Prevention
Active immunization using formalin-detoxified diphtheria toxin effectively prevents diphtheria. Preschool children (6 weeks to 7 years of age) should be immunized with three 0.5 ml intramuscular injections of diphtheria-tetanus-acellular pertussis (DTaP) vaccine spaced 4 to 8 weeks apart. A fourth dose should be given 6 to 12 months later. Immunity to the toxin is not lifelong, and if primary immunization was completed before 4 years of age, a booster is recommended at the time of school entry. Subsequently, booster injections need to be given every 10 years to maintain protective immunity. A single dose of vaccine is sufficient for most age groups, with the exception of persons 30 to 49 years of age, who may require three doses to generate protective antibody titers.16 Surveys indicate that high percentages of adults in the
United States and Europe fail to demonstrate a significant immune response to diphtheria toxoid. It has been estimated that epidemic diphtheria is favored when more than 70% of the population lacks protective immunity, a condition now present in many developed countries. A toxoid booster inoculation every 10 years is strongly recommended for all adults.
Nondiphtheria Corynebacterium and Rhodococcus
In addition to the species diphtheriae, the genus Corynebacteri-um contains a large number of species that for decades were considered to be culture contaminants and constituents of the normal human flora. These organisms were previously termed diphtheroids. As the number of immunocompromised hosts and persons with prosthetic devices has increased, the role of nondiphtheria corynebacteria as true pathogens has become evident17 [see Table 2]. C. urealyticum and C. jeikeium are two non-diphtheria strains that are particularly important nosocomial pathogens.
C. Urealyticum
C. urealyticum is a slow-growing, urease-positive organism that is widely distributed on the skin of hospitalized patients. C.urealyticum is one cause of alkaline-encrusted cystitis, a urinary tract infection that is severe and difficult to treat.18 The urea-splitting activity of the organism leads to alkaline urine and the formation of struvite stones. Factors that predispose an individual to this infection include previous urinary tract infections, urolog-ic instrumentation, immunosuppression, underlying inflammation of the bladder, and bladder neoplasia. Less commonly, C. urealyticum can cause septicemia, endocarditis, osteomyelitis, and pneumonia. This organism is often resistant to most antibiotics; therefore, vancomycin is recommended for initial treatment pending sensitivity testing [see Table 1 ].
Table 1 Antibiotic Treatment of Infections Caused by Gram-Positive Bacilli
|
Pathogen (Disease) |
Drug |
Dosage |
Comment |
|
Bacillus anthracis (anthrax) |
Ciprofloxacin or doxycycline + one or two additional antibiotics: rifampin vancomycin penicillin G ampicillin chloramphenicol imipenem clindamycin clarithromycin |
400 mg I.V. q. 12 hr followed by 500 mg p.o., b.i.d. x 60 days 100 mg I.V. q. 12 hr followed by 100 mg p.o., b.i.d. x 60 days 600 mg p.o., q.d. 1 g I.V. q. 12 hr 20 million U/day I.V. divided q. 4-6 hr 2 g I.V. q. 4 hr 1 g I.V. q. 6 hr 500-1,000 mg I.V. q. 6 hr 600 mg I.V. q. 8 hr 500 mg p.o., b.i.d. |
Prolonged treatment necessary because spores may persist and later germinate; no one combination regimen preferred; some experts favor the addition of clindamycin, which theoretically may block toxin production; chloramphenicol associated with granulocytopenia |
|
Vancomycin |
1 g I.V. q. 12 hr |
First-line therapy; duration depends on the type of infection |
|
|
B. cereus |
Imipenem |
500-1,000 mg I.V. q. 6 hr |
Alternative |
|
Clindamycin |
600 mg I.V. q. 8 hr |
Alternative |
|
|
Ciprofloxacin |
400 mg I.V. q. 12 hr |
Alternative |
|
|
Vancomycin ± gentamicin |
1 g I.V. q. 12 hr 5 mg/kg/day I.V. or divided q. 8 hr |
First-line therapy; duration depends on the type of infection |
|
|
Other Bacillus species |
Clindamycin ± gentamicin |
600 mg I.V. q. 8 hr 5 mg/kg/day I.V. or divided q. 8 hr |
Alternative |
|
Imipenem |
500-1,000 mg I.V. q. 6 hr |
Alternative |
|
|
Erysipelothrix (erysipeloid) |
Penicillin G |
Benzathine form; single 600,000 U I.M. dose |
First-line therapy |
|
Erythromycin |
250-500 mg p.o., q.i.d. x 10 days |
Alternative |
|
|
Erysipelothrix (endocarditis) |
Penicillin G |
20 million U/day I.V. divided q. 4-6 hr x 4-6 wk |
First-line therapy; recommended for endocarditis |
|
Ceftriaxone |
1 g I.V. q.d. x 4-6 wk |
For penicillin-allergic patient |
|
|
Cefazolin |
1.5-2 g I.V. q. 8 hr x 4-6 wk |
For penicillin-allergic patient |
C. JEIKEIUM
C. jeikeium frequently colonizes the skin of hospitalized patients. Patients at highest risk for colonization and subsequent infection with C. jeikeium include those receiving broad-spectrum antibiotics and those requiring prolonged hospitalization. In patients with neoplastic disease, other risk factors include prolonged neutropenia and breaks in the integument.19 In most patients, infection presents as bacteremia. The incidence is highest in neutropenic patients and those who have undergone cardiac surgery.17 Bacteremia is most often associated with colonization of an intravenous catheter.20 Prosthetic endocarditis and native valve endocarditis have been reported, as have rare cases of extravascular infections, including cutaneous lesions, pneumonia, peritonitis, prosthetic knee infection, and ventricu-lostomy infection. Most isolates of this organism tend to be multiply resistant and frequently are sensitive only to van-comycin21 [see Table 1]. Contaminated catheter lines can often be sterilized with antibiotics alone.20 In patients with prosthetic valve infection, however, the foreign material often has to be removed to control the infection.
