Clostridium difficile is a spore-forming, obligate anaerobic, gram-positive bacillus that is spread via the fecal-oral route. The most common manifestations of C difficile–associated disease (CDAD) are mediated by toxins A and B produced by the organism.
PATHOGENESIS AND EPIDEMIOLOGY
Treatment with antibiotics and chemotherapeutic agents (eg, fluorouracil, methotrexate) that alter the natural gastrointestinal flora favor the emergence of C difficile. Risk factors for developing CDAD include recent gastrointestinal surgery, prolonged stays in healthcare facilities, immunocompromised patients, proton pump inhibitor therapy, repeated enemas, prolonged use of nasogastric tubes (or other gastrointestinal feeding devices), inflammatory bowel disease, cystic fibrosis, Hirschsprung disease, and a history of cancer. Breastfeeding, on the other hand, may offer some protective benefits. Studies report that 3% to 7% of children with C difficile develop a complication, such as hypotension, ileus, or toxic megacolon.
CDAD results directly from toxin-mediated effects to the large intestine. The exact incubation period is unknown, but symptoms are known to develop up to 10 weeks after discontinuation of antibiotics. Infants and children are more likely than adults to carry C difficile asymptomatically in the gastrointestinal tract; it is estimated that 15% to 63% of neonates, up to 33% of infants and toddlers younger than 2 years of age, and up to 8.3% of children older than 2 years of age are asymptomatic carriers. It is postulated that infants do not manifest illness because they lack the necessary toxin-binding sites in their colon. In children who have diarrhea not caused by C difficile, many may still carry C difficile. Over the past decade, more severe, sometimes fatal infections have been seen with outbreaks of C difficile infection caused by a virulent strain (NAP-1/027) that appears to have increased production of toxins A and B, as well as binary toxin, and fluoroquinolone resistance.
In 2011, the estimated incidence of C difficile infection in the United States in children < 18 years old was 24.2 cases per 100,000 population, with approximately two-thirds of cases being community-associated. With the rate of C difficile colonization or infection in hospitalized patients being 13 per 1000, CDAD is now the most common cause of healthcare-associated infection, with an estimated 453,000 incidents of CDAD, including 29,300 deaths, in the United States, resulting in an estimated cost of $5 billion in 2011.
Colonization is defined as a patient who exhibits no clinical symptoms but tests positive for the C difficile organism and/or its toxin. Colonization is more common than symptomatic CDAD.
The presentation of CDAD can range from mild diarrhea to life-threatening disease. Initial signs and symptoms of CDAD include watery diarrhea, fever, loss of appetite, nausea, and abdominal tenderness. Progressive signs and symptoms include bloody diarrhea, cramping, and flatulence. If pseudomembranous colitis is suspected, it requires a colonoscopy to confirm the diagnosis. More severe complications include toxic megacolon, perforation, and bacteremia with distant metastatic infection. Therefore, a high index of suspicion is critical, as is awareness of the limitations of current diagnostic tests.
Asymptomatic colonization occurs frequently in neonates and young infants, and therefore, current guidelines recommend not testing children under 1 year of age.
Stool cultures that are positive for C difficile are not diagnostic. The diagnosis of C difficile colitis should only be made if toxin is found in the stool. Commercially available enzyme immunoassays (EIAs) can detect both toxins A and B. Approximately 5% to 20% of patients, however, may require more than 1 stool sample be sent to detect toxin. Molecular assays using nucleic acid amplification tests (NAATs) are approved by the US Food and Drug Administration (FDA) and are now the preferred test. NAATs combine good sensitivity and specificity, have turnaround times comparable to EIAs, and are not required to be part of a 2- or 3-step algorithm. In a recent study, the sensitivity of the real-time polymerase chain reaction (PCR) assay for toxin A/B was superior compared with EIA for toxin A/B (95% vs 35%, respectively), and the specificities were equal (100%).
The presence of symptoms compatible with CDAD and identification of the toxin in a patient over 1 year of age are considered diagnostic for CDAD. When symptoms are severe and CDAD is a consideration, endoscopic evaluation is indicated even in the absence of toxin identified by assays. There are typical findings of pseudomembranous colitis on colonoscopy, characterized by the presence of an adherent inflammatory “pseudomembrane” overlying the mucosa (Fig. 245-1).
