BACTERIAL INFECTIONS CAUSED BY: GRAM-NEGATIVE BACILLI

Escherichia coli

E. coli normally inhabits the GI tract. When E. coli organisms have colonizing, enterotoxic, cytotoxic, or invasive virulence traits, they become major causes of watery, inflammatory, or bloody diarrhea, occasionally with the hemolytic-uremic syndrome. If normal anatomic barriers are disrupted, the organism may spread to adjacent structures or invade the bloodstream.

The extraintestinal site most often infected by E. coli is the urinary tract, which is generally colonized from the outside. Hepatobiliary, peritoneal, cutaneous, and pulmonary infections also occur. E. coli is an important cause of bacteremia, which often occurs without an overt portal of entry. This organism is also an opportunistic pathogen, causing disease in patients who have defects in host resistance as a result of other disease (eg, cancer, diabetes, cirrhosis) or who have received treatment with corticosteroids, radiation, antineoplastic drugs, or antibiotics.

E. coli bacteremia and meningitis are common in newborns, particularly preterm infants (see Neonatal Infections: Neonatal Meningitis and Neonatal Sepsis) under Enterotoxigenic and enteropathogenic E. coli cause diarrhea in infants and traveler's diarrhea in adults. Enterohemorrhagic strains of E. coli, such as type O157:H7, cause bloody diarrhea, which may be complicated by the hemolytic-uremic syndrome. Such strains have most often been acquired from undercooked ground beef. Other strains of enteroaggregative E. coli are emerging as potentially important causes of persistent diarrhea in children in tropical areas and in patients with AIDS.

When E. coli infection is suspected on clinical grounds, the diagnosis must be confirmed by culture and appropriate biochemical or virulence tests; Gram stain does not differentiate E. coli from other gram-negative bacteria. The specific enteric virulence traits are detected only by research methods. Treatment may be started empirically, then modified on the basis of antibiotic sensitivity studies. Although many strains are still sensitive to ampicillin and tetracyclines, other drugs are used increasingly, including ticarcillin, piperacillin, the cephalosporins, aminoglycosides, trimethoprim-sulfamethoxazole (TMP-SMX), and quinolones (in adults). Surgery may be required to drain pus, excise necrotic lesions, or remove foreign bodies.

Klebsiella, Enterobacter, and Serratia infections

These are usually acquired in the hospital, mainly by patients with diminished host resistance. As a rule, Klebsiella, Enterobacter, and Serratia cause infections in the same sites as does E. coli, and they are also an important cause of bacteremia. They tend to respond to broad-spectrum penicillins (ticarcillin, piperacillin) and the aminoglycosides; however, since many isolates are resistant to multiple antibiotics, sensitivity studies are essential. Enterobacter strains are prone to develop resistance to cephalosporins even if they are initially sensitive.

Klebsiella pneumonia, a rare pulmonary infection characterized by severe pneumonia (sometimes with expectoration of dark brown or red currant-jelly sputum), lung abscess formation, and empyema, is most common in diabetics and alcoholics. If treated early, it responds to cephalosporins and aminoglycosides.

The Proteeae: The Proteeae are gram-negative organisms that do not ferment lactose and rapidly deaminate phenylalanine. They constitute at least three genera: Proteus (P. mirabilis, P. vulgaris, and P. myxofaciens), Morganella (M. morganii), and Providencia (P. rettgeri, P. alcalifaciens, and P. stuartii). P. mirabilis causes most human infections and is distinguished from the others by its failure to form indole. These organisms are normally found in soil, water, and the flora of normal feces. They are often present in superficial wounds, draining ears, and sputum, particularly in patients whose normal flora has been eradicated by antibiotic therapy. They may cause deep-seated infections (particularly in the ears and mastoid sinuses, peritoneal cavities, and urinary tracts of patients with chronic UTIs or with renal or bladder stones) and bacteremia.

P. mirabilis is often, but not always, sensitive to ampicillin, carbenicillin, ticarcillin, piperacillin, the cephalosporins, and the aminoglycosides. The other species tend to be more resistant but generally are sensitive to the latter three penicillins (not to ampicillin) and to gentamicin, tobramycin, and amikacin.

Salmonella Infections (Salmonelloses)

The 2200 known serotypes of Salmonella may be grouped into those (1) highly adapted to human hosts, (2) adapted to nonhuman hosts, or (3) unadapted to specific hosts. The first group includes S. typhi and S. paratyphi A, B (S. schottmuelleri), and C (S. hirschfeldii), which are pathogenic only in humans and commonly cause enteric fever. The second group causes disease almost exclusively in animals, although two strains within this group, S. dublin and S. choleraesuis, also cause disease in humans. The third group, designated S. enteritidis, includes > 2000 serotypes that cause gastroenteritis and accounts for 85% of all Salmonella infections in the USA.

TYPHOID FEVER

A systemic disease caused by S. typhi and characterized by fever, prostration, abdominal pain, and a rose-colored rash.

Epidemiology and Pathology

About 400 to 500 cases of typhoid fever are reported annually in the USA. Typhoid bacilli are shed in the feces of asymptomatic carriers or in the stool or urine of those with active disease. Inadequate hygiene after defecation may spread S. typhi to communal food or water supplies. In endemic areas where sanitary measures are generally inadequate, S. typhi is transmitted more frequently by water than by food. In developed countries, transmission is chiefly by food that has been contaminated by healthy carriers during preparation. Flies may spread the organism from feces to food. Occasional transmission by direct contact (anal-oral route) may occur in children during play and in adults during sexual practices. Rarely, hospital personnel who have not taken adequate enteric precautions have acquired the disease when changing soiled bedclothes.

The organism enters the body via the GI tract and gains access to the bloodstream via the lymphatic channels. Monocytic inflammation occurs in the ileum and colon, within the lamina propria and Peyer's patches, where local tissue necrosis is common. Ulceration, hemorrhage, and intestinal perforation may result in severe cases.