Rhodococcus Equi
Rhodococcus equi, also known as Corynebacterium equi, primarily infects immunocompromised hosts with defects in cell-mediated immunity, particularly patients with AIDS22 and those with solid-organ transplants.23 Cases in normal hosts have also been reported.24,25 R. equi is found in the soil and at particularly high concentrations in horse manure. Infection is generally acquired through the lungs.
The primary manifestation in most cases is cavitary lung disease resembling tuberculosis, nocardiosis, or fungal infection. Lung consolidation without cavitation is also seen. Bronchoscopy,thoracentesis, or surgery may be required to make the diagnosis, although blood cultures are frequently positive.24 R. equi organisms may be mistaken for contaminating diphtheroids, or because they are modified acid-fast positive, the infection may be misdiagnosed as tuberculosis. Extrapulmonary infections may also occur.
Table 2 Clinical Syndromes Caused by Nondiphtheria Corynebacterium Species
|
Species |
Clinical Syndrome |
|
C. ulcerans |
Pharyngitis, skin ulcer, diphtheria |
|
C. pseudotuberculosis (C. ovis) |
Suppurative lymphadenitis |
|
C. (Arcanobacterium) haemolyticum |
Pharyngitis, scarlatiniform rash |
|
C. pseudodiphtheriticum (C. hofmannii) |
Endocarditis, pneumonia, tracheo-bronchitis, lymphadenitis |
|
C. urealyticum (formerly group D2) |
Alkaline-encrusted cystitis, urinary tract infections |
|
C. jeikeium (group JK) |
Nosocomial septicemia, wound infection, endocarditis |
|
Rhodococcus equi (C. equi) |
Necrotizing pneumonia in patients with AIDS |
Macrolides and rifampin act synergistically in combination, and regimens containing these two agents are often recommended. These antibiotics achieve high intracellular levels, an important characteristic for clearing R. equi, because this pathogen primarily multiplies in cells. The organism is also sensitive to van-comyin and aminoglycosides, and vancomycin is often included in the initial regimen [see Table 1]. Cephalosporins should be avoided because of the frequent development of resistance, and multidrug resistance is becoming more common.26 Short courses of therapy are associated with relapse; therefore, therapy needs to be continued for many weeks. Mortality in AIDS patients is approximately 15%; however, half of the survivors are never completely cured of R. equi infection.22
Listeriosis
Listeria monocytogenes, a food-borne pathogen, is the cause of listeriosis, a serious and often fatal infection.
Microbiology
L. monocytogenes is an aerobic and facultatively anaerobic, non-spore-forming, gram-positive rod. As opposed to coryne-bacteria, this organism is motile, possessing one to five flagella. Listeria organisms grow at a wide range of temperatures (3° to 42° C), which explains its ability to contaminate refrigerated foods. This bacterium can also grow at acidic concentrations of a pH of 5 or higher and salt concentrations of as high as 10% to 12%. Listeria organisms can be readily cultured on blood agar plates, where they cause slight zones of P-hemolysis. Listeria organisms on occasion can appear somewhat coccoid and, therefore, may be mistaken for diphtheroids or Streptococcus pneumo-niae on Gram stains of cerebrospinal fluid. There are at least 11 serotypes of L. monocytogenes. Serotypes 1b and 4b are most commonly associated with listeriosis.