Colonoscopic image of pseudomembranous colitis in a patient with the acute onset of bloody diarrhea due to Clostridium difficile. Note the pseudomembranes adherent to the mucosal surface. (Used with permission from Colin Rudolph.)
Potentially offending antimicrobial or chemotherapeutic agents should be discontinued if possible in an attempt to restore balance to the gut flora. Supportive care addressing hydration, nutrition, and electrolyte abnormalities should be provided. In approximately 20% of immunocompetent patients, CDAD will resolve within 2 to 3 days after discontinuing the offending agent with no additional treatment necessary. Immediate initiation of antimicrobial therapy for CDAD is indicated for patients with immunodeficiency, Hirschsprung disease, inflammatory bowel disease, or severe disease, or in patients whose diarrhea persists beyond 3 days after the offending agent is discontinued.
C difficile is susceptible to metronidazole and vancomycin, and both are effective for the treatment of mild CDAD. Metronidazole is the more cost-effective choice for the initial treatment of patients with CDAD. The recommended dose is 30 to 50 mg/kg/d (maximum 2 g/d) orally divided in 4 doses, and the length of therapy should be at least 10 days. Up to 40% of patients experience a relapse after discontinuing such therapy, but the infection usually responds to a second course of the same treatment. Up to 10% have a second relapse, and oral vancomycin is recommended in this case. Vancomycin is also recommended as initial therapy for CDAD with hypoalbuminemia (< 2.5 g/dL), severe manifestations, and infection suspected or proven to be due to NAP-1/027. The dose is 40 mg/kg/d (maximum 2 g/d) orally divided in 4 doses. Alternative treatments include rifaximin and nitazoxanide. Fidaxomicin is a macrolide drug that is approved for individuals with CDAD who are at least 18 years of age; however, there is limited experience in children.
On the basis that restoration of the normal fecal microbiota may be valuable for resolving infections refractory to oral metronidazole or vancomycin, fecal transplantation of donor stool has been reported to be highly successful. The exact complement of fecal bacteria that is required to restore a normal fecal microbiota is not established.
Monoclonal antibodies offer potential for improving treatment and prevention of CDAD in the future. Phase III clinical studies for bezlotoxumab (an investigational C difficile antitoxin) showed reduction in C difficile recurrence through 12 weeks compared to placebo, when used in conjunction with antibiotics for the treatment of C difficile.
Since the excretion of the organism and the toxin can be prolonged after clinical cure, follow-up testing for C difficile is discouraged. Antimotility agents should be avoided. Surgical intervention may be required in severe cases of CDAD unresponsive to medical therapy or to manage complications such as toxic megacolon or colonic perforation.
The first step in prevention of CDAD is the judicious use of antibiotics. Probiotics are both safe and moderately effective in preventing CDAD in immunocompetent children. There is very limited evidence to support the use of probiotics to prevent simple antibiotic-associated diarrhea and no evidence that it is beneficial for treatment of CDAD.
In the hospital environment, contact precautions should be implemented for patients with known or suspected CDAD to prevent nosocomial transmission of C difficile. Note that alcohol-based hand hygiene products (now commonly used in healthcare facilities as a substitute for soap and water) are not sporicidal and should not be relied upon to prevent person-to-person spread of C difficile. Hand washing with soap and water involving vigorous mechanical scrubbing and rinsing is more effective for physical removal of bacterial spores. Adherence to glove use in the care of symptomatic patients is critically important for preventing transmission of C difficile. There is evidence that chlorhexidine baths reduce hospital-acquired CDAD, but the optimal strategy for this application is not established. Children with CDAD should be excluded from child care for the duration of their diarrhea.
Clostridium botulinum is a gram-positive, obligate anaerobic bacillus most commonly found in the soil. C botulinum generates spores that survive extreme weather and temperature conditions, so unlike the toxins, which are heat labile, the spores are relatively heat resistant. Neuromuscular blockade by one of these neurotoxins produced by the organism results in a descending paralysis of varying degrees.
Classically, 3 clinical presentations of botulism are described: infant botulism, foodborne botulism, and wound botulism. An average of 110 cases of botulism are reported each year in the United States according to the Centers for Disease Control and Prevention (CDC). Approximately 72% of cases are infant botulism, 25% are foodborne botulism (vegetables being the most common source in the United States), and the remaining 3% are wound botulism. In the United States, foodborne botulism has been largely reduced by implementing safe canning and food manufacturing processes. However, improperly home-canned foods are still a cause of outbreaks. Recently, inadvertent botulism has been described as an iatrogenic disease occurring in patients treated with botulinum toxin injections for dystonia, other movement disorders, or cosmetic procedures. The increase in iatrogenic botulism underscores the importance of using botulinum toxin only for clinically established and approved indications.