About 3% of untreated patients shed organisms in their stool for > 1 yr and are referred to as chronic enteric carriers. Some carriers have no history of clinical illness and apparently were asymptomatically infected. Obstructive uropathy related to schistosomiasis may predispose certain typhoid patients to developing a urinary carrier state. Most of the estimated 2000 carriers in the USA are elderly women with chronic biliary disease. Epidemiologic data indicate that typhoid carriers are more likely than the general population to acquire hepatobiliary cancer.

Symptoms and Signs

The incubation period (usually 8 to 14 days) is inversely related to the number of organisms ingested. Onset is usually gradual, with fever, headache, arthralgias, pharyngitis, constipation, anorexia, and abdominal pain and tenderness. Less common symptoms include dysuria, nonproductive cough, and epistaxis.

If no therapy is begun, the temperature rises in steps over 2 to 3 days, remains elevated (usually to 39.4 to 40° C [103 to 104° F]) for another 10 to 14 days, begins to fall gradually at the end of the 3rd wk, and reaches normal levels during the 4th wk. Prolonged fever is often accompanied by relative bradycardia and prostration, and CNS symptoms such as delirium, stupor, or coma occur in severe cases. 

NONTYPHOIDAL SALMONELLA INFECTIONS

The epidemiology of the other salmonelloses is similar to but more complicated than that of typhoid fever, since disease may also occur in humans by direct and indirect contact with numerous species of infected animals, the foodstuffs derived from them, and their excreta. Infected meat-producing animals, poultry, raw milk, eggs, and egg products are common sources of Salmonella. Other reported sources include infected pet turtles, carmine red dye, and contaminated marijuana.

Subtotal gastrectomy, achlorhydria (or ingestion of antacids), sickle cell anemia, splenectomy, louse-borne relapsing fever, malaria, bartonellosis, cirrhosis, leukemia, lymphoma, and HIV infection predispose to Salmonella infection. Except for typhoid fever, Salmonella enteritidis infections remain a significant public health problem in the USA. Many serotypes of S. enteritidis have been given names and are referred to informally as if they were separate species, even though they are not. The most common Salmonella serotypes in the USA include S. typhimurium, S. heidelberg, S. newport, S. infantis, S. agona, S. montevideo, and S. saint-paul.

Symptoms and Signs

Salmonella infection may present clinically as gastroenteritis, enteric fever, a bacteremic syndrome, or focal disease. Each Salmonella serotype can produce any or all of the clinical syndromes described below, although a given serotype is often associated with a specific syndrome. An asymptomatic carrier state may also occur.

Gastroenteritis usually starts 12 to 48 h after ingestion of organisms with nausea and crampy abdominal pain, followed by diarrhea, fever, and sometimes vomiting. Usually the stool is watery but may be paste-like semisolid. Rarely, mucus or blood is present. The disease is usually mild, lasting 1 to 4 days. Occasionally, a more severe, protracted illness occurs. In stool specimens stained with methylene blue, WBCs are often seen, indicating inflammatory colitis. Diagnosis is confirmed by culturing Salmonella from stool specimens or rectal swabs.

Enteric fever is a systemic syndrome characterized by fever, prostration, and septicemia. The prototype, typhoid fever, is described above. An identical presentation, although often less severe, is caused by S. paratyphi A, B, and C.

Focal manifestations of Salmonella infection may occur with or without sustained bacteremia. In patients with bacteremia, localized infection may occur, involving the GI tract (liver, gallbladder and appendix), endothelial surfaces (atherosclerotic plaques, ileofemoral or aortic aneurysms, heart valves), pericardium, meninges, lungs, joints, bones, GU tract, or soft tissues. Preexisting solid tumors will occasionally be seeded and develop abscesses that may, in turn, become a source of Salmonella bacteremia. S. choleraesuis and S. typhimurium are the most common causes of focal infection.

Bacteremia is relatively uncommon in patients with gastroenteritis. However, S. choleraesuis, S. typhimurium, and S. heidelberg, among others, can cause a sustained bacteremic syndrome lasting >= 1 wk. Although blood cultures are positive, stool cultures are generally negative. Patients with AIDS or HIV infection may have recurrent episodes of bacteremia or other invasive infections (eg, septic arthritis) due to Salmonella. Multiple Salmonella infections in a patient without other risk factors should prompt HIV testing.

Carriers do not appear to play a major role in large outbreaks of nontyphoidal gastroenteritis. Persistent shedding of organisms in the stool for >= 1 yr occurs in only 0.2 to 0.6% of patients with nontyphoidal Salmonella infections.

Diagnosis is made by isolating the organism from stool or another infected site. The prognosis is usually good, unless severe underlying disease is present.

Shigellosis (Bacillary Dysentery)

An acute infection of the bowel caused by Shigella organisms.

Etiology, Epidemiology and Pathology

The genus Shigella is divided into four major subgroups: A, B, C, and D, which are subdivided into serologically determined types. The genus is distributed worldwide and is the typical cause of inflammatory dysentery, responsible for 5 to 10% of diarrheal illness in many areas. S. flexneri and S. sonnei are found more widely than S. boydii and the particularly virulent S. dysenteriae. S. sonnei is the most common isolate found in the USA.

The source of infection is the excreta of infected individuals or convalescent carriers. Direct spread is by the fecal-oral route; indirect spread is by contaminated food and inanimate objects. Flies serve as mechanical vectors. Waterborne disease is unusual. Epidemics occur most frequently in overcrowded populations with inadequate sanitation. Shigellosis is particularly common in younger children living in endemic areas; adults usually have less severe disease.

Convalescents and subclinical carriers may be significant sources of infection, but true long-term carriers are rare. Infection imparts little or no immunity; reinfection with the same strain is possible.

Shigella organisms penetrate the mucosa of the lower intestine, causing mucus secretion, hyperemia, leukocytic infiltration, edema, and often superficial mucosal ulcerations. The watery diarrhea associated with Shigella infection may be mediated by an enterotoxin that causes increased intestinal secretion.

Symptoms and Signs

The incubation period is 1 to 4 days. In young children, onset is sudden, with fever, irritability or drowsiness, anorexia, nausea or vomiting, diarrhea, abdominal pain and distention, and tenesmus. Within 3 days, blood, pus, and mucus appear in the stools. The number of stools may increase to >= 20/day, and weight loss and dehydration become severe. If untreated, a child may die in the first 12 days; if the child survives, acute symptoms subside by the 2nd wk.

