Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

51. Gram-Positive Aerobic Bacilli

Jeffrey Loutit MB, ChB

David Relman MD

LISTERIA MONOCYTOGENES

Essentials of Diagnosis

  • Incriminated foods include unpasteurized milk, soft cheeses, undercooked poultry, and unwashed raw vegetables.
  • Asymptomatic fecal and vaginal carriage can result in sporadic neonatal disease from transplacental and ascending routes of infection.
  • Incubation period for foodborne transmission is 21 days.
  • Organism causes disease especially in neonates, pregnant women, immunocompromised hosts, and elderly.
  • Organism is grown from blood, cerebrospinal fluid (CSF), meconium, gastric washings, placenta, amniotic fluid, and other infected sites.

General Considerations

  1. Epidemiology.L monocytogenesis found in soil, fertilizer, sewage, and stream water; on plants; and in the intestinal tracts of many mammals. It is a foodborne pathogen that causes bacteremic illness and meningoencephalitis, with few if any gastrointestinal manifestations. Contaminated food appears to be the most common source for both sporadic and outbreak-related cases. An estimated 2500 cases occur each year in the United States. The median incubation period for foodborne transmission is ~ 30 days. Foods that have been linked to outbreaks of listeriosis include Mexican style cheeses, unpasteurized milk, and undercooked chicken. The organisms can multiply at 4°C; therefore, foods refrigerated for prolonged periods are well-recognized sources for microbial transmission. Although the incidence of listeriosis is relatively low, there are several populations at increased risk for disease. These populations include persons older than 70 years, pregnant women, and patients with defects in cell-mediated immunity, including transplant hosts, those receiving high-dose corticosteroids, and patients with AIDS. The case fatality rate associated with listeriosis is ~ 23%; listeriosis is estimated to account for almost one-third of all food-related disease deaths. Asymptomatic vaginal and fecal carriage in pregnant women can result in sporadic neonatal disease, either from transplacental infection or from exposure during delivery.
  2. Microbiology.L monocytogenesis a facultative anaerobic, non–spore-forming, gram-positive bacillus that can grow in acidic conditions, high salt concentrations, and a wide temperature range, including the temperatures of household refrigerators. There are ≥ 13 serotypes of L monocytogenes, of which types 1B and 4B are the most commonly associated with disease.
  3. Pathogenesis.L monocytogenesdisplays unusual capabilities in its interactions with host cells and its mechanisms of pathogenesis. After entering the small intestine, the organisms induce their uptake into epithelial cells and macrophages. E-cadherin serves as a host cell receptor. Once internalized, the bacteria rupture the phagolysosomal vacuolar membrane, using a pore-forming hemolysin, listeriolysin O, and escape into the host cell cytoplasm. Listeriamultiplies readily within this environment; it also moves about the cytoplasm by nucleating host cell actin polymerization at one pole of the bacterial  cell, using its protein ActA (Figure 51-1). An actin “comet tail” is formed as actin regulatory proteins are recruited, and the process extends. The actin tail itself is fixed, and the bacteria are propelled by polymerization at the proximal end of the tail at speeds of ~ 0.1 µm/s. Many of the bacteria migrate to the periphery of the cytoplasm, pushing against the host cell outer membrane to form elongated protrusions. These protrusions are then ingested by adjacent cells; Listeria bacteria then secrete phospholipases and listeriolysin O that rupture the double membrane that separates them from this second cell's cytoplasm. This mechanism allows Listeria spp. to spread from cell to cell without directly contacting the extracellular environment. Several other pathogens induce actin polymerization as a means of movement within the host cell cytoplasm, including Shigella spp., Rickettsia spp., and vaccinia virus.

Clinical Findings (Box 51-1)

