THYPOID FEVER Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused primarily by Salmonella

typhi. The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within one month of onset. Survivors may be left with long-term or permanent neuropsychiatric complications. S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation, crowding, and social chaos. It may have responsible for the Great Plague of Athens at the end of the Pelopennesian War. [1] The nameS typhi is derived from the ancient Greek typhos, an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world, it remains endemic in developing countries.[2] Transmission S typhi has no nonhuman vectors. The following are modes of transmission:

Oral transmission via food or beverages handled by an

individual who chronically sheds the bacteria through stool or, less commonly, urine

Hand-to-mouth transmission after using a contaminated Oral transmission via sewage-contaminated water or

toilet and neglecting hand hygiene

shellfish (especially in the developing world)[3] An inoculum as small as 100,000 organisms causes infection in more than 50% of healthy volunteers.[4] Pathophysiology All pathogenic Salmonella species are engulfed by phagocytic cells, which then pass them through the mucosa and present them to the macrophages in the lamina propria. Nontyphoidal salmonellae are phagocytized throughout the distal ileum and colon. With toll-like receptor (TLR)5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8), causing inflammation and suppressing the infection.[5, 6] In contrast to the nontyphoidal salmonellae, S typhi enters the host's system primarily through the distal ileum. S typhi has specialized fimbriae that adhere to the epithelium over clusters of lymphoid tissue in the ileum (Peyer patches), the main relay point for macrophages traveling from the gut into the lymphatic

system.S typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation. The bacteria then induce their host macrophages to attract more macrophages.[5] It co-opts the macrophages' cellular machinery for their own reproduction[7] as it is carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes. Once there, the S typhi bacteria pause and continue to multiply until some critical density is reached. Afterward, the bacteria induce macrophage apoptosis, breaking out into the bloodstream to invade the rest of the body.[6] The gallbladder is then infected via either bacteremia or direct extension of S typhiinfected bile. The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer patches. Bacteria that do not reinfect the host are typically shed in the stool and are then available to infect other hosts.[6, 2] Laboratory Studies The diagnosis of typhoid fever (enteric fever) is primarily clinical. Importantly, the reported sensitivities of tests for S typhi vary greatly in the literature, even among the most recent articles and respected journals.

Culture

The criterion standard for diagnosis of typhoid fever has

long been culture isolation of the organism. Cultures are widely considered 100% specific.
o

Culture of bone marrow aspirate is 90% sensitive until

at least 5 days after commencement of antibiotics. However, this technique is extremely painful, which may outweigh its benefit.[31]
o

Blood,

intestinal

secretions

(vomitus

or

duodenal

aspirate), and stool culture results are positive for S typhi in approximately 85%-90% of patients with typhoid fever who present within the first week of onset. They decline to 20%30% later in the disease course. In particular, stool culture may be positive for S typhi several days after ingestion of the bacteria secondary to inflammation of the intraluminal dendritic cells. Later in the illness, stool culture results are positive because of bacteria shed through the gallbladder.
o

Multiple blood cultures (>3) yield a sensitivity of 73%-

97%. Large-volume (10-30 mL) blood culture and clot culture may increase the likelihood of detection. [32]
o

Stool culture alone yields a sensitivity of less than 50%, samples of rose spots reportedly yield a

and urine culture alone is even less sensitive. Cultures of punch-biopsy sensitivity of 63% and may show positive results even after administration of antibiotics. A single rectal swab culture upon hospital admission can be expected to detect S typhi in 30%40% of patients. S typhi has also been isolated from the

cerebrospinal fluid, peritoneal fluid, mesenteric lymph nodes, resected intestine, pharynx, tonsils, abscess, and bone, among others.
o

Bone marrow aspiration and blood are cultured in a

selective medium (eg, 10% aqueous oxgall) or a nutritious medium (eg, tryptic soy broth) and are incubated at 37C for at least 7 days. Subcultures are made daily to one selective medium (eg, MacConkey agar) and one inhibitory medium (eg, Salmonella-Shigella agar). Identification of the organism with these conventional culture techniques usually takes 48-72 hours from acquisition.

Polymerase chain reaction (PCR):[35, 36] PCR has been used for the diagnosis of typhoid fever with varying success. Nested PCR, which involves two rounds of PCR using two primers with different sequences within the H1-d flagellin gene of S typhi, offers the best sensitivity and specificity. Combining assays of blood and urine, this technique has achieved a sensitivity of 82.7% and reported specificity of 100%. However, no type of PCR is widely available for the clinical diagnosis of typhoid fever. Specific serologic tests
o

Assays that identify Salmonella antibodies or antigens support the diagnosis of typhoid fever, but these results should be confirmed with cultures or DNA evidence. The Widal test was the mainstay of typhoid fever diagnosis for decades. It is used to measure

agglutinating antibodies against H and O antigens of S typhi. Neither sensitive nor specific, the Widal test is no longer an acceptable clinical method.
o

Indirect

hemagglutination,

indirect

fluorescent

Vi

antibody, and indirect enzyme-linked immunosorbent assay (ELISA) for immunoglobulin M (IgM) and IgG antibodies to S typhi polysaccharide, as well as monoclonal antibodies against S typhi flagellin,[37] are promising, but the success rates of these assays vary greatly in the literature. Other nonspecific laboratory studies
o

Most rate

patients (ESR),

with

typhoid

fever

are and

moderately relative

anemic, have an elevated erythrocyte sedimentation thrombocytopenia, lymphopenia.

o

Most also have a slightly elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT) and decreased fibrinogen levels. Circulating fibrin degradation products commonly rise to levels seen in subclinical disseminated intravascular coagulation (DIC). Liver transaminase and serum bilirubin values usually rise to twice the reference range. Mild hyponatremia and hypokalemia are common.

