1218 PART 5 Infectious Diseases

The neurologic examination is the key to clinical diagnosis of botulism, as it readily uncovers the cranial nerve deficits that are invariably

present in botulism and focuses the differential diagnosis. In principle,

the distinct syndrome of bilateral cranial palsies and descending flaccid

paralysis in a fully conscious patient should render the diagnosis and

prompt treatment of botulism straightforward. The presentation of two

or more patients with this syndrome is almost pathognomonic, since

other illnesses considered during the differential diagnosis of botulism

do not produce outbreaks. In practice, however, sporadic (lone) cases

of botulism are misdiagnosed, and sometimes the diagnosis is missed

even in the setting of an outbreak. In part, these failures may be due to

the rarity of botulism and the clinician’s unfamiliarity with its presentation. A possible cause of misdiagnosis is failure to perform a complete

neurologic examination; indeed, review of some botulism patients’

charts reveals documentation of the first neurologic examination,

which suggested the correct diagnosis, days after hospital admission.

As stated earlier, the combination of ptosis, dysarthria, and perceived

gate instability from muscle paralysis in some cases may be misinterpreted as intoxication from alcohol or other substances. In other cases,

rapidly progressing botulism may result in pharyngeal collapse and

respiratory distress relatively early in the course, leading the clinical

team to focus on airway management and primary respiratory diagnoses and thus delaying the neurologic evaluation.

Standard clinical studies, including bloodwork and radiology,

are not useful in diagnosing botulism. In contrast to the findings in

Guillain-Barré syndrome (GBS; see below), lumbar-puncture cerebrospinal fluid (CSF) values—and specifically the protein level—are

usually normal in botulism. The CSF protein level may be very slightly

elevated in a minority of botulism cases. The fact that botulism produces no abnormal findings on brain imaging may help rule out rare

basilar strokes that produce nonlateralizing symptoms. The Tensilon

test helps rule out myasthenia gravis. Electromyography, when performed by an experienced practitioner, can provide support for the

diagnosis. Botulism is indicated by findings consistent with neuromuscular junction blockage, normal axonal conduction, and potentiation

with rapid repetitive stimulation in affected muscles.

Once a neurologic examination reveals the cranial nerve palsies of

botulism and any additional bilateral flaccid paralysis, the differential

diagnosis may include GBS, myasthenia gravis, Lambert-Eaton syndrome, and tick paralysis. Less likely conditions include tetrodotoxin

or shellfish poisoning, antimicrobial-associated paralysis, and rarer

poisonings. A careful history and physical examination can further

narrow the range of diagnoses. GBS is a rare (~1 case per 100,000

population per year in the United States) autoimmune demyelinating

polyneuropathy that follows acute infection by Campylobacter jejuni,

certain viruses, and other bacteria. In 95% of cases, GBS presents as

an ascending paralysis. Recent reports from Peru indicate massive

outbreaks of GBS of unknown cause, challenging the previously held

notion that conditions causing flaccid paralysis other than botulism

occur only as sporadic cases. The 5% of GBS cases presenting as the

Miller Fisher variant are characterized by the triad of ophthalmoplegia,

ataxia, and areflexia, which may resemble early descending paralysis.

The CSF protein level is elevated in GBS, but the increase may take

place days after symptom onset; thus, normal CSF levels should be

taken into account along with the duration of symptoms, and lumbar

puncture may need to be repeated. Electromyography performed by

an experienced operator may yield findings indicative of GBS and not

botulism. A strongly positive Tensilon test, with or without the presence of autoantibodies, confirms myasthenia gravis; borderline positive

Tensilon tests have been reported in botulism patients. In most stroke

patients, the physical examination should reveal asymmetric paralysis

and upper motor neuron signs; brain imaging can help reveal rare

basilar strokes that can produce symmetric bulbar palsies. The history

and physical examination should rule out Lambert-Eaton syndrome,

which is characterized by proximal limb weakness in patients with

advanced cancer.