  1. Central Nervous System (CNS) Infection.Although most cases of listeriosis occur after ingestion of contaminated food, few patients complain of gastrointestinal symptoms or display gastrointestinal signs. The CNS is the site most commonly involved, where disease results in three different clinical presentations: meningitis, meningoencephalitis, and rhomboencephalitis. Meningitis is the most common manifestation of listeriosis in adults and children. L monocytogenes, after Escherichia coli and the group B streptococci, is the third most common cause of bacterial meningitis in adults and neonates, and it accounts for 5–15% of cases. The clinical manifestations of Listeria meningitis are similar to other forms of bacterial meningitis; however, the proportion of neutrophils among CSF leukocytes is often lower, and Gram stains of CSF are usually negative. In some cases, meningitis is accompanied by clinical signs of encephalitis. This organism, unlike other bacterial causes of meningitis, exhibits a tropism for brain parenchyma and, in particular, the brain stem, resulting in rhomboencephalitis. The latter is often preceded by 4–10 days of nonspecific flulike symptoms, followed by cranial nerve deficits, particularly of the sixth and seventh nerves. Brain stem involvement may lead to hemiparesis, ataxia, and even respiratory compromise. In most cases of meningoencephalitis, the CSF monocyte differential counts may reach 80–90%, but cases with no pleocytosis and normal CSF protein and glucose levels have been reported. Brain abscess is a rare manifestation of CNS listeriosis.
 

Figure 51-1. Intracellular life-cycle of Listeria monocytogenes. (Reproduced with permission from Southwick and Purich [1996].)

  1. Bacteremia.Bacteremia or non-CNS focal infection occurs in 5–30% of adult cases. The diagnosis is based on positive blood cultures. Listeriacauses focal infections in bone, native and prosthetic joints, eyes, spinal cord, pleura, peritoneum, and liver. Endocarditis, myocarditis, and mycotic aneurysms have also been described. Approximately one-third of women who contract Listeria infection are pregnant. Women in their third trimester are at greatest risk, but symptoms are usually mild, often mimicking a flulike illness. Blood cultures, if obtained, may be positive, but symptoms usually resolve spontaneously without therapy.
  2. Neonatal Infection.Neonatal Listeriainfection may present as an amnionitis, and infection is associated with premature labor. An uncommon clinical syndrome called granulomatosis infantiseptica has been described. This syndrome is caused by dissemination of L monocytogenes in utero. Abscesses and granulomata form within the fetal liver, lung, spleen, kidneys, brain, and skin. The mortality rate is high, ranging from 35% to 55%.

BOX 51-1 Listeriosis in Children and Adults

 

Children

Adults

More Common

· Neonatal disease Early onset: pneumonia, septicemia Late onset: meningitis

· Asymptomatic carriage

· Influenzalike illness

Less Common

· Granulomatosis infantisepticam

· Amnionitis

· Bacteremia and/ or meningitis in patients with decreased cell-mediated immunity

Diagnosis

L monocytogenes can be easily cultivated in the microbiology laboratory from blood, CSF, meconium, gastric washings, placenta, amniotic fluid, and other specimens. A CSF Gram stain with gram-positive or-variable rods should suggest Listeria infection, but this organism may be mistaken as a diphtheroid.

Treatment

There are no clinical trials comparing different antibiotic regimens for the treatment of listeriosis. Ampicillin or penicillin is generally recommended as the treatment of choice (Box 51-2). Gentamicin is added for severe infections, because the combination of ampicillin and an aminoglycoside is more effective than ampicillin alone in animal models. These agents should be given intravenously. The duration of therapy required to prevent relapse is not known; however, 10–14 days is recommended in patients without meningitis, 2–3 weeks is recommended for those with meningitis, and 3–6 weeks is recommended for immunosuppressed patients. Another effective agent is trimethoprim-sulfamethoxazole, because high intracellular levels are achieved, and it is bactericidal for Listeria species.

BOX 51-2 Treatment of Listeriosis

 

Children

Adults

First Choice

· Penicillin G, 300,000 U/kg/d in 6 divided doses

· Ampicillin, 200 mg/kg/d in 6 divided doses

Second Choice

· Trimethoprim, 20 mg/kg/d, plus sulfamethoxazole, 100 mg/kg/d in 4 divided doses

· Trimethoprim-sulfamethoxazole as per children

Penicillin Allergic

· Trimethoprim, 20 mg/kg/d, plus sulfamethoxazole, 100 mg/kg/d in 4 divided doses

· Trimethoprim-sulfamethoxa-zole as per children

Prognosis

Listeria infection of the CNS is associated with a high mortality rate. Of patients with meningoencephalitis, 36–51% die. Most of those who survive have persistent neurologic sequelae. Early recognition and rapid institution of antibiotics are critical for improving outcome.

Prevention

Patients at risk for listeriosis should be advised on how to minimize their exposure to this organism (Box 51-3). This advice should include cooking well all food from animal sources, washing raw vegetables thoroughly, and keeping uncooked meat separated from vegetables and cooked foods. Patients should also avoid consumption of unpasteurized milk, soft cheeses, or foods made with raw milk, and they should wash hands, knives, and cutting boards after handling uncooked food. An additional recommendation for high-risk persons is to heat all leftovers or ready-to-eat foods until these foods are steaming hot.