Adults may present without fever, with nonbloody and nonmucoid diarrhea, and with little or no tenesmus; however, first symptoms may be episodes of gripping abdominal pain, urgency to defecate, and passage of formed feces initially that temporarily relieves the pain. These episodes recur with increasing severity and frequency. Diarrhea becomes marked, with soft or liquid stools containing mucus, pus, and often blood. Rectal prolapse and consequent fecal incontinence may result from severe tenesmus. The disease usually resolves spontaneously in adults: mild cases in 4 to 8 days, severe cases in 3 to 6 wk. Significant dehydration and electrolyte loss with circulatory collapse and death occur mainly in infants < 2 yr and in debilitated adults.

Rarely, shigellosis starts suddenly with rice-water or serous (occasionally bloody) stools. The patient may vomit and rapidly become dehydrated. Infection may present with delirium, convulsions, and coma, but little or no diarrhea; death may occur in 12 to 24 h.

Secondary bacterial infections may occur, especially in debilitated and dehydrated patients. Severe mucosal ulcerations may cause significant acute blood loss. Other complications are uncommon but include toxic neuritis, arthritis, myocarditis, and, rarely, intestinal perforation. The hemolytic-uremic syndrome may complicate shigellosis in children. 

HAEMOPHILUS INFECTIONS

Haemophilus are nonmotile, small gram-negative rods or coccobacilli that require specific factors X (hematin) and V (nicotinamide adenine dinucleotide) for growth. Many Haemophilus sp are normally found in the upper respiratory tract and rarely cause disease.

H. influenzae is a leading cause of meningitis, bacteremia, septic arthritis, pneumonia, tracheobronchitis, otitis media, conjunctivitis, sinusitis, and acute epiglottitis in young children. These infections, as well as endocarditis, may occur in adults, although far less commonly. They are discussed under Infectious Arthritis, Acute Bacterial Meningitis and Acute Epiglottitis. Most H. influenzae strains that cause serious infections in children or adults are encapsulated type b strains.

Other Haemophilus strains may cause respiratory infections, or, less commonly, endocarditis. H. parainfluenzae and H. aphrophilus are rare causes of bacteremia, endocarditis, and brain abscess. H. influenzae serotype aegyptius may cause mucopurulent conjunctivitis and bacteremic Brazilian purpuric fever. H. ducreyi causes the venereal disease chancroid.

Antibiotic choices are strongly dependent on the site of infection, eg, meningitis and epiglottitis. H. influenzae type b conjugate vaccines are available for children >= 2 mo of age and are effective at preventing invasive infections such as meningitis, epiglottitis and bacteremia (see Childhood Immunizations.

BRUCELLOSIS (Undulant, Malta, Mediterranean, or Gibraltar Fever)

A disease caused by Brucella organisms and characterized by an acute febrile stage with few or no localizing signs and a chronic stage with relapses of fever, weakness, sweats, and vague aches and pains.

Etiology and Epidemiology

The causative microorganisms of human brucellosis are Brucella abortus (cattle), B. melitensis (sheep and goats), and B. suis (hogs--B. suis biotype 4, previously called B. rangiferi, in Alaskan and Siberian caribou). B. canis (dogs) has caused sporadic infections. Brucella infections of deer, bison, horses, moose, hares, chickens, and desert rats have also been reported.

Brucellosis is acquired by direct contact with secretions and excretions of infected animals and by ingesting raw milk or the products of milk containing viable Brucella organisms. It is rarely transmitted from person to person. Most prevalent in rural areas, brucellosis is an occupational disease of meatpackers, veterinarians, hunters, farmers, and livestock producers; children may become infected by consuming raw milk or unpasteurized cheese. Brucellosis is very rare in the USA, Europe, and Canada, but cases continue to be reported from the Middle East, Mediterranean regions, Mexico, and Central America.

Symptoms and Signs

The incubation period varies from 5 days to several months and averages 2 wk. Onset may be sudden, with chills and fever, severe headache, pains, malaise, and occasionally diarrhea; or it may be insidious, with mild prodromal malaise, muscular pain, headache, and pain in the back of the neck, followed by a rise in evening temperature. As the disease progresses, the temperature increases to 40 or 41° C (104 or 105° F), then subsides gradually to normal or near-normal in the morning, when profuse sweating occurs.

Typically, intermittent fever persists for 1 to 5 wk, followed by a 2- to 14-day remission with symptoms greatly diminished or absent; the febrile phase then recurs. Sometimes this pattern occurs only once; occasionally, subacute or chronic brucellosis ensues, with repeated febrile waves (undulations) and remissions recurring over months or years. In some patients, fever may be only transient.

After the initial phase, constipation is usually pronounced; anorexia, weight loss, abdominal pain, joint pain, headache, backache, weakness, irritability, insomnia, mental depression, and emotional instability occur. Splenomegaly appears, and lymph nodes may be slightly or moderately enlarged; hepatomegaly may be present in up to 50% of patients.

Patients with acute, uncomplicated brucellosis usually recover in 2 to 3 wk. 

Complications are rare but include subacute bacterial endocarditis, meningitis, encephalitis, neuritis, orchitis, cholecystitis, hepatic suppuration, and bone lesions.

TULAREMIA - Rabbit or Deer Fly Fever

An acute disease usually characterized by a primary local ulcerative lesion, regional lymphadenopathy, profound systemic symptoms, a typhoidlike febrile illness, bacteremia, or, occasionally, atypical pneumonia.

Etiology, Epidemiology and Pathology

There are four types of tularemia. The causative organism, Francisella tularensis, is a small, pleomorphic, nonmotile, nonsporulating, aerobic bacillus that enters the body by ingestion, inoculation, inhalation, or contamination. It can penetrate apparently unbroken skin, but may actually enter through microlesions. Type A, a more virulent serotype for humans, is found in rabbits and rodents. Type B usually produces a mild ulceroglandular infection and is found in water and aquatic animals. Transmission among animals is by blood-sucking arthropods and cannibalism.

