage of S. Typhi can be treated for 4 to 6 weeks with an appropriate oral antimicrobial. Treatment with oral amoxicillin, trimethoprim-sulfamethoxazole, ciprofloxacin, or norfloxacin has been shown to be approximately 80% effective in eradicating chronic carriage of susceptible organisms.241,242 Antimicrobial agents are infrequently effective in eradicating the carrier state when anatomic abnormalities, such as biliary or kidney stones, are present. In such cases, surgery combined with antimicrobial therapy is often required for eradication. Patients with urinary carriage associated with S. haematobium should be treated with praziquantel before eradication of S. Typhi is attempted. Chronic suppressive antimicrobial therapy should be considered for those patients with persistent carriage in whom no anatomic abnormality can be identified or who relapse after cholecystectomy. NONtYPHOIDaL SALMONELLA Salmonella gastroenteritis is usually a self-limited disease, and therapy primarily should be directed to the replacement of fluid and electrolyte losses. In a large meta-analysis, antimicrobial therapy for uncomplicated nontyphoidal Salmonella gastroenteritis, including short-course or single-dose regimens with oral fluoroquinolones, amoxicillin, or trimethoprim-sulfamethoxazole, did not significantly decrease the length of illness, including duration of fever or diarrhea, and was associated with an increased risk of relapse, positive culture after 3 weeks, and adverse drug reactions.243 Therefore, antimicrobials should not be used routinely to treat uncomplicated nontyphoidal Salmonella gastroenteritis or to reduce convalescent stool excretion.

Although fewer than 5% of all patients with Salmonella gastroenteritis develop bacteremia, certain patients are at increased risk for invasive infection and may benefit from preemptive antimicrobial therapy. Antimicrobial therapy should be considered for neonates (probably up to 3 months of age), those older than 50 years with suspected atherosclerosis, and for persons with immunosuppression, cardiac valvular or endovascular abnormalities, or significant joint disease. Treatment should consist of an oral or intravenous antimicrobial administered for 48 to 72 hours or until the patient becomes afebrile. Immunocompromised persons, including those with AIDS, who develop Salmonella gastroenteritis may require 7 to 14 days of therapy, typically with a fluoroquinolone, to reduce the risk of extraintestinal spread.244 For susceptible organisms, oral therapy with a fluoroquinolone, trimethoprim-sulfamethoxazole, or amoxicillin is adequate. Although fluoroquinolones are not recommended for administration to children younger than 10 years of age, they may have a role in treating severe nontyphoidal salmonellosis in this age group, particularly among immunocompromised patients.245 Occasionally, antimicrobial prophylaxis has been required to control institutional outbreaks, especially in long-term care facilities or pediatric wards, where compliance with infection control measures may be difficult.246 BaCtErEMIa Because of the increasing prevalence of antimicrobial resistance, empirical therapy for life-threatening bacteremia or focal infection suspected to be caused by nontyphoidal Salmonella should include a thirdgeneration cephalosporin and a fluoroquinolone until susceptibilities are known. High-grade bacteremia (i.e., >50% of three or more blood cultures positive) should prompt a search for endovascular abnormalities by echocardiogram or other imaging techniques, such as computerized tomography or indium-labeled white blood cell scan. Low-grade bacteremia not involving vascular structures should be treated with intravenous antimicrobial therapy for 7 to 14 days. Documented or suspected endovascular infection should be treated with intravenous ceftriaxone or ampicillin or intravenous fluoroquinolone for 6 weeks followed by oral therapy. Early surgical resection of infected aneurysms or other infected endovascular sites is recommended.200,201 Patients with infected prosthetic vascular grafts that could not be resected have been maintained successfully on chronic suppressive oral therapy.247 rECUrrENt SALMONELLA BaCtErEMIa IN PErSONS WItH aIDS In persons with AIDS and a first episode of Salmonella bacteremia, at least 4 to 6 weeks of therapy is recommended with a fluoroquinolone, trimethoprim-sulfamethoxazole, or ceftriaxone to attempt eradication of the organism and to decrease the risk of recurrent bacteremia.244 Persons who relapse following 4 to 6 weeks of antimicrobial therapy should receive long-term suppressive therapy with an oral fluoroquinolone or trimethoprim-sulfamethoxazole, based on susceptibility testing.244 FOCaL INFECtIONS Treatment recommendations for the management of focal Salmonella infections are summarized in Table 223-2. For extraintestinal nonvascular infections, antimicrobial therapy for 2-4 weeks (depending on the infection site) is usually recommended. In cases of chronic osteomyelitis, abscesses, and urinary or hepatobiliary infection associated with anatomic abnormalities, surgical resection or drainage may be required in addition to prolonged antimicrobial therapy to eradicate infection. CarrIEr StatE Treatment of persons with asymptomatic carriage of nontyphoidal Salmonella is controversial. In a randomized, placebo-controlled trial