Etiology and epidemiology
L. monocytogenes is found in soil, dust fertilizer, sewage, stream water, plants, processed foods, and the intestinal tract of many mammals. Investigations of multiple outbreaks indicate that both sporadic and common-source outbreaks of listeriosis are the result of food contamination. Outbreaks have been linked to raw vegetables, Mexican-style cheese, milk, undercooked chicken, and foods purchased in delicatessens.27 Prepared refrigerated foods stored for prolonged periods and requiring no further high-temperature heating are most likely to be contaminated because Listeria organisms can readily multiply on refrigerated foods.
The overall incidence of listeriosis is low: 0.7 cases per 100,000 population. This infection more often occurs in persons older than 70 years (2.1 cases per 100,000); pregnant women (12 cases per 100,000); patients with defects in cell-mediated immunity, including renal transplant recipients; patients receiving high doses of corticosteroids; and patients with AIDS (100 cases per 100,000).28 At a large referral hospital, Listeria organisms were the third most common cause of community-acquired bacterial meningitis in adults (12% of cases).29 Despite its relatively low incidence, listeriosis concerns public health officials because this disease is associated with a high fatality rate (23%), unlike infections from other food-borne pathogens, such as Salmonella organisms, which are rarely fatal. Given the increasing numbers of elderly and immunocompromised patients, the incidence of lis-teriosis is likely to increase.
Pathogenesis
L. monocytogenes has an unusual life cycle30 [see Figure 3a]. Several proteins (internalins31) on the surface of the bacterium allow attachment and subsequent ingestion of Listeria organisms by host cells. Once internalized, the bacterium is surrounded by host cell membrane, forming a phagolysosome, a closed space that is generally toxic for pathogens. Listeria organisms evade destruction by producing the exotoxin listeriolysin O, which lyses the confining membranes. All pathogenic strains of Listeria organisms produce listeriolysin O, and their escape into cytoplasm of the host cell is required for pathogenesis. Once in the growth-permissive cytoplasm, the bacteria proliferate, with doubling times of about 1 hour. The Listeria surface protein ActA possesses binding sequences to attract actin regulatory proteins that stimulate actin filament assembly.30,32 About 2 hours after entry into the cytoplasm, actin filaments polarize at one end of the bacteria and provide the force for movement through the cytoplasm [see Figure 3b]. Many of the bacteria migrate to the periphery of the cytoplasm, where they push against the host cell’s outer membrane to form elongated protrusions or filopods that can be ingested by adjacent cells. Once a bacterium enters the adjacent cell, the life cycle begins anew. Listeria organisms, therefore, can spread from cell to cell without directly contacting the extracellular environment. A number of other virulence factors, in addition to ActA and internalins, have been identified, and their contributions to Listeria pathogenesis are being defined.
The Listeria organism’s intracellular lifestyle explains many of this pathogen’s unique clinical characteristics.30 Although the association between contaminated foods and the Listeria organism has been well documented, evidence of gastrointestinal disease has been absent in most cases. The Listeria organism’s capacity to enter the gastrointestinal tract without causing erosive lesions is explained by the ability of this pathogen to stimulate phagocytosis by gastrointestinal cells and macrophages. Subsequently, the Listeria pathogen commandeers host cell actin regulatory proteins to spread from cell to cell and eventually enter the bloodstream either in monocytes or as free organisms after cell lysis.
Figure 3 (a) Life cycle of Listeria monocytogenes in host cells. (b) New actin filament assembly drives the bacterium through the cytoplasm. The Listeria surface protein ActA induces host cell actin to assemble into a rocket tail. The actin filament tail progressively lengthens, with new host cell actin monomers being added at the junction between the bacterium and the actin filament tail. The older regions of the actin tail attach to the host cell’s cytoskeleton, providing a purchase so that the forces of actin filament lengthening can be applied to the bacterium to drive it through the cytoplasm. Bacteria are able to move at rapid speeds (0.02 to 1.4 pm/sec).
The ability of the Listeria organism to avoid the extracellular environment also explains the increased incidence of listeriosis in immunocompromised patients, neonates, and pregnant women. Increased risk of listeriosis has not been associated with deficiencies of immunoglobulins or complement. However, clinical conditions and therapies (particularly corticosteroids) that lead to deficiencies in cell-mediated immunity, the primary defense for controlling intracellular pathogens, increase the risk for liste-riosis. For example, treatment with fludarabine and prednisone in patients with chronic lymphocytic leukemia markedly lowers the CD4+ T cell counts and increases the incidence of listeriosis.33 Patients with AIDS are most likely to contract Listeria infection when their CD4+ T cell counts fall below 40/mm3.34
Clinical Manifestations
Listeriosis varies in its clinical presentation; primary manifestations most often are sepsis, meningitis, or both. Other extravas-cular infections are also reported, but they are surprisingly rare.