Hunters, butchers, farmers, fur handlers, and laboratory workers are most commonly infected. In winter months, most cases result from contact (especially during skinning) with infected wild rabbits; in summer months, infection usually follows handling of other infected animals or birds or contact with infected ticks or other arthropods. Rarely, cases result from eating undercooked infected meat or drinking contaminated water. In the Western states, ticks, deer flies, horse flies, and direct contact with animals are other sources of infection. Human-to-human transmission has not been reported.

In disseminated cases, characteristic focal necrotic lesions in various stages of evolution are scattered throughout the body. They are 1 mm to 8 cm; whitish yellow; seen externally as the primary lesions on the finger, eye, or mouth; and commonly found in lymph nodes, spleen, liver, kidney, and lung. In pneumonia, foci of necrosis occur in the lung. Microscopically, the focal necrosis is surrounded by monocytes and young fibroblasts that are, in turn, surrounded by large collections of lymphocytes. Although severe systemic toxicity may occur, no toxins have been demonstrated.

Symptoms and Signs

Onset occurs suddenly, 1 to 10 (usually 2 to 4) days after contact, with headache, chills, nausea, vomiting, fever of 39.5 or 40° C (103 or 104° F), and severe prostration. Extreme weakness, recurring chills, and drenching sweats develop. Within 24 to 48 h, an inflamed papule appears at the infection site (finger, arm, eye, or roof of the mouth), except in glandular or typhoidal tularemia. The papule rapidly becomes pustular and ulcerates, producing a clean ulcer crater with a scanty, thin, colorless exudate. The ulcers are usually single on the extremities but multiple in the mouth or eye. Usually, only one eye is affected. Regional lymph nodes enlarge and may suppurate and drain profusely. A typhoidlike state frequently develops by the 5th day, and the patient may show signs of an atypical pneumonia, with symptoms like those of other pneumonias. Delirium may accompany tularemic pneumonia. Although signs of consolidation are frequently present, reduced breath sounds and occasional rales may be the only signs in tularemic pneumonia. A dry, nonproductive cough is associated with a retrosternal burning sensation. A nonspecific roseola-like rash may appear at any stage of the disease. Splenomegaly and perisplenitis may occur. Leukocytosis is common, but the WBC count may be normal with an increase only in the proportion of polymorphonuclear leukocytes. In untreated cases, temperature remains elevated for 3 to 4 wk and resolves gradually. Mediastinitis, lung abscess, and meningitis are rare complications.

Diagnosis

A history of contact with rabbits or wild rodents or of exposure to arthropod vectors, the sudden onset of symptoms, and the characteristic primary lesion are usually diagnostic. Laboratory infections are frequently typhoidal or pneumonic, with no demonstrable primary lesion, and are difficult to diagnose. Recovery of the organism from the lesion, lymph nodes, or sputum is diagnostic but potentially dangerous in the laboratory. Because this organism is highly infectious, the diagnostic laboratory should not attempt isolation without protective hoods. Extreme caution is required in handling infected tissues or culture media. Agglutination tests usually become positive after the 10th day and almost never before the 8th day. A rising titer supports the diagnosis. The serum of brucellosis patients may also react positively to F. tularensis antigens but usually in much lower titers.

Prophylaxis, Prognosis and Treatment

When entering endemic areas, clothing that keeps ticks away from the skin should be worn, repellents used, and a search for ticks should be thorough. When handling rabbits and rodents, especially in endemic areas, protective clothing, including rubber gloves and face masks, should be worn. Any ticks should be removed at once; organisms may be present in the animal and in tick feces on the animal's fur. Wild birds and game must be thoroughly cooked before eating; water that may be contaminated must be disinfected before use.

Mortality is almost nil in treated cases and about 6% in untreated cases. Death usually results from overwhelming infection, pneumonia, meningitis, or peritonitis. Relapses are uncommon but occur in inadequately treated cases. One attack confers immunity.

The drug of choice is streptomycin (0.5 g IM q 12 h until the temperature is normal); thereafter, 0.5 g/day for 5 days. Gentamicin 3 to 5 mg/kg/day IM or IV in 3 divided doses is also effective. Chloramphenicol or tetracycline 500 mg po q 6 h may be given until the temperature is normal, then 250 mg qid for 5 to 7 days; however, relapses occasionally occur with these two drugs, and they may not prevent node suppuration. F. tularensis is susceptible in vitro to 3rd-generation cephalosporins. When the diagnosis is unclear on presentation and tularemia is suspected, cefotaxime 1 to 2 g IV q 8 h or ceftriaxone 1 g IV q 12 h plus streptomycin or gentamicin at the above dosages is useful initial therapy. Supportive therapy for pneumonia is the same as for pneumococcal pneumonia.

Continuous wet saline dressings are beneficial for primary skin lesions and may diminish the severity of the lymphangitis and lymphadenitis. Large abscesses may be drained, but this is rarely necessary unless therapy is delayed. In ocular tularemia, applying warm saline compresses and using dark glasses give some relief; 2% homatropine 1 to 2 drops q 4 h may be instilled in severe cases. Intense headache usually responds to codeine 15 to 60 mg po or sc q 3 to 4 h.

CHOLERA

An acute infection by Vibrio cholerae involving the entire small bowel, characterized by profuse watery diarrhea, vomiting, muscular cramps, dehydration, oliguria, and collapse.

Etiology, Epidemiology and Pathophysiology

The causative organism, Vibrio cholerae, serogroups 01 and 0139, is a short, curved, motile, aerobic rod. Both the El Tor and classic biotypes of V. cholerae can cause severe disease; however, mild or asymptomatic infection is much more common with the El Tor biotype.

Cholera is spread by ingestion of water, seafood, and other foods contaminated by the excrement of persons with symptomatic or asymptomatic infection. Cholera is endemic in portions of Asia, the Middle East, Africa, South and Central America, and the Gulf Coast of the USA. Cases transported into Europe, Japan, and Australia have caused localized outbreaks. In endemic areas, outbreaks usually occur during warm months and the incidence is highest in children; in newly affected areas, epidemics may occur during any season and all ages are equally susceptible. A milder form of gastroenteritis caused by noncholera vibrios is discussed below under Campylobacter and Noncholera Vibrio Infections.