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Part III Infectious Diseases and their Etiologic agents

conducted in Thailand among asymptomatic food workers, two 5-day regimens (norfloxacin, 400 mg twice daily, and azithromycin, 500 mg once daily) were similar to placebo in eradicating nontyphoidal Salmonella carriage and increased the risk of reinfection with antimicrobial-resistant S. Schwarzengrund.248

Prevention and Control

The prevention and control of salmonellosis require both an understanding of the complex cycles of transmission and ongoing surveillance to characterize trends in Salmonella incidence and prevalence and to identify outbreaks. Safe drinking water and effective sewage treatment can reduce the burden of enteric fever in developing countries, but substantial economic and social barriers continue to hinder progress on this front. The emergence of nalidixic acidresistant S. Typhi in Asia has increasingly shifted emphasis from treatment to vaccination.249 In developed countries, control of foodborne salmonellosis requires identification of controllable hazards, monitoring, and verification to limit the introduction and multiplication of Salmonella from the farm to the table.250 Recognition of foodborne outbreaks requires that clinicians have a high index of suspicion, order the appropriate laboratory test, and promptly report positive culture results to local public health departments. Vaccination of feed animals, further limiting the use of antimicrobials as growth promoters, and improved food safety practices should further reduce the burden of foodborne salmonellosis. Active population-based surveillance for foodborne diseases has improved estimates of disease burden,43 and use of algorithms and rapid molecular subtyping has improved the ability to detect outbreaks of salmonellosis associated with widely distributed agricultural and manufactured foods.251 Although most cases of Salmonella infection occur sporadically, large numbers of persons potentially may become infected when commercial kitchens serve Salmonella-contaminated foods that have not been sufficiently cooked or that have been mishandled. Commercial food service establishments can reduce the risk

of foodborne Salmonella illness if they do not serve food containing raw or undercooked eggs, use pasteurized eggs whenever possible, and avoid cross-contamination of food items. Use of pasteurized eggs for all recipes calling for bulk-pooled eggs is recommended for all nursing homes and hospitals.103 The most cost-effective approach to the control of salmonellosis in food handlers is attention to good personal hygiene and maintenance of time-temperature standards for food handling. Routine screening of food handlers for carriage after gastroenteritis is commonly performed before they are allowed to return to work. However, there is little justification for this approach because few outbreaks are related to specific food handlers, prolonged carriage in food handlers after gastroenteritis is rare, and the number of organisms present is small. Therefore, it is reasonable to allow individuals to return to work after diarrhea is resolved. Two consecutive negative stool samples should be required only for food handlers whose work involves touching unwrapped foods that are consumed raw or served without further cooking. Routine surveillance of food handlers for asymptomatic stool carriage of Salmonella is not recommended. To limit the risk of nosocomial transmission to patients and health care workers, patients excreting Salmonella should be managed with Standard Precautions, including the use of personal protective equipment, including gloves, when they perform direct patient care or handle soiled articles. Control of Salmonella outbreaks in long-term care facilities or neonatal care areas may be difficult because of poor compliance with isolation precautions, the increased susceptibility of these patients, and frequent transfers between health care facilities.252,253 Although Salmonella infection in newborns, the elderly, or the immunocompromised can be severe, the risk of transmission of Salmonella from health care workers to patients appears to be very small.97 Once the health care worker is asymptomatic and passing formed stool, the individual should be allowed to return to work if Standard Precautions are observed. However, local and state regulations should be followed because some require work exclusion for health care workers who have salmonellosis until two or more stool cultures obtained at least 24 hours apart are negative.

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