In foodborne botulism, it is the preformed toxin that is directly ingested from inappropriately handled food. Wound botulism is caused by contamination of the wound with C botulinum.
PATHOGENESIS AND EPIDEMIOLOGY
Infant botulism results from ingested spores of C botulinum that germinate in the colon and produce a neurotoxin. The neurotoxin is absorbed and carried by the circulatory system to the peripheral cholinergic synapses. The toxin binds irreversibly and produces a flaccid paralysis by producing a presynaptic blockade, preventing the release of acetylcholine. The toxin also blocks acetylcholine from parts of the autonomic system, inducing symptoms of dry mouth and reduced sweating.
Infant botulism has been the most common form of botulism reported in the United States. There is no gender predilection. Between 2006 and 2011, there has been an annual average of 96 laboratory-confirmed cases with an age range of < 1 to 60 weeks. The median age of presentation is 16 weeks. Infant botulism occurs at a significantly younger age in formula-fed infants compared to breast-fed infants. There are no clear epidemiologic risk factors for the development of infant botulism. Possible spore sources include foods, dust, and soil. A history of honey ingestion is present in a minority of cases, and honey is not recommended for children younger than 12 months of age. C botulinum spores have also been identified in corn syrup. In most cases, the source of the spores is unidentifiable.
Infant botulism displays a wide spectrum of presentations from transient mild weakness and hypotonia that may go unnoticed, to a fulminant, even fatal, illness. Choking with feeds and/or decreased tone are what often initially illicit parental concern. The infant is usually afebrile unless the course is complicated by a secondary bacterial infection (such as aspiration pneumonia).
The classic presentation of infant botulism includes decreased stool frequency (constipation) followed by poor feeding due to a weak suck, a weak cry, and progressive, symmetrical descending weakness beginning with the cranial nerves. This results in an expressionless face, ptosis, weak cry, and impaired gag or suck reflexes, which are followed by a generalized progressive hypotonia. Deep tendon reflexes are normal initially but diminish later in the course of the illness. Despite a sad, lethargic appearance and a feeble cry, the infant conveys a paradoxical sense of alertness because the toxin does not cross the blood-brain barrier. Impaired respiratory effort may evolve to respiratory failure.
Botulism should be suspected in any infant who presents with poor feeding, constipation, and symmetric progressive weakness. Clinical suspicion is the cornerstone of diagnosis, and the initiation of treatment should not be delayed awaiting laboratory confirmation. Sepsis is the most common admitting diagnosis. Other frequent admission diagnoses include dehydration, viral syndrome, and failure to thrive. The differential diagnosis includes drug or heavy metal poisoning, hypothyroidism, metabolic disorders, myasthenia gravis, poliomyelitis, Guillain-Barré syndrome, Werdnig-Hoffmann disease, and Hirschsprung disease.
A stool specimen for toxin assay is the confirmatory test of choice for infant botulism. Although not always helpful, if electromyography (EMG) is used, the most prominent finding is an incremental increase of evoked muscle potentials at high-frequency nerve stimulation (20–50 Hz). Additionally, small-amplitude, overly abundant motor action potentials may be seen after stimulation of muscle, but their absence does not exclude the diagnosis.
In infant botulism, supportive care is the mainstay of therapy. In addition, the early use of botulism immune globulin-intravenous (human BIG-IV or baby BIG) is now standard. Specific treatment with BIG-IV is highly effective, shortening hospital stays from 5.5 to 2.5 weeks and reducing morbidity and mortality. It is not recommended in other forms of botulism. Treatment with BIG-IV should be instituted as soon as possible and not delayed awaiting laboratory confirmation. It is available from the California Department of Public Health (24-hour phone number: 510-231-7600). BIG-IV immediately binds and neutralizes all circulating botulinum toxin and remains present in neutralizing amounts in the circulation for up to 6 months. This allows regeneration of nerve endings to proceed and leads to full recovery. Treatment with BIG-IV within 0 to 3 days after admission shortens the hospital stay by up to 1 week or more when compared to administration 4 to 7 days after admission. Equine-derived heptavalent botulinum antitoxin has been used on a case-by-case basis to treat type F infant botulism since that antitoxin is not contained in BIG-IV, unlike the other 6 toxin serotypes (A–E and G).