Susceptibility to infection varies and is greater for persons with blood group O. Because the vibrio is sensitive to gastric acid, hypochlorhydria and achlorhydria are predisposing factors. Persons living in endemic areas gradually acquire a natural immunity. V. cholerae 01 and 0139 produce a protein enterotoxin that induces hypersecretion of an isotonic electrolyte solution by an intact small-bowel mucosa. Mucinase may be important in reducing a protective effect of intestinal mucin, while neuraminidase may alter the structure of gangliosides in mucosal cell membranes, increasing the content of the specific ganglioside increasing the content of the specific ganglioside (GM1) that binds the enterotoxin. A cell-associated hemagglutinin may aid the process of mucosal colonization, but pili appear to be more important.

Symptoms and Signs

The incubation period is 1 to 3 days. Cholera can be subclinical; a mild, uncomplicated episode of diarrhea; or a fulminant, potentially lethal disease. Abrupt, painless, watery diarrhea and vomiting are usually the initial symptoms; stool loss in adults may exceed 1 L/h but is usually much less. The resultant severe water and electrolyte depletion leads to intense thirst, oliguria, muscle cramps, weakness, and marked loss of tissue turgor, with sunken eyes and wrinkling of skin on the fingers. The manifestations of cholera result from the loss of isotonic, watery stools rich in sodium, chloride, bicarbonate, and potassium. Hypovolemia, hemoconcentration, oliguria and anuria, and severe metabolic acidosis with potassium depletion (but with normal serum sodium concentration) occur, and, if untreated, circulatory collapse with cyanosis and stupor may follow. Prolonged hypovolemia can cause renal tubular necrosis.
Uncomplicated cholera is self-limited; recovery occurs within 3 to 6 days. The fatality rate can be > 50% in untreated severe cases--usually due to dehydration--but is < 1% with prompt and adequate fluid and electrolyte therapy. Most patients are free of V. cholerae within 2 wk, but a few become chronic biliary tract carriers.

Diagnosis 

The diagnosis is confirmed by isolation of V. cholerae in cultures from direct rectal swabs or fresh stools and its subsequent identification as serogroup 01 or 0139 through agglutination by specific antiserum. Cholera must be distinguished from clinically similar disease caused by enterotoxin-producing strains of Escherichia coli and occasionally by Salmonella and Shigella organisms.

Prophylaxis 

To control cholera, human excrement must be properly disposed of and water supplies purified. Drinking water should be boiled or chlorinated and vegetables and fish cooked thoroughly. A killed oral whole cell-B subunit vaccine (not licensed in the USA) provides 85% protection against the 01 serogroup for 4 to 6 mo. Protection lasts up to 3 yr in adults but wanes rapidly in children and is greater for the classical than the El Tor biotype. There is no cross-protection between 01 and 0139 serogroups, so vaccines proven effective against both serogroups are a future goal. Parenteral cholera vaccine gives only short-term, partial protection and is not recommended. Prompt prophylaxis with tetracycline 500 mg po q 6 h in adults (50 mg/kg/day in 4 divided doses for children) can decrease secondary cases among household contacts of cholera patients, but mass prophylaxis is inappropriate and some strains are not sensitive. Trimethoprim-sulfamethoxazole (TMP-SMX) can also be used for prophylaxis in children < 9 yr.

Treatment

Rapid correction of hypovolemia and metabolic acidosis and prevention of hypokalemia are important. For severely dehydrated patients, especially those unable to drink, IV infusion, when possible, should be started promptly with either (1) 100 mL/kg of lactated Ringer's solution, (2) a 2:1 mixture of 0.9% sodium chloride and 0.17 molar (1/6 molar) sodium lactate, or (3) 0.9% sodium chloride. The infusion should be given rapidly (1 to 2 mL/kg/min) until BP is normal and pulse is strong, and the remainder given over 3 h. Water should also be given freely by mouth. To replace potassium losses, potassium chloride 10 to 15 mEq/L can be added to the IV solution, or potassium bicarbonate 1 mL/kg of a 100 g/L solution po qid can be given. This is especially important for children, who tolerate potassium loss poorly. 

Amounts for replacement of continuing losses should equal measured stool volume. Adequacy of hydration is confirmed by frequent clinical evaluation (pulse rate and strength, skin turgor, and urine output). Plasma, plasma volume expanders, and vasopressors should not be used in place of water and electrolytes. 

Oral administration of a glucose-electrolyte solution is effective in replacing stool losses and may be used after initial IV rehydration. It is also useful--sometimes as the only means of rehydration--in epidemic areas where supplies of parenteral fluids are limited. Patients with mild or moderate dehydration who can drink may be rehydrated with the oral solution exclusively (about 75 mL/kg in 4 h). Those with more severe dehydration need more and may need to receive the fluid by nasogastric tube. The oral solution recommended by the WHO contains: 20 g glucose; 3.5 g sodium chloride; 2.9 g trisodium citrate, dihydrate (or 2.5 g sodium bicarbonate); and 1.5 g potassium chloride per liter of water. This should be continued ad libitum after rehydration in amounts at least equal to continuing stool and vomitus losses. Solid food should be given after vomiting stops and appetite returns. 

Early treatment with an effective oral antimicrobial eradicates vibrios, reduces stool volume by 50%, and stops diarrhea within 48 h. The choice of an antimicrobial should be based on the susceptibility of V. cholerae isolated from the community. Drugs effective for susceptible strains include tetracycline (adults, 500 mg po qid for 72 h; children 50 mg/kg/day in 4 divided doses for 72 h [maximum daily dose, 2 g]); doxycycline (in adults a single dose of 300 mg po is nearly as effective); furazolidone (adults, 100 mg po qid for 72 h; children, 5 mg/kg/day in 4 divided doses for 72 h); erythromycin (adults, 100 mg qid for 72 h; children, 50 mg/kg/day divided into 4 doses for 72 h); TMP-SMX (adults, 160 mg bid [TMP] and 800 mg bid [SMX]; children, 5 mg/kg bid [TMP] and 25 mg/kg bid [SMX] for 72 h); or norfloxacin (adults, 400 mg po bid). Avoiding tetracycline can eliminate the small risk of tooth discoloration by that drug in children < 8 yr.