Laboratory testing confirms clinically diagnosed botulism cases

and determines the BoNT serotype causing the disease. In addition,

laboratory testing can confirm epidemiologic data by demonstrating

presence of BoNT in the suspected food. Botulism cases are confirmed

by the laboratory when BoNT is identified in serum or stool specimens

or when a BoNT-producing species of Clostridium is isolated from

stool specimens or wound cultures. Identification of preformed BoNT

in food consumed by patients also confirms foodborne botulism.

The gold standard for identification and serotyping of BoNT in

clinical or food specimens is the mouse bioassay. The drawback is that

this highly sensitive and specific method requires the use of animals.

Specimens are injected IP into the mice with and without antitoxin;

the mice are then observed for up to 96 h for signs of botulism. If the

specimen contains BoNT at levels sufficient to affect the mice quickly,

results may be available within 24 h of injection. Low levels of toxin

may produce signs later, so that mice should be monitored for 4 days

after injection. Many in vitro methods have been developed for detection of BoNT and BoNT-producing species of Clostridium in clinical

and food specimens. For instance, public health laboratories in the

United States can use a real-time polymerase chain reaction test that

detects bont genes encoding serotypes A through G. This test is a useful

screening method to determine whether BoNT-producing species of

Clostridium are present in cultures of clinical specimens, but positive

results must be confirmed. Another in vitro method, the Endopep mass

spectrometry (Endopep-MS) assay, is highly sensitive and specific and

can detect BoNT in clinical specimens and foods. The advantage of

Endopep-MS is that it detects active BoNT and therefore represents an

ideal alternative to the mouse bioassay. Immune-based assays can provide rapid and sensitive results; their main limitation is that they detect

antigens, which may not necessarily represent active BoNT. Cell-based

in vitro assays are also a possible alternative to the mouse bioassay as

they detect biological activity of BoNT.

TREATMENT

Botulism

Treatment for botulism consists of two components: meticulous

monitoring and supportive care, including admittance to the intensive care unit when indicated, and administration of botulinum

antitoxin, the only specific therapy for botulism, as quickly as

possible. Paralysis from botulism can be rapidly progressive. Vital

capacity, and often hemodynamic parameters, should be frequently

monitored and mechanical ventilation instituted immediately if

needed. Paralysis induced by BoNT lasts weeks or months, and

patients with extensive paralysis require painstaking care to avoid

complications associated with protracted immobilization, including

respirator-dependent pneumonia, decubitus ulcers, and psychological trauma. Patients who have recovered from severe botulism

report that their appearance and immobility often led caregivers

to assume they were unconscious; as a consequence, patients were

sometimes subjected to painful procedures without warning and

to insensitive comments. Signage should remind all caregivers that

botulism patients are conscious but “locked in.” Psychological support should be instituted for intubated botulism patients from the

outset. With proper supportive care, >95% of botulism patients in

the United States recover, even without antitoxin therapy; however,

antitoxin, if promptly administered, can substantially reduce the

extent and duration of illness (see below).

Botulinum antitoxin is the only specific treatment for botulism.

The antitoxin prevents the progression of paralysis but does not

reverse existing paralysis. If given early enough in the course of

disease, it may avert respiratory compromise, obviate mechanical

intubation, and forestall protracted paralysis and hospitalization

along with associated complications. Accordingly, it is essential

to administer antitoxin as soon as possible. A recent systematic

literature review and meta-analysis covering nearly a century of

the published literature in noninfant botulism patients confirmed

long-known findings from smaller studies by showing significantly

reduced mortality rates among patients treated with equine antitoxin, especially when treatment was administered within 48 h

of symptom onset. Another large systematic literature review of

1219CHAPTER 153 Botulism

pediatric noninfant botulism recently showed significantly reduced

mortality risk among children treated with equine antitoxin. Published studies have demonstrated a substantial reduction in the

duration and severity of illness among patients with infant botulism

who are treated with human-derived botulinum antitoxin.