Theoretically, antibiotic usage may lead to lysis of C botulinum, releasing further neurotoxin, which could result in prolonged or more severe illness. Therefore, antibiotics should not be routinely employed. Aminoglycosides, due to their potential for additional neuromuscular blockade, should particularly be avoided because they may exaggerate the paresis.
The symptoms of foodborne botulism begin several hours to days after the ingestion of a preformed toxin. Similar to infant botulism, these patients present with some degree of flaccid paralysis that manifests initially with prominent cranial nerve paralysis with descending progression and an absence of sensory nerve involvement. Early symptoms include blurred or double vision, dizziness, trouble swallowing, and difficulty speaking. Because the toxin is in the gastrointestinal tract, decreased stool frequency and increased consistency are also common features.
The neurologic manifestations of wound-associated botulism are indistinguishable from those seen in foodborne botulism; however, gastrointestinal symptoms are absent. Associated wounds are not necessarily outwardly impressive, although they are frequently deep and associated with avascular injuries. The average incubation period in cases of trauma is 7 days (range 4–21 days). This clinical entity should be kept in mind with injection drug users; recurrent wound botulism has been described in this population.
Iatrogenic botulism demonstrates the same clinical characteristics as naturally occurring botulism. Some patients develop associated autonomic nervous system effects following the toxin injections. Patients treated with toxin for cervical dystonia often experience dysphagia. This focal weakness likely results from the local spread of toxin from the injected muscles. Generalized weakness and autonomic symptoms are likely a result of circulating toxin in the blood.
Routine laboratory tests are typically unremarkable. The tensilon test helps distinguish botulism from myasthenia gravis. In suspected cases, serum and stool samples should be sent for toxin confirmation. Detection of toxin in the patient’s serum, stool, wound, or food is diagnostic. This testing is performed at the CDC.
Patients older than 1 year of age and adults with botulism should be treated with equine-derived heptavalent botulinum antitoxin that contains antitoxin against all 7 (A–G) botulinum toxin types. Immediate administration of antitoxin is critical, because it arrests the progression of paralysis, although it does not reverse it. Similar to infant botulism, antibiotics should not be routinely used because of concerns of lysis of C botulinum and further neurotoxin release. Aminoglycosides should especially be avoided in cases of botulism for the reasons previously mentioned.
Antibiotics are recommended for wound botulism after antitoxin has been administered. Penicillin G (250,000–400,000 U/kg/d, up to 24 million U/d, divided every 4 hours) provides coverage. For penicillin-allergic patients, metronidazole orally, 30 to 50 mg/kg/d divided every 8 hours (maximum 2250 mg/d), or intravenously, 22.5 to 40 mg/kg/d divided every 8 hours (maximum 1500 mg/d), is an alternative.
Clostridium perfringens is the most common cause of clostridial myonecrosis. It is also implicated in cellulitis, necrotizing fasciitis, and food poisoning.
PATHOGENESIS AND EPIDEMIOLOGY
C perfringens is readily found in soil samples, contaminated surgical and other objects, and the intestinal contents of animals and humans. It is also present in raw meat and poultry. Factors that facilitate the growth of C perfringens include penetration of deep tissue, extensive tissue devitalization, tissue anoxia, an anaerobic environment, polymicrobial infection, and the presence of a foreign body.
Myonecrosis may occur after trauma, postoperatively, or spontaneously in the presence of other primary pathology. Nontraumatic myonecrosis occurs occasionally from clostridia in the gastrointestinal tract of immunocompromised hosts. Food poisoning caused by C perfringens is usually due to the ingestion of the organism that produces enteric toxins. Symptoms may also result from ingestion of preformed toxin. Necrotizing enteritis (pigbel) is associated with β-enterotoxin produced by C perfringens type C following consumption of undercooked pork. It is rarely seen in the United States.