PLAGUE (Bubonic Plague; Pestis; Black Death)

An acute, severe infection appearing most commonly in a bubonic or pneumonic form, caused by the bacillus Yersinia pestis. 

Etiology and Epidemiology 

Yersinia pestis (formerly Pasteurella pestis) is a short bacillus that often shows bipolar staining (especially with Giemsa stain) and may resemble safety pins. Plague occurs primarily in wild rodents (eg, rats, mice, squirrels, prairie dogs); it may be acute, subacute, or chronic, and urban (mainly murine) or sylvatic. Massive human epidemics have occurred (eg, the Black Death of the Middle Ages); more recently, plague has occurred sporadically or in limited outbreaks. In the USA, > 90% of human plague occurs in the southwestern states, especially New Mexico, Arizona, California, and Colorado. Bubonic plague is the most common form. Plague is transmitted from rodent to humans by the bite of an infected flea vector. Human-to-human transmission occurs by inhaling droplet nuclei through the cough of patients with bubonic or septicemic plague who have pulmonary lesions (primary pneumonic plague). In endemic areas in the USA, a number of cases have been associated with household pets, especially cats. Transmission from cats can be by bite, or, if the cat has pneumonic plague, by inhalation of infected droplets.

Symptoms and Signs 

In bubonic plague, the incubation period is usually 2 to 5 days but varies from a few hours to 12 days. Onset is abrupt and often associated with chills; the temperature rises to 39.5 to 41° C (103 to 106° F). The pulse may be rapid and thready; hypotension may occur. Enlarged lymph nodes (buboes) appear with or shortly before the fever. The femoral or inguinal lymph nodes are most commonly involved (50%), followed by axillary (22%), cervical (10%), or multiple (13%) nodes. Typically, the nodes are extremely tender and firm, surrounded by considerable edema; they may suppurate in the 2nd wk. The overlying skin is smooth and reddened but often not warm. A primary cutaneous lesion, varying from a small vesicle with slight local lymphangitis to an eschar, occasionally appears at the bite. The patient may be restless, delirious, confused, and uncoordinated. The liver and spleen may be palpable. The WBC count is usually 10,000 to 20,000/µL with a predominance of immature and mature neutrophils. The nodes may suppurate in the 2nd wk. Primary pneumonic plague has a 2- to 3-day incubation period, followed by abrupt onset of high fever, chills, tachycardia, and headache, often severe. Cough, not prominent initially, develops within 20 to 24 h; sputum is mucoid at first, rapidly shows blood specks, and then becomes uniformly pink or bright red (resembling raspberry syrup) and foamy. Tachypnea and dyspnea are present, but pleurisy is not. Signs of consolidation are rare, and rales may be absent. Chest x-rays show a rapidly progressing pneumonia. Septicemic plague usually occurs with the bubonic form as an acute, fulminant illness. Abdominal pain, presumably due to mesenteric lymphadenopathy, occurs in 40% of patients. Pharyngeal plague and plague meningitis are less common forms. Pestis minor, a benign form of bubonic plague, usually occurs only in endemic areas. Lymphadenitis, fever, headache, and prostration subside within a week.

Diagnosis and Prognosis 

Diagnosis is based on recovery of the organism, which may be cultured from blood, sputum, or lymph node aspirate. Because surgical drainage may disseminate the organism, needle aspiration of a bubo is preferred. Y. pestis can grow on ordinary culture media or be isolated by animal (especially guinea pig) inoculation. Serologic tests include complement fixation, passive hemagglutination, and immunofluorescent staining of a node or tissue biopsy or secretions. Prior vaccination does not exclude plague in the differential diagnosis, since clinical illness may occur in vaccinated persons. The mortality rate for untreated patients with bubonic plague is about 60%, with most deaths occurring from sepsis in 3 to 5 days. Most untreated patients with pneumonic plague die within 48 h of symptom onset. Septicemic plague may be fatal before bubonic or pulmonary manifestations predominate.

Prophylaxis and Treatment 

Rodents should be controlled and repellents used to minimize fleabites. Although immunization with standard killed plague vaccine gives protection, vaccination is not indicated for most travelers to countries reporting cases of plague. Travelers should consider prophylaxis with tetracycline 500 mg po q 6 h during exposure periods. Immediate treatment reduces mortality to < 5%. In septicemic or pneumonic plague, treatment must begin within 24 h with streptomycin 30 mg/kg/day IM in 4 divided doses q 6 h for 7 to 10 days. Many physicians give higher initial dosages, up to 0.5 g IM q 3 h for 48 h. Tetracycline 30 mg/kg IV or po in 4 divided doses is an alternative. Gentamicin is probably also effective, although no controlled clinical trials have been conducted. For plague meningitis, chloramphenicol should be given in a loading dose of 25 mg/kg IV, followed by 50 mg/kg/day in 4 divided doses IV or po. A multidrug-resistant strain has been reported from Madagascar. Routine aseptic precautions are adequate for patients with bubonic plague. Those with primary or secondary pneumonic plague require strict (airborne agent) isolation. All pneumonic plague contacts should be under medical surveillance; their temperatures should be taken q 4 h for 6 days. If this is not possible, tetracycline 1 g/day po for 6 days can be given; however, this can produce drug-resistant strains.

MELIOIDOSIS 

An infection of humans and animals caused by Burkholderia (Pseudomonas) pseudomallei. The organism can be isolated from soil and water and is endemic in Southeast Asia; Australia; Central, West, and East Africa; India; and China. Humans may contract melioidosis by contamination of skin abrasions or burns, by ingestion, or by inhalation but not directly from infected animals or other humans. In endemic areas, melioidosis is likely to occur in patients with AIDS.

Symptoms, Signs and Diagnosis 

Infection may be latent for years; it may be asymptomatic or occur in various forms. 