BOX 51-3 Control of Listeriosis

Prophylactic Measures

· Therapy of infection diagnosed during pregnancy may prevent vertical transmission

· Avoid contact between untreated manure from herds of cattle or sheep and foods for human consumption

· Pregnant women and immunosuppressed patients should avoid unpasteurized dairy products, soft cheeses, undercooked meats, and raw unwashed vegetables

Isolation Precautions

· Standard precautions, but cases should be reported to the regional health department for recognition and control of common source outbreaks

ANTHRAX

Essentials of Diagnosis

  • Contact with infected animals, carcasses, hair, wool, or hides from goats, sheep, cattle, swine, horses, buffalo, or deer.
  • Incubation period lasting 1–7 days, usually 2–5 days, after exposure.
  • Painless lesion progressing to papule, to vesicle, to necrosis, and to eschar.
  • Rapid development of chest pain, dyspnea, and circulatory collapse after brief flulike syndrome.
  • Direct gram-stained smear and/or cultures of lesions or discharges.
  • Widened mediastinum on chest radiograph in inhalational disease.

General Considerations

Anthrax is primarily a disease of herbivores, but humans acquire the disease through contact with infected animals or animal products.

  1. Epidemiology.Historically, anthrax has been an occupational disease of persons who handle animal hair, skin, and other contaminated products. The incidence of this disease in the United States has fallen dramatically; only six cases of anthrax were reported to the Centers for Disease Control and Prevention from 1978 through 1998. The cutaneous form of the disease is most common. Continued concern about this disease stems from the unfortunate development of anthrax spores as biological weapons by a number of nations.
  2. Microbiology.Bacillus anthracis, a sporulating gram-positive rod, is the causative agent of anthrax. B anthracisis distinguished from other Bacillus species in the laboratory based on its colony morphology and capsule.
  3. Pathogenesis.B anthracispersists in soil as a nonreplicating spore. These spores are highly resistant to temperature extremes, drying, UV light, high pH, high salinity levels, and routine methods of disinfection. The virulence of B anthracis is due to the presence of a polysaccharide capsule that prevents phagocytosis and to the production of 2 two-component exotoxins. Each of these toxins is of an A-B structure. They share the same B component, known as protective antigen, which binds each of these binary toxins to host cells and mediates internalization. Lethal toxin causes rapid cell death by the action of its A subunit, a zinc metalloprotease that cleaves a critical intracellular signaling molecule. Edema toxin contains an A subunit that acts as a calmodulin-dependent adenylate cyclase and catalyzes production of cyclic AMP within host cells. This toxin is believed to be responsible for the dramatic tissue edema that characterizes cutaneous anthrax. The genes encoding the three toxin components are located on one plasmid, and the genes encoding the capsule are on a second plasmid. Strains missing either of these plasmids are avirulent. Expression of these toxins takes place upon germination of spores within macrophages and vegetative growth of the bacilli, after they have been inoculated into an animal host. Subcutaneous inoculation occurs via abrasions or breaks in the skin, and it leads to cutaneous disease with occasional systemic dissemination. Inhaled spores are deposited in the alveoli, phagocytosed by macrophages, and taken to regional lymph nodes where bacterial growth and disease first become manifest. Gastrointestinal anthrax results from ingestion of grossly contaminated or undercooked meat, and it is extremely rare. Only the spore is infectious for humans; hence, human-to-human transmission of disease does not occur.

Clinical Findings

There are three forms of the disease in humans: cutaneous, inhalational, and gastrointestinal (Box 51-4).

  1. Cutaneous Anthrax.Cutaneous disease accounts for > 95% of all cases of anthrax. This disease begins as a small, painless, but often pruritic papule. As the papule enlarges, it becomes vesicular and, within 2 days, ulcerates to form a distinctive black (hence the name of the disease) eschar, with surrounding edema. Gram stain of the vesicular fluid may reveal gram-positive rods and rare polymorphonuclear leukocytes.
  2. Inhalational Anthrax.Inhalational anthrax is much less frequent and accounts for < 5% of cases; the incubation period is ~ 10 days, but it may be more prolonged in some cases. This form of the disease begins with an upper-respiratory flulike syndrome, and after a few days it takes a fulminant course, manifested by dyspnea, cough and chills, and a high-grade bacteremia. Inhalational anthrax is not a disease of the lung parenchyma, but is rather a hemorrhagic mediastinitis. Nearly all patients with this disease die within several days.
  3. Gastrointestinal Anthrax.Gastrointestinal disease is accompanied by mucosal ulceration, mesenteric adenitis, and ascites; it is reported in Africa and Asia but has not been described in the United States.