The equine botulinum antitoxin used to treat noninfant botulism

consists of antibodies produced in horses immunized with botulinum toxoids (inactivated toxins) and toxins. The antibodies are

type-specific (anti-A neutralizes BoNT type A and so forth). The

currently licensed antitoxin product in the United States, heptavalent botulinum antitoxin (BAT), contains antibodies to BoNT types

A, B, C, D, E, F, and G. These equine antibodies have undergone

despeciation to reduce antigenicity and the risk of anaphylaxis to foreign protein. A recent systematic literature review, along with studies

of BAT use, indicated that <2% of recipients experience serious

adverse reactions. Administration of one vial of BAT elicits circulating antitoxin concentrations sufficient to neutralize toxin levels one

to two orders of magnitude higher than those found in the serum of

most botulism patients. As noted earlier, clinicians suspecting botulism in a patient should immediately call their state health department’s emergency contact to be put in touch with a botulism clinical

consultant who will review the case and assist in its management,

including shipment of BAT from the federal stockpile at no charge.

The botulinum antitoxin used to treat infants, BabyBIG, consists of

human antibodies obtained from hyperimmunized volunteers. The

product is licensed for treatment of infant botulism due to BoNT

types A and B and, as noted earlier, can be obtained through the

Infant Botulism Treatment and Prevention Program.

There is no prophylactic treatment for botulism. Persons who

may have been exposed to botulinum toxin should be evaluated by

a physician and carefully observed for the development of symptoms of botulism. If symptoms appear, the patient should be treated

immediately with botulinum antitoxin.

■ PREVENTION

No vaccine is licensed for the prevention of botulism. In the United

States, a botulinum toxoid vaccine was available through the CDC until

2011, but it was discontinued because of a decline in immunogenicity

of some serotypes and an increase in occurrence of moderate local

reactions. Several vaccine candidates are currently in clinical trials.

Because most foodborne botulism cases are caused by home-canned

or home-preserved foods, the prevention of foodborne botulism

depends mainly on proper preparation and preservation that ensures

the destruction of spores of BoNT-producing species of Clostridium

that may be present in the food or on the creation of an environment

that will not allow the germination and growth of these spores, such as

low pH or low water activity. Water activity is a measure of how much

water is free, unbound, and thus available to microorganisms to use

for growth. If foods have low water activity, it means they do not have

much free water, and growth of C. botulinum will be limited or inhibited. Using pressure canners and properly cleaning items employed in

the canning process can reduce the risk of foodborne botulism. Among

other resources, the USDA Complete Guide to Home Canning provides

a detailed description of safe home-canning practices. Other ways of

preventing foodborne botulism include refrigerating homemade oils

infused with garlic or herbs and discarding any of these oils that have

not been used after 4 days; maintaining baked potatoes or similar foods

wrapped in aluminum foil at temperatures above 140°F until served

and then refrigerating leftovers; refrigerating canned or pickled foods

after opening; and boiling home-canned foods before eating, especially

those foods that are low in acid.

Wound botulism largely affects people who inject drugs, especially

black tar heroin. Using safe injection practices may help prevent wound

botulism and many other infections, such as HIV and hepatitis C virus

infections. Thus, educating injection drug users on the prevention of

wound botulism and other infections is vital in protecting their health.

As wound botulism can also follow traumatic injuries, keeping wounds

clean is key.

The risk factors for infant botulism are not fully understood, but

possible sources of spores of BoNT-producing species of Clostridium

include foods and dust. In most cases of infant botulism, no source of

spores is identified. Honey is the only food that has been identified as

an epidemiologically associated reservoir of spores of BoNT-producing

species of Clostridium. Honey should not be fed to infants ≤1 year of age.

■ GLOBAL CONSIDERATIONS

Botulism has been reported from all parts of the world. The European

Centre for Disease Prevention and Control has reported an average of

110 botulism cases each year from 2007 to 2018. During that period,

1315 botulism cases were reported from 25 countries, with the most

cases in Italy (311 cases), Romania (239 cases), and Poland (202 cases).

Foodborne botulism is the most common form of botulism in Europe.