Acute pulmonary infection is the most common form. It varies from mild to overwhelming necrotizing pneumonia. Onset may be abrupt or gradual, with headache, anorexia, pleuritic or dull aching chest pain, and generalized myalgia. Fever usually exceeds 39° C (102° F). Cough, tachypnea, and rales are characteristic; sputum may be blood-tinged. Chest x-rays usually show upper lobe consolidation, frequently cavitating and resembling TB. Nodular lesions, thin-walled cysts, and pleural effusion may also occur. The WBC count ranges from normal to 20,000/µL. 

Disseminated septicemic infection begins abruptly, with septic shock and multiple organ involvement manifested by disorientation, extreme dyspnea, severe headache, pharyngitis, upper abdominal colic, diarrhea, and pustular skin lesions. High fever, hypotension, tachypnea, a bright erythematous flush, and cyanosis are present. Muscle tenderness may be striking. Signs of arthritis or meningitis are sometimes present. Pulmonary signs may be absent, or may include rales, rhonchi, and pleural rubs. Chest x-rays usually show irregular nodular (4 to 10 mm) densities. The liver and spleen may be palpable. Liver function tests, AST, and bilirubin often are abnormal. The WBC count is normal or slightly increased. 

Nondisseminated septicemic infection occurs when bacteremia only involves a single organ. It is not usually associated with shock. 

Localized (chronic suppurative) infection causes secondary abscesses in the skin, lymph nodes, or any organ. Osteomyelitis is relatively common. Patients may be afebrile. An acute suppurative form is uncommon. 

Culture of B. pseudomallei (which grows on most laboratory media in 48 to 72 h) and hemagglutination, agglutination, and complement fixation tests on paired sera aid the diagnosis.

_{PSEUDOMONAS INFECTIONS} 

_{Pseudomonas aeruginosa, a gram-negative motile bacillus, is an opportunistic pathogen that frequently causes hospital-acquired infections.} 

_Epidemiology 

_{Pseudomonas is ubiquitous and favors moist environments. In humans, P. aeruginosa is the most common species. Others that may sometimes cause human infection are P. paucimobilis, P. putida, P. fluorescens, and P. acidovorans. P. aeruginosa can be found occasionally in the axilla and anogenital areas of normal skin, but rarely in stools unless antibiotics are being given. The organism is commonly a contaminant of lesions populated with more virulent organisms, but occasionally it causes infection in tissues that are exposed to the external environment. Pseudomonas infections usually occur in hospitals, where the organism is frequently found in sinks, antiseptic solutions, and urine receptacles. Transmission to patients by health care personnel may occur, especially on burn and neonatal ICUs. Other species, formerly classified as Pseudomonas, are important nosocomial pathogens, such as Burkholderia cepacia and Stenotrophomonas maltophilia.} 

_{Most infections caused by P. aeruginosa occur in hospitalized patients who are debilitated or immunocompromised. P. aeruginosa is the second most common cause of infections in ICUs and a frequent cause of ventilator-associated pneumonias. In addition to hospital-acquired infections, HIV-infected patients are at risk for community-acquired P. aeruginosa infections and often exhibit signs of advanced HIV infection when they become infected.} 

_{Pseudomonas infections can develop in many anatomic sites, including skin, subcutaneous tissue, bone, ears, eyes, urinary tract, and heart valves. The site varies with the portal of entry and the patient's vulnerability. In burns, the region below the eschar can become heavily infiltrated with organisms, serving as a focus for subsequent bacteremia--an often lethal complication of burns. Bacteremia without a detectable urinary focus, especially if due to Pseudomonas sp other than aeruginosa, suggests contaminated IV fluids, drugs, or antiseptics used in placing the IV catheter. In HIV-infected patients, Pseudomonas most commonly causes pneumonia or sinusitis.}

Symptoms and Signs 

Clinical presentation depends on the site involved. In hospitalized patients, pulmonary infection can occur in association with endotracheal intubation, tracheostomy, or IPPB treatment when Pseudomonas has joined with other gram-negative bacilli in colonizing the oropharynx. Pseudomonas bronchitis is common late in the course of cystic fibrosis; isolates have a characteristic mucoid colonial morphology. Blood isolates of Pseudomonas are common in patients with burns and underlying malignancy. The clinical presentation is gram-negative sepsis, sometimes with ecthyma gangrenosum, characterized by purple-black areas about 1 cm in diameter with an ulcerated center and surrounding erythema; it is found most often in the axillary or anogenital areas. Pseudomonas is a common cause of UTI, especially in patients who have had urologic manipulation, have obstructive uropathy or have received broad-spectrum antibiotics. External otitis with purulent drainage, common in tropical climates, is the most common form of Pseudomonas infection involving the ear. A more severe form, referred to as malignant external otitis, can develop in diabetic patients; it is manifested by severe ear pain, often with unilateral cranial nerve palsies, and requires parenteral therapy. Ocular involvement with Pseudomonas generally presents as corneal ulceration, most often after trauma, but contamination of contact lenses or lens fluid has been implicated in some cases. The organism may be found in draining sinuses, especially after trauma or deep puncture wounds of the foot. Drainage often has a sweet, fruity smell. Many of these puncture wounds result in P. aeruginosa cellulitis and osteomyelitis, which may require early surgical debridement in addition to antibiotics. Rarely, Pseudomonas causes endocarditis, usually on prosthetic valves in patients who have had open-heart surgery or on natural valves in IV drug abusers. Right-sided endocarditis can be treated medically, but usually the infected valve must be removed to cure an infection involving the mitral, aortic, or prosthetic valve.