BOX 51-4 Anthrax Syndromes in Children and Adults

More Common

· Cutaneous disease accounts for 95% of cases

Less Common

· Spectrum of disease includes inhalational, gastrointestinal, and meningeal

Diagnosis

An appropriate epidemiologic history involving animal exposure is the cornerstone of the diagnosis of cutaneous anthrax. Other diagnostic features include edema out of proportion to the size of the skin lesion, the lack of pain during the initial phases of the infection, and the rarity of polymorphonuclear leukocytes on Gram stain. The organism can be readily cultivated and forms nonhemolytic gray-white colonies. A critical diagnostic feature of inhalational anthrax is a widened mediastinum on chest radiography. Patients with this disease usually die before organism growth in blood cultures is detected; however, organisms can sometimes be detected in blood with the Gram stain, owing to the high burden of bacteria in the endovascular compartment.

Treatment (Box 51-5)

Cutaneous anthrax responds well to penicillin G, which should be continued for 7–10 days. Doxycycline is also effective for cutaneous disease. Other antibiotics, such as ciprofloxacin and chloramphenicol, are alternative drugs for penicillin-allergic patients. The addition of streptomycin to penicillin may offer additional benefit. Penicillin resistance has been reported among some naturally occurring isolates; these strains have remained sensitive to ciprofloxacin. Despite the early use of antibiotics, cutaneous lesions continue to progress through the eschar phase. Surgery or excision of lesions is contraindicated. With appropriate antibiotic therapy, fatalities are rare (< 1%).

BOX 51-5 Treatment of Anthrax

 

Children

Adults

First Choice

· Penicillin G, 250,000–400,000 U/kg/d in 4–6 doses IV; consider addition of streptomycin

· Penicillin G, 16–24 million U/d IV divided every 4–6 h; consider addition of streptomycin

Second Choice

· Ciprofloxacin, 20–30 mg/kg/d IV in 2 doses
OR

· Doxycycline, 2–4 mg/kg/d IV in 2 doses
OR

· Chloramphenicol, 12–25 mg/kg/d IVin 4 doses

· Ciprofloxacin, 800 mg/d IVin 2 doses

· Doxycycline, 200 mg/d IV in 2 doses
OR

· Chloramphenicol, 50 mg/kg/d IV in 4 doses

Pediatric Considerations

· Doxycycline should not be given to children <8 y old, and ciprofloxacin should not be given to children in general, unless disease is life-threatening

 

Penicillin Allergic

· Doxycycline (dosage as above)

· Ciprofloxacin (dosage as above)

Despite the use of antibiotics as described above, inhalational anthrax is almost always fatal, once it becomes clinically manifest. If anthrax is suspected, public health authorities should be notified immediately.

Prevention

Doxycycline or ciprofloxacin (Box 51-6) may prevent development of inhalational disease if given to exposed individuals before onset of disease. Either of these antibiotics should be given for at least 6 weeks before or 2 weeks after the third dose of anthrax vaccine. The currently licensed anthrax vaccine contains protective antigen, and it has been shown to be effective in limited studies against inhalational disease in monkeys and cutaneous disease in humans.

OTHER BACILLUS SPECIES

General Considerations

Bacillus species other than B anthracis are found in soil, decaying organic matter, and water, but they are rare causes of disease. Risk factors associated with Bacillus infection include the presence of intravascular catheters, intravenous drug use, sickle cell disease, and immunosuppression—particularly corticosteroid use, transplantation, AIDS, and neutropenia secondary to chemotherapy. The hardy growth characteristics of Bacillus spp. cause them to arise as common laboratory contaminants; however, they are also capable of causing severe invasive illness.