Infection during pregnancy Nearly one third of individuals who contract listeriosis are pregnant women, with infection occurring most frequently in the third trimester. The symptoms tend to be relatively mild, consisting of a flulike illness with chills, fever, and muscle aches. Back pain, a less frequent complaint, suggests a urinary tract infection; however, urinalysis and urine culture results are normal. Blood cultures, although not always obtained, are positive. Symptoms usually resolve spontaneously without therapy.
Neonatal listeriosis The Listeria organism can cross the pla-cental barrier, probably as a result of cell-to-cell spread mediated by host cell actin. The organism may cause amnionitis and precipitate premature labor, leading to septic abortion. Transplacen-tal transmission can also cause the unique clinical syndrome of granulomatosis infantiseptica. The organism can disseminate in utero, forming abscesses and granulomas involving the fetal liver, spleen, lungs, kidneys, brain, and skin.36 Mortality is high, ranging from 35% to 55%.
Chorioamnionitis is the most common early manifestation of perinatal Listeria infection. A Gram stain of the meconium frequently reveals gram-positive bacilli, suggesting the diagnosis. In addition to causing congenital infection, the Listeria pathogen can cause meningitis in neonates 7 to 28 days of age. Listerial meningitis is the third most common form of meningitis in neonates, accounting for 5% to 15% of cases.
Adult meningitis and meningoencephalitis Meningitis is the most common manifestation of listeriosis. The Listeria pathogen has a predilection for the central nervous system, particularly the meninges. Although the clinical presentation of listerial meningitis is similar to that of other forms of bacterial meningitis (i.e., Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis), several characteristics distinguish Listeria infections. Meningeal signs develop less frequently in patients with listerial meningitis than in patients with other forms of bacterial meningitis.37 However, tremor and grand mal or focal motor seizures are observed with a higher frequency, suggesting more extensive invasion of the CNS.30 The CSF response may reflect the intracellular nature of Listeria organisms. Compared with the CSF cell counts in other forms of bacterial meningitis, both the total number of white blood cells and the percentage of neu-trophils tend to be reduced in patients with listerial meningitis. Because Listeria primarily grows in cells, it is less commonly found in Gram stains of CSF (positive in 5% to 33% of cultures versus 80% in other forms of bacterial meningitis).
Meningoencephalitis, a direct invasion of the cerebral cortex, can also result from Listeria infection, but it is not a recognized complication of other forms of bacterial meningitis. The ability of the Listeria pathogen to cross the meninges and blood-brain barrier is also likely to be the result of endothelial cell or macro-phage phagocytosis of the organisms and utilization of the host cell contractile system to migrate to and grow in the brain. Liste-ria organisms most commonly invade the brain stem, causing a syndrome that has been called rhomboencephalitis.39 The disease is usually biphasic; CNS manifestations are preceded by 7 to 10 days of malaise, fatigue, headache, nausea or vomiting, and fever. These symptoms are followed by the development of multiple cranial nerve deficits, particularly of the sixth and seventh nerves. Brain stem damage can also cause hemiparesis, ataxia, and respiratory dysfunction, often followed by respiratory arrest. In cases of meningoencephalitis, CSF monocyte counts may reach 80% to 90%. In some cases, the CSF may contain no cells or only a few cells and have normal protein and glucose levels. Magnetic resonance imaging reveals areas of increased resonance and is the best way to visualize the brain stem. Computed tomography with contrast generally shows areas of increased uptake with or without ring enhancement.
The diagnosis of both listerial meningitis and meningoen-cephalitis frequently is delayed. A monocytic response in the CSF and a negative CSF Gram stain can lead the clinician to confuse listerial meningitis and meningoencephalitis with herpes and other forms of viral encephalitis, viral meningitis, tuberculous meningitis, Lyme disease, syphilis, cryptococcal meningitis, Wegener granulomatosis, or CNS sarcoidosis. Particularly in the immunocompromised host, the possibility of Listeria infection must always be considered as a possible cause of CNS infection.
Bacteremia Bacteremia without meningitis or focal infections occurs in 5% to 30% of adult cases. There are no distinctive clinical features except for peripheral monocytosis, which is present in a small percentage of patients. Diagnosis is based on blood culture findings.
Miscellaneous infections Like many other pathogens that are able to enter the bloodstream, the Listeria organism can cause focal infections at many extravascular sites, including bones, normal and prosthetic joints, eyes,40 spinal cord, pleura, peritoneum, and liver.41 Isolated brain abscesses have also been re-ported.37 In rare cases, the Listeria organism causes endocarditis, myocarditis, and mycotic aneurysms. Although Listeria enters via the gastrointestinal tract, symptomatic gastroenteritis is uncommon. However an outbreak of febrile gastroenteritis associated with contaminated delicatessen precooked turkey was reported in Los Angeles.