Clostridial myonecrosis is marked by significant, disproportionate pain that is sudden and progressive at the site of injury. It is accompanied by local, tense swelling, pallor, and a thin hemorrhagic exudate. Pallor gives way to a bronze or magenta discoloration, and hemorrhagic purplish bullae appear. Myonecrosis caused by Clostridium species is called gas gangrene. Crepitus from gas production is suggestive but not pathognomonic and may not be present at all. A peculiar offensive odor, sometimes described as sweet, may be noted, with a brown serosanguinous discharge. Eventually, the muscle becomes “gangrenous”—black, friable, and liquefied.
The toxins from this organism have systemic effects such as direct cardiodepressive effects. Systemic findings include tachycardia disproportionate to the degree of fever, pallor, diaphoresis, hypotension, renal failure, and changes in mental status. Untreated clostridial myonecrosis can lead to disseminated myonecrosis, suppurative visceral infection, sepsis, and death within hours. Additionally, C perfringens can also cause a simple localized cellulitis.
In food poisoning from C perfringens, the illness starts 8 to 12 hours after ingestion of contaminated products containing high numbers of organisms. Symptoms usually last under 24 hours and include nausea, severe abdominal pain, and profuse nonbloody, watery diarrhea. Fever is absent, and vomiting is uncommon.
Neonatal necrotizing enterocolitis has been associated with C perfringens, Clostridium butyricum, and C difficile. The exact role of these organisms needs further elucidation. Neutropenic enterocolitis (typhlitis) is a similar syndrome that occurs in the cecum of neutropenic patients. Clostridium septicum is the usual agent. Symptoms are fever, right lower quadrant abdominal pain, and diarrhea. Initial treatment is with antibiotics, but surgical resection may be necessary.
Clostridial myonecrosis is a clinical diagnosis including the characteristic appearance of necrotic muscle noted at surgery. Early recognition is critical for a successful outcome. Anaerobic cultures of wound exudate and blood should be performed. Tissue specimens and aspirates (not swab specimens) are appropriate for anaerobic culture. If gram-positive bacilli are present with a consistent clinical picture, the diagnosis of clostridial myonecrosis should be assumed until proven otherwise. A radiograph of the affected site can demonstrate gas in the tissue, but this is a nonspecific finding and not always present.
In foodborne illnesses, isolation of large concentrations of C perfringens or demonstration of enterotoxin in the stool supports the diagnosis. For most cases of self-limited food poisoning, however, diagnostic testing is not performed.
A high index of suspicion and immediate surgical excision of necrotic tissue with removal of any foreign material are essential to the management of clostridial myonecrosis. Decompressing fascial compartments is essential to prevent further tissue anoxia. Broad-spectrum antibiotics are indicated until culture and sensitivity reports allow for appropriate antibiotic adjustments given the prevalence of polymicrobial necrotizing infections.
High-dose penicillin G (250,000–400,000 U/kg/d, up to 24 million U/d, divided every 4 hours) administered intravenously has excellent activity against C perfringens and should be included in the initial antibiotic regimen. Approximately 5% of clostridial species show variable degrees of resistance to penicillin. Clindamycin (40 mg/kg/d divided every 8 hours), metronidazole, meropenem, and ertapenem (not approved for individuals ≤ 18 years of age) can be considered as alternative drugs for patients with a penicillin allergy or for treatment of polymicrobial infections. The combination of penicillin G and clindamycin is considered superior to penicillin alone because of clindamycin’s toxin-inhibiting action. Polyvalent clostridial myonecrosis antitoxin has no proven benefit. Hyperbaric oxygen may be beneficial when used adjunctively along with antibiotics and aggressive surgical debridement. Clostridial cellulitis can be treated with antibiotics alone and with any associated fluid collection being drained.
Treatment of food poisoning is primarily symptomatic support. Antibiotics are not indicated.
For the prevention of myonecrosis, during initial wound management, prompt and careful debridement, flushing of contaminated wounds, and removal of foreign material should always be performed. Clindamycin (20–30 mg/kg/d) may be of value for prophylaxis in patients with grossly contaminated wounds. In hospitalized cases, isolation is not necessary.
For foodborne illness, prevention is achieved by cooking foods thoroughly and maintaining food at warmer than 60°C. Meat dishes should be served hot shortly after cooking. Foods should never be held at room temperature to cool; they should be refrigerated after removal from warming devices or serving tables as soon as possible and within 2 hours of preparation. Refrigerators should keep food cooler than 7°C (45°F).
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American Academy of Pediatrics Committee on Infectious Diseases. Clostridial myonecrosis. In: Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:297–298.
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