B cereus and B subtilis are the most frequent Bacillus spp. to cause invasive infection. Pneumonia, meningoencephalitis, endocarditis (native and prosthetic valves), and intravascular catheter infection have been well described. High-grade bacteremia with B cereus can be seen in the presence of indwelling intravenous catheters and always necessitates the removal of the catheter along with appropriate antimicrobial therapy. B cereus also causes soft-tissue and bone infections, including necrotizing fasciitis, particularly after contamination of wounds by soil. The characteristics of diseases associated with Bacillus spp. are indistinguishable from those associated with other pyogenic bacteria, and diagnosis depends on culture data.

Clinical Findings

B cereus accounts for 1–3% of all foodborne disease reported in the United States, although 10–14% of humans are colonized by this organism in their intestinal tract. There are two clinical syndromes associated with ingestion of this organism, an emetic and a diarrheal syndrome. The emetic syndrome is characterized by a short incubation period (1–6 h). Patients present with vomiting and abdominal cramping.


The emetic syndrome is usually associated with ingestion of contaminated cooked rice and is caused by a preformed, heat-resistant 5- to 10-kDa emetic toxin. The diarrheal syndrome has a longer incubation period (6–14 h), and it is characterized by watery diarrhea, abdominal cramping, and, less commonly, by vomiting. The diarrheal syndrome is associated with ingestion of contaminated vegetables, sauces, and puddings, and it is attributed to at least two heat-labile enterotoxins produced by B cereus. The durations of illness are 2–10 h for the emetic syndrome and 16–48 h for the diarrheal syndrome. The symptoms in both syndromes are self-limited, and supportive care only is necessary. Outbreaks of foodborne illness caused by B subtilis, B licheniformis, and B pumilus have also been reported.

BOX 51-6 Control of Anthrax

Prophylactic Measures

· Doxycycline, 200 mg (2–4 mg/kg in children), OR ciprofloxacin, 1 g (20–30 mg/kg in children) orally per d in 2 divided doses may be used for exposed individuals (neither doxycycline nor ciprofloxacin should be given to children <8 y old or <18 y old, respectively, if the likelihood of exposure is high)

· Surveillance and control of industrial and agricultural sources of B anthracis

· Cell-free vaccine is available for those at risk but is not licensed for children or pregnant women

Isolation Precautions

· Standard precautions

· Contaminated dressings or bedclothes should be burned or steam-sterilized to destroy the spores

B cereus is also a major cause of ocular infections such as endophthalmitis after eye trauma, and it is often associated with intraocular foreign bodies. The onset of infection is rapid, leading to destruction of the vitreous and retinal tissue with subsequent loss of vision within 12–48 h. Panophthalmitis and endophthalmitis with B cereus have also been described in injection drug abusers, without ocular trauma.

Treatment

B cereus is resistant to penicillin and other beta-lactam drugs, including cephalosporins. Active antimicrobial agents include vancomycin, clindamycin, aminoglycosides, carbapenems, and ciprofloxacin. Non-B cereus spp. are susceptible to penicillin and cephalosporins. Appropriate empiric therapy for suspected Bacillus spp. infections (other than anthrax) is vancomycin or clindamycin, with or without an aminoglycoside. Intraocular infections require aggressive therapy with systemic antibiotics plus intravitreous clindamycin or an aminoglycoside. Intravitreous dexamethasone and early vitrectomy are also recommended for sight-threatening B cereus ocular infection.

DIPHTHERIA

Essentials of Diagnosis

  • Mildly painful tonsillitis/pharyngitis with associated membrane, cervical adenopathy, and signs of systemic toxicity; “bull neck” appearance.
  • Hoarseness and stridor.
  • Palatal paralysis.