A serum alanine amino transferase (ALT)tolactate dehydrogenase (LDH) ratio of more than 9:1 appears to be helpful in distinguishing typhoid from viral hepatitis. A ratio of greater than 9:1 supports a diagnosis of acute viral hepatitis, while ratio of less than 9:1 supports typhoid hepatitis.

Antibiotics Class Summary Definitive treatment of typhoid fever (enteric fever) is based on susceptibility. As a general principle of antimicrobial treatment, intermediate susceptibility should be regarded as equivalent to resistance. Between 1999 and 2006, 13% of S typhiisolates collected in the United States were multidrug resistant. Until susceptibilities of this are determined, consider for the both antibiotics 2003 should be

empiric, for which there are various recommendations. The authors article World Health and Organization (WHO) guidelines to be outdated. These recommend fluoroquinolone treatment complicated uncomplicated cases of typhoid fever, but 38% of S typhi isolates taken in the United States in 2006 were fluoroquinolone resistant (nalidixic acidresistant S typhi [NARST]), and the rate of multidrug resistance was 13%. (Multidrug-resistant S typhi is, by definition, resistant to the original first-line agents, ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole.)

The particular sensitivity pattern of the organism in its area of acquisition should be the major basis of empiric antibiotic choice. It may soon become necessary to treat all cases presumptively for multidrug resistance until sensitivities are obtained. Note that nalidixic acid is a nontherapeutic drug that is used outside of the United States as a stand-in for fluoroquinolones in sensitivity assays. In the United States, it is still used specifically for S typhi infection.[39, 17] History of antibiotic resistance Chloramphenicol was used universally to treat typhoid fever from 1948 until the 1970s, when widespread resistance occurred. Ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ) then became treatments of choice. However, in the late 1980s, some S typhi and S paratyphi strains (multidrug resistant [MDR] S typhi or S paratyphi) developed simultaneous plasmid-mediated resistance to all three of these agents. Fluoroquinolones are now recommended by most authorities for the treatment of typhoid fever. They are highly effective against susceptible organisms, yielding a better to cure rate than cephalosporins. Unfortunately, resistance first-generation

fluoroquinolones is widespread in many parts of Asia. In recent years, third-generation cephalosporins have been used in regions with high fluoroquinolone resistance rates, particularly in south Asia and Vietnam. Unfortunately, sporadic resistance has

been reported, so it is expected that these will become less useful over time. Chloramphenicol (Chloromycetin)

Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gramnegative and gram-positive bacteria. Since its introduction in 1948, has proven to be remarkably effective for enteric fever worldwide. For sensitive strains, still most widely used antibiotic to treat typhoid fever. In the 1960s, S typh i strains with plasmidmediated resistance to chloramphenicol began to appear and later became widespread in many endemic countries of the Americas and Southeast Asia, highlighting need for alternative agents. Produces rapid improvement in patient's general condition, followed by defervescence in 3-5 d. Reduced preantibiotic-era case-fatality rates from 10%-15% to 1%-4%. Cures approximately 90% of patients. Administered PO unless patient is nauseous or experiencing diarrhea; in such cases, IV route should be used initially. IM route should be avoided because it may result in unsatisfactory blood levels, delaying defervescence.

Amoxicillin (Trimox, Amoxil, Biomox)

Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. At least as effective as chloramphenicol in rapidity of defervescence and relapse rate. Convalescence carriage occurs less commonly than with other agents when organisms are fully susceptible. Usually given PO with a daily dose of 75-100 mg/kg tid for 14 d.

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antibacterial activity of TMP-SMZ includes common urinary tract pathogens, exceptPseudomonas aeruginosa. As effective as chloramphenicol in defervescence and relapse rate. Trimethoprim alone has been effective in small groups of patients.

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA,Staphylococcus epidermidis, and most gramnegative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared. Proven to be highly effective for typhoid and paratyphoid fevers. Defervescence occurs in 3-5 d,

and convalescent carriage and relapses are rare. Other quinolones (eg, ofloxacin, norfloxacin, pefloxacin) usually are effective. If vomiting or diarrhea is present, should be given IV. Fluoroquinolones are highly effective against multiresistant strains and have intracellular antibacterial activity. Not currently recommended for use in children and pregnant women because of observed potential for causing cartilage damage in growing animals. However, arthropathy has not been reported in children following use of nalidixic acid (an earlier quinolone known to produce similar joint damage in young animals) or in children with cystic fibrosis, despite high-dose treatment.

Cefotaxime (Claforan)

Arrests bacterial cell wall synthesis, which inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms. Excellent in vitro activity against S typhi and other salmonellae and has acceptable efficacy in typhoid fever. Only IV formulations are available. Recently, emergence of domestically acquired ceftriaxone-resistantSalmonella infections has been described. Azithromycin (Zithromax)

Treats mild to moderate microbial infections. Administered PO at 10 mg/kg/d (not exceeding 500 mg), appears to be effective to treat uncomplicated typhoid fever in children 4-17 y. Confirmation of these results could provide an alternative for treatment of typhoid fever in children in developing countries, where medical resources are scarce. Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum gramnegative activity against gram-positive organisms; Excellent in vitro activity against S typhi and other salmonellae. Cefoperazone (Cefobid)

Discontinued in the United States. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against grampositive organisms. Ofloxacin (Floxin)

A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect. Levofloxacin (Levaquin)

For pseudomonal infections and infections due to multidrugresistant gram-negative organisms.