Treatment 

When infection is localized and external, treatment with 1% acetic acid irrigations or topical agents such as polymyxin B or colistin is effective. Necrotic tissue must be debrided and abscesses drained. When parenteral therapy is required, tobramycin or gentamicin 5 mg/kg/day in divided doses cures most Pseudomonas UTIs. With clinical response, dosage can be reduced to 3 mg/kg/day to minimize adverse effects. Dosage must be reduced in renal insufficiency. Amikacin should be used in treating Pseudomonas that has enzyme-mediated resistance to tobramycin and gentamicin. Many experts recommend treating serious Pseudomonas infections with an aminoglycoside plus an antipseudomonal beta-lactam. Several penicillins, including ticarcillin, piperacillin, mezlocillin, and azlocillin, are active against Pseudomonas. Other drugs with excellent activity include ceftazidime, cefepime, aztreonam, imipenem, meropenem, and ciprofloxacin. Ticarcillin is used most often at dosages of 16 to 20 g/day IV. Piperacillin, azlocillin, cefepime, ceftazidime, meropenem, and imipenem are active in vitro against some strains resistant to ticarcillin. In systemic infections or in granulocytopenic patients, an aminoglycoside active against Pseudomonas should be combined with an antipseudomonal penicillin. In neutropenic patients with marginal renal function, nonaminoglycoside combinations such as double beta-lactams or a beta-lactam plus a fluoroquinolone are also satisfactory. UTIs can often be treated with oral indanyl carbenicillin or with ciprofloxacin or other fluoroquinolones. However, fluoroquinolones should not be used in children because of potential effects on cartilage. When two antipseudomonal drugs are used, emergence of resistant strains during therapy is reduced.

CAMPYLOBACTER INFECTIONS 

Campylobacter are motile, curved, microaerophilic, gram-negative bacilli that can cause septic thrombophlebitis, bacteremia, endocarditis, osteomyelitis, prosthetic septic arthritis, and diarrhea. Epidemiology Three species are believed to be human pathogens. C. fetus subspecies fetus typically cause bacteremia in adults, often when underlying predisposing diseases such as diabetes, cirrhosis, or malignancy are present. These organisms may also cause relapsing infections, which are difficult to treat in patients with immunoglobulin deficiencies. C. jejuni can cause meningitis in infants, and C. jejuni and C. coli cause diarrhea in any age group. Campylobacter sp are commonly isolated bacterial pathogens, with C. jejuni accounting for > 90% of isolates from infected patients with diarrhea. Contact with infected animals, domestic or wild, and ingestion of contaminated food (especially undercooked poultry) or water have been implicated in outbreaks; however, for sporadic cases, the source of the infecting organism frequently is obscure. There is an association between summer outbreaks of C. jejuni diarrheal illness and subsequent development (up to 30% of cases) of Guillain-Barré syndrome. Another species, originally called C. pylori but renamed Helicobacter pylori, is associated with gastritis, peptic ulcer disease, and gastric cancers and is studied under Nonerosive Gastritis.

Symptoms, Signs and Diagnosis 

The most common presentation is enteritis. Enteritis resembling salmonellosis or shigellosis affects all ages, but peak incidence appears to be from age 1 to 5 yr. The diarrhea is watery and sometimes bloody; WBCs are seen in stained smears of stool. Fever (temperature of 38 to 40° C [100 to 104° F]), which follows a relapsing or intermittent course, is the only constant feature of systemic Campylobacter infection, although abdominal pain and hepatosplenomegaly are frequent. Infection can also present as subacute bacterial endocarditis, septic arthritis, meningitis, or an indolent FUO. Diagnosis, particularly to differentiate Campylobacter infection from ulcerative colitis, requires microbiologic evaluation. Campylobacter can be recovered from blood and various body fluids by using standard culture media, but isolation from stool requires selective media: Skirrow's medium, using 7% lysed horse blood agar with added vancomycin, polymyxin B, and trimethoprim.

Treatment 

Ciprofloxacin 500 mg po tid for 5 days or azithromycin 500 mg/day po for 3 days eradicates the organisms in most cases. Erythromycin 1 to 2 g/day po in 4 divided doses is also effective in treating Campylobacter diarrhea. For patients with extraintestinal infections, treatment should be prolonged (2 to 4 wk) to prevent relapses.

NONCHOLERA VIBRIO INFECTIONS 

These vibrios are biochemically or serologically distinct from Vibrio cholerae and produce wound infections, enteric sepsis, or diarrhea, depending on the species involved. 

Etiology and Epidemiology 

The noncholera vibrios are V. parahaemolyticus, V. mimicus, V. alginolyticus, V. hollisae, V. vulnificus, and the so-called nonagglutinable vibrios. V. parahaemolyticus is a halophilic organism incriminated in food-borne (in inadequately cooked seafood, usually shrimp) outbreaks of diarrhea in Japan and in coastal areas of the USA. The organism neither produces enterotoxin nor invades the bloodstream, but it does damage the intestinal mucosa. Severe infections with nonagglutinable vibrios have usually been reported in patients with liver disease and other immunodeficiencies, although otherwise healthy persons can develop severe infections. Neither V. alginolyticus nor V. vulnificus causes enteritis, but both can cause marine wound infection.

Symptoms, Signs and Diagnosis 

After a 15- to 24-h incubation period, the illness begins acutely with cramping abdominal pain, watery diarrhea (stools may be bloody and may contain polymorphonuclear leukocytes), tenesmus, weakness, and sometimes low-grade fever. Symptoms subside spontaneously in 24 to 48 h. Nonagglutinable vibrios may cause a cholera-like illness, and they have been isolated from wounds and from blood. Wounds infected through warm seawater can become cellulitic and progress rapidly, in some cases resulting in necrotizing fasciitis with typical hemorrhagic, bullous lesions. V. vulnificus, when ingested by a compromised host (often someone with chronic liver disease or immunodeficiency), crosses the intestinal mucosa without causing enteritis and produces septicemia with a high mortality rate. Wound and bloodstream infections are readily diagnosed with routine cultures. When enteric infection is suspected, Vibrio organisms can be cultured from stool on thiosulfate citrate bile salts sucrose medium; contaminated seafood also yields positive cultures. 

Prevention and Treatment 

High-risk patients with skin wounds should avoid handling uncooked seafood and exposure to seawater. Noncholera Vibrio infections can be treated with a single dose of ciprofloxacin 1 g po or doxycycline 300 mg po. Close attention to repleting volume and electrolyte losses in diarrheal disease is needed. For patients with necrotizing fasciitis, surgical debridement is required in addition to antibiotics.

Source: Merck