General Considerations

  1. Epidemiology.Humans are the only known natural hosts for C diphtheriae, the organism that causes diphtheria. This organism is usually spread via upper respiratory tract droplets, but it can also be spread by direct contact with skin lesions. Transmission appears to be more common when people are living indoors in crowded conditions. Disease is transmitted by those incubating the disease, those convalescing from infection, and also healthy carriers. The organism itself can survive for < 6 months in dust, which may also serve as the vehicle for transmission. Immunization against diphtheria toxin prevents the serious complications of disease, by blocking the ability of the toxin to enter cells and also by reducing colonization of the nasopharynx by toxin-producing strains. Diphtheria is a rare disease in the United States; however, this disease can easily spread in populations that lack adequate levels of antitoxin immunity, as dramatically demonstrated in the former Soviet Union in the early 1990s.
  2. Microbiology.C diphtheriaeis a gram-positive rod with club-shaped swellings at each end. Most strains produce an exotoxin, diphtheria toxin, which is encoded by a gene carried by a lysogenic bacteriophage and is responsible for the disease.
  3. Pathogenesis.C diphtheriaeattaches to the mucosal surfaces of the nasopharynx. There it remains in the superficial layers of the mucosa. When iron concentrations are low, lysogenic diphtheria bacilli produce high concentrations of diphtheria toxin. The conversion of nontoxigenic, nonlysogenic C diphtheriae to toxin-producing strains can occur within the nasopharynx after bacterial infection with the beta-corynephage. Diphtheria toxin is composed of A and B fragments. The B fragment is recognized by a specific host cell membrane receptor resulting in endocytosis of the entire molecule. Once the toxin is inside the endosome, acidification results in a conformational change of the B fragment. A membrane channel is formed, allowing passage of fragment A into the host cell cytoplasm. Fragment A blocks protein synthesis by cleaving NAD and covalently attaching ADP-ribose to the essential host protein, elongation factor-2. ADP-ribosylation interferes with the ability of elongation factor-2 to add amino acids to a peptide chain, blocking protein synthesis. Its effects are seen throughout the body but are most prominent in the heart and kidney and on nerves. Local cytotoxic effects lead to production of the characteristic “pseudomembrane.” Anti-toxin antibody can neutralize toxin adsorbed to cells, but, once the toxin penetrates, its toxic affects are irreversible.

Clinical Findings (Box 51-7)

  1. Respiratory Diphtheria.The incubation period for respiratory diphtheria is generally 2–4 days, but it can last < 7 days. Initial symptoms include a low-grade fever. Sore throat and malaise are the most common manifestations of pharyngeal diphtheria. Unvaccinated patients tend to have more severe disease. The development of cell necrosis, secondary to the exotoxin, is commensurate with the presence of the characteristic membrane (Figure 51-2A). Initially the membrane is white and smooth, but later it becomes gray with patches of green and black necrosis. As the membrane spreads, it can interfere with airflow. Involvement of the posterior pharynx is often accompanied by cervical adenopathy and swelling, giving rise to a “bull neck” appearance (Figure 51-2B). With extensive disease there is increased release of exotoxin, resulting in myocardial and neurologic complications, thereby increasing the mortality associated with this disease.
  2. Cutaneous Diphtheria.Cutaneous diphtheria usually begins with pustules that progress to ulcer formation with a gray-brown membrane at the base. Commonly, C diphtheriaewill superinfect existing skin lesions such as insect bites, ecthyma, and impetigo. Cutaneous infections induce high levels of antitoxin antibody that prevent progression to systemic disease; therefore, the infections tend to be indolent and are not usually associated with signs of intoxication. Cutaneous infection poses a greater risk of environmental contamination and transmission to others than does pharyngeal infection.
  3. Cardiac Disease.Myocarditis with clinically-significant cardiac dysfunction is observed in 10–20% of patients with pharyngeal disease. The likelihood and severity of myocarditis are correlated with the extent and severity of respiratory tract compromise. ST segment and T-wave changes and first-degree block are found by electrocardiography in less severe disease, whereas left bundle branch block and atrioventricular block are associated with high mortality. In severe cases, patients usually sustain permanent injury to the myocardium.
  4. Neurologic Disease.Neurologic complications occur in ~ 10% of respiratory cases and are predicted by the severity of respiratory tract involvement. Symptoms and signs develop 10–28 days after the respiratory complaints and reflect both cranial nerve involvement and a peripheral neuropathy that can lead to complete paralysis. These complications are usually reversible.

BOX 51-7 Diphtheria Syndromes in Children and Adults

More Common

· Membranous nasopharyngitis

· Obstructive laryngotracheitis

· Abrupt onset low-grade fever, malaise

Less Common

· Cutanous

· Vaginal

· Conjunctival

· Otic

· Complications including cardiac and neurologic toxicity

Diagnosis

Prompt recognition and treatment of respiratory diphtheria are critical for preventing complications and mortality. A dark pharyngeal membrane that cannot be removed without bleeding, systemic toxicity, neurologic abnormalities such as 9th and 10th cranial nerve deficits, and/or electrocardiograph changes should alert the clinician to the possibility of diphtheria. The microbiology laboratory should be notified about the possibility of diphtheria, because special media, such as Loeffler's or tellurite selective media, must be used to prevent overgrowth of normal flora.