Most laboratory-confirmed cases reported from Italy, Romania, and

Poland were due to BoNT serotype B. The country of Georgia has

a high incidence of botulism (0.9 case per 100,000 persons) relative

to rates in the European Union (<0.1/100,000) and the United States

(0.01/100,000). From 1980 to 2002, a total of 879 cases of botulism

were reported in Georgia; all of them were foodborne, most were

associated with home-preserved vegetables, and the majority were due

to serotype B. From 1958 to 1983, 986 foodborne botulism outbreaks

affecting 4377 individuals were reported from China. Most cases were

due to serotype A and were associated with bean products. Botulism

in Thailand has been associated with fermented bamboo shoots and

fermented soybeans. In 2006, a large foodborne botulism outbreak

associated with bamboo shoots occurred in Thailand and affected

209 people who attended a local festival. In South America, Brazil and

Argentina have reported several outbreaks of foodborne botulism. For

instance, between 2001 and 2008, Brazil reported 18 outbreaks, most

of which were associated with meat-based foods such as home-canned

meat, homemade pork liver pâté, and commercially canned liver pâté.

From 1994 to 2007, Argentina reported 36 outbreaks, most frequently

involving home-canned vegetables. Although reports of foodborne

botulism in Africa are rare, five outbreaks were reported in South

Africa between 1959 and 2002, with the majority due to serotype B

and associated with noncommercial foods. In addition, one outbreak

of 91 cases was reported in Egypt in 1991 and was due to serotype E

associated with a traditional salted fish.

Wound botulism cases have been reported most frequently from

the United States, next most frequently from the United Kingdom,

and occasionally from Italy, France, and Australia. Clusters of wound

botulism are rare, but, according to a report from the European Centre for Disease Prevention and Control, 23 cases of wound botulism

among people who had injected heroin were reported in Norway and

Scotland between December 2014 and February 2015. Other countries

that have reported wound botulism cases include Argentina, China,

and Ecuador.

Although rarely reported, infant botulism cases have been noted on

all continents except Africa. Outside the United States (where there

were 2419 cases), Argentina reported the largest number of cases (366)

and Australia the next largest number (32) between 1976 and 2006.

Canada, Italy, and Japan also reported a relatively large number of cases

(27, 26, and 22, respectively).

■ FURTHER READING

Centers for Disease Control and Prevention: Botulism in the

United States, 1899–1996, Handbook for Epidemiologists, Clinicians,

and Laboratory Workers. Atlanta, Centers for Disease Control and

Prevention, 1998.

Centers for Disease Control and Prevention: National Botulism

Surveillance. Available at https://www.cdc.gov/botulism/surveillance

.html. Accessed September 27, 2020.

Chatham-Stephens K et al: Clinical features of foodborne and wound

botulism: A systematic review of the literature, 1932–2015. Clin

Infect Dis 66:S11, 2017.

European Centre for Disease Prevention and Control: Botulism. Available at https://www.ecdc.europa.eu/en/botulism. Accessed

September 27, 2020.

1220 PART 5 Infectious Diseases

The genus Clostridium encompasses >60 species that may be commensals of the gut microflora or may cause a variety of infections in

humans and animals through the production of a plethora of proteinaceous exotoxins. C. tetani and C. botulinum, for example, cause

specific clinical disease by elaborating single but highly potent toxins.

In contrast, C. perfringens and C. septicum cause aggressive necrotizing

infections that are attributable to multiple toxins, including bacterial

proteases, phospholipases, and cytotoxins.

ETIOLOGIC AGENT

Vegetative cells of Clostridium species are pleomorphic, rod-shaped, and

arranged singly or in short chains (Fig. 154-1); the cells have rounded

or sometimes pointed ends. Although clostridia stain gram-positive

in the early stages of growth, they may appear to be gram-negative or

gram-variable later in the growth cycle or in infected tissue specimens.

Most strains are motile by means of peritrichous flagella; C. septicum

swarms on solid media. Nonmotile species include C. perfringens,

C. ramosum, and C. innocuum. Most species are obligately anaerobic,

although clostridial tolerance to oxygen varies widely; some species

(e.g., C. septicum, C. tertium) will grow but will not sporulate in air.

Clostridia produce more protein toxins than any other bacterial

genus, and >25 clostridial toxins lethal to mice have been identified.