Treatment

All patients should be hospitalized and isolated. Rapid institution of antitoxin is critical because it is most effective if given within 4 days of the onset of illness (Box 51-8). Hyperimmune antiserum produced in horses has been used for > 100 years. The dose of antitoxin is adjusted to the severity of disease. Sensitivity of the patient to horse protein must be assessed (see recommendations in Box 51-8). An initial scratch test may be performed on the volar forearm with a 1:100 dilution. If negative, this should be followed by an intracutaneous injection of 0.02 mL of a 1:1000 dilution of antitoxin in saline. No additional benefit is provided by repeated doses. Antibiotics should be initiated as soon as possible to kill organisms, stop toxin production, and eliminate the carrier state. Erythromycin for 2 weeks is the treatment of choice and should be given intravenously until the patient is able to handle oral medications. Procaine penicillin for 2 weeks is an alternative. Other measures include airway and cardiac support. If diphtheria is suspected, the patient should be isolated until two cultures from the affected site are negative. Cultures should be taken from all persons who have been in close contact with a diphtheria patient, to determine whether they are pharyngeal carriers. All carriers need to be treated with erythromycin or penicillin for 14 days.

 

Figure 51-2. Nasopharyngeal diphtheria. A. Characteristic membrane and cell necrosis. B. Cervical adenopathy and swelling (“bull neck” appearance). (Reproduced with permission from Margileth AM: In Mandell G and Brook I: Cervical Lymphadenopathy. Atlas of Infectious Diseases, Vol IV. Upper Respiratory and Head and Neck Infections. Churchill Livingstone, 1995.)

BOX 51-8 Treatment of Diphtheria

 

Children

Adults

First Choice

· Antitoxin (available from CDC [phone (404) 639-8200])
Pharyngeal/laryngeal disease (<48 h), 20,000–40,000 U IV
Nasopharynx disease, 40,000–60,000 U IV
Extensive disease or >3 d, 80,000–120,000 U IV PLUS
Erythromycin, 40–50 mg/kg/d (max, 2 g/d)

· As for children (erythromycin, 2 g/d in 4 doses)

Second Choice

· Penicillin G, 100,000–150,000 U/kg/d divided every 6 h (max 1.2 million U)
OR

· Penicillin aqueous procaine, 25,000–50,000 U/kg/d divided every 12 h (max 1.2 million U)

· As for children (penicillin G, 12 million–20 million U/d divided every 4–6 h)

Penicillin Allergic

· Erythromycin

· Erythromycin

BOX 51-9 Control of Diphtheria

Prophylactic Measures

· Notify public health officials

· Close contact tracing

· Observe close contacts for 7 d

· Culture close contacts

· Antimicrobial prophylaxis for close contacts:
   Oral erythromycin, 40–50 mg/kg/d (children); 2 g/d (adults) × 7 d
   Single IM dose benzathine penicillin G, 600,000 U for those <30 kg or 1.2 million U for those>30 kg

· Immunization with toxoid vaccine
   Primary series
      Children 6 wk–7 y, DTaP (3 IM injections at 4- to 8-wk intervals, then a 4th IM dose 6–12 mo after 3rd dose)
      Children >7 y and adults, dT (2 IM injections at 4- to 8-wk intervals, then a 3rd IM dose 6–12 mo after 2nd dose)
   Booster
      Children receiving primary series <4 wk, DTaP at school entry, then every 10 y
      Children/adults, dT every 10 y

Isolation Precautions

· Droplet precaution isolation until 2 negative nasopharyngeal cultures

 

Prevention

Children 6 weeks to 7 years of age should be immunized with three injections of vaccine containing formalin-inactivated diphtheria toxin (Box 51-9). Susceptibility to diphtheria correlates inversely with serum levels of anti-toxin antibody. Because these levels wane, adults should receive booster vaccinations every 10 years.

CORYNEBACTERIUM JEIKEIUM

Infection with Corynebacterium jeikeium, formerly known as Corynebacterium CDC group JK, almost invariably occurs in a hospital setting, because these bacteria commonly colonize the skin of hospitalized patients. Patients at highest risk for colonization include those receiving broad-spectrum antibiotics and those with neutropenia. The most common form of disease is bacteremia and is most often seen in neutropenic patients after breaks in the integument of their skin, such as with intravascular catheters. Endocarditis with this organism has been described, but it is rare, as are extravascular infections such as pneumonia, peritonitis, and prosthetic knee infections. The treatment of choice is vancomycin (1 g every 12 h); the length of therapy is dictated by the disease process. Prosthetic valve endocarditis with C jeikeium often requires removal of the valve for control of the infection.

OTHER CORYNEBACTERIUM SPECIES

Corynebacterium species colonize the skin and are therefore frequently recovered as contaminants in blood cultures; however, serious infections can occur. In particular, immunocompromised hosts and those with indwelling vascular catheters have an increased risk of infection with these organisms. C ulcerans, C pseudotuberculosis, C bovis, C striatum, and C pseudodiphtheriticum rarely cause human disease, but severe upper respiratory tract, cardiac, and CNS diseases have been reported. Rhodococcus equi (previously C equi) has recently been reported to cause pneumonia and cavitary pulmonary disease in patients with AIDS and renal transplantation. The treatment of choice for this organism is erythromycin or imipenem-cilastatin, plus rifampin.

ERYSIPELOTHRIX RHUSIOPATHIAE

General Considerations

Erysipelothrix rhusiopathiae is a gram-positive bacillus that causes occupationally related skin infections and, rarely, septicemia in humans.

  1. Epidemiology.E rhusiopathiaeis ubiquitous in nature and is an uncommon cause of human disease. It can infect mammals, birds, fish, shellfish, and insects, and it may reside in swine, which serve as a reservoir. Disease in humans is most commonly seen in persons with an appropriate exposure, usually including butchers, slaughterhouse workers, and especially fish handlers. Most cases of skin infection (“erysipeloid”) occur in the summer and early fall. The organism is often traumatically inoculated and intense inflammation of the dermis follows.
  2. Microbiology and Pathogenesis.The organism is non-spore forming and nonmotile and is a facultative anaerobe. The organism may appear as a beaded gram-positive rod owing to partial decolorization during the staining process. It grows well on sheep blood agar and exhibits alpha hemolysis. The organism tolerates a high-salt environment and can survive in saltwater. E rhusiopathiaeis catalase negative, oxidase negative, and weakly fermentative.

Clinical Findings

Skin lesions are usually purplish-red with a sharply defined, raised, serpiginous border; they most commonly involve the proximal region of the hands and fingers. Lesions spread slowly, and, over time, the central portion heals leaving a pale center with a surrounding purplish-red border. Proximal lymphadenopathy and systemic symptoms are rare. Acute or subacute endocarditis secondary to E rhusiopathiae is uncommon, but is severe when it occurs. The aortic valve is most commonly involved, and 40% of patients will have or just had the characteristic skin lesion of erysipeloid.

Diagnosis

The diagnosis requires an appropriate epidemiologic history. The skin lesion may resemble erysipelas caused by Streptococcus pyogenes, but the rate of progression is slower, and there is a lack of lymphangitis, lymphadenopathy, and systemic symptoms. Full-thickness skin biopsy with appropriate culture will yield the organism in the majority of cases. Blood cultures should also be obtained.

Treatment

Treatment of choice for E rhusiopathiae infection is penicillin. Erysipeloid is usually self-limited and resolves over the course of 3 weeks, but therapy will hasten the resolution of symptoms. Endocarditis should be treated with intravenous penicillin at 12–20 million U/day, in 4–6 divided doses for 4–6 weeks. It is noteworthy that E rhusiopathiae is resistant to vancomycin. Despite appropriate therapy, the mortality rate for patients with E rhusiopathiae endocarditis is 30–40%.

REFERENCES

Bisgard KM, et al: Respiratory diphtheria in the United States, 1980 through 1995. Am J Publ Health 1998;88: 787.

Cossart P, Lecuit M: Interactions of Listeria monocytogenes with mammalian cells during entry and actin-based movement: bacterial factors, cellular ligands and signaling. EMBO J 1998;17:3797.

Dixon TC et al: Anthrax. N Engl J Med 1999;341:815.

Dobie RA, Tobey DN: Clinical features of diphtheria in the respiratory tract. JAMA 1979;242:2197.

Mead PS et al: Food-related illness and death in the United States. Emerg Infect Dis 1999;5:607.

Portnoy DA et al: Molecular determinants of Listeria monocytogenes pathogenesis. Infect Immun 1992;60:1263.

Shafazand S et al: Inhalational anthrax: epidemiology, diagnosis, and management. Chest 1999;116:1369.

Southwick FS, Purich DL: Intracellular pathogenesis of listeriosis. N Engl J Med 1996;334:770.