These proteins include neurotoxins, enterotoxins, cytotoxins, collagenases, permeases, necrotizing toxins, lipases, lecithinases, hemolysins,

proteinases, hyaluronidases, DNases, ADP-ribosyltransferases, and

neuraminidases. Botulinum and tetanus neurotoxins are the most

potent toxins known, with lethal doses of 0.2–10 ng/kg for humans.

Epsilon toxin, a 33-kDa protein produced by C. perfringens types B

and D, causes edema and hemorrhage in the brain, heart, spinal cord,

and kidneys of animals. It is among the most lethal of the clostridial

toxins and is considered a potential agent of bioterrorism. The genomic

sequences of some pathogenic clostridia are now available and are

154 Gas Gangrene and Other

Clostridial Infections

Amy E. Bryant, Dennis L. Stevens

FIGURE 154-1 Scanning electron micrograph of C. perfringens.

Fleck-Derderian S et al: The epidemiology of foodborne botulism

outbreaks: A systematic review. Clin Infect Dis 66:S73, 2017.

Griese SE et al: Pediatric botulism and use of equine botulinum antitoxin in children: A systematic review. Clin Infect Dis 66:S17, 2017.

Koepke R et al: Global occurrence of infant botulism, 1976–2006.

Pediatrics 122:e73, 2008.

National Center for Home Food Preservation: USDA Complete

Guide to Home Canning, 2015 Revision. Available at https://nchfp.uga

.edu/publications/publications_usda.html. Accessed September 27,

2020.

O’Horo JC et al: Efficacy of antitoxin therapy in treating patients with

foodborne botulism: A systematic review and meta-analysis of cases,

1923–2016. Clin Infect Dis 66:S43, 2017.

Peck M et al: Historical perspectives and guidelines for botulinum

neurotoxin subtype nomenclature. Toxins (Basel) 9:38, 2017.

Pirazzini M et al: Botulinum neurotoxins: Biology, pharmacology,

and toxicology. Pharmacol Rev 69:200, 2017.

Rao AK et al: Clinical criteria to trigger suspicion for botulism: An

evidence-based tool to facilitate timely recognition of suspected cases

during sporadic events and outbreaks. Clin Infect Dis 66:S38, 2017.

(Also available at https://academic.oup.com/cid/article/66/suppl_1/

S38/4780423. Accessed September 27, 2020.)

Yu PA et al: Safety and improved clinical outcomes in patients treated

with new equine-derived heptavalent botulinum antitoxin. Clin

Infect Dis 66:S57, 2017.

likely to facilitate a comprehensive approach to understanding the

virulence factors involved in clostridial pathogenesis.

EPIDEMIOLOGY AND TRANSMISSION

Clostridium species are widespread in nature, forming endospores that

are commonly found in soil, feces, sewage, and marine sediments. The

ecology of C. perfringens in soil is greatly influenced by the degree and

duration of animal husbandry in a given location and is relevant to

the incidence of gas gangrene caused by contamination of war wounds

with soil. For example, the incidence of clostridial gas gangrene is

higher in agricultural regions of Europe than in the Sahara Desert of

Africa. Similarly, the incidences of tetanus and food-borne botulism

are clearly related to the presence of clostridial spores in soil, water, and

many foods. Clostridia are present in large numbers in the indigenous

microbiota of the intestinal tract of humans and animals, in the female

genital tract, and on the oral mucosa. It should be noted that not all

commensal clostridia are toxigenic.

Clostridial infections remain a serious public-health concern worldwide. In developing nations, food poisoning, necrotizing enterocolitis,

and gas gangrene are common because large portions of the population are poor and have little or no immediate access to health care.

These infections remain prevalent in developed countries as well. Gas

gangrene commonly follows knife or gunshot wounds or vehicular

accidents or develops as a complication of surgery or gastrointestinal

carcinoma. Severe clostridial infections have emerged as a health

threat to injection drug users and to women undergoing childbirth or

abortion. Historically, clostridial gas gangrene has been the scourge of

the battlefield. The global political situation portends another possible

scenario involving mass casualties of war or terrorism, with extensive

injuries conducive to gas gangrene. Thus, there is an ongoing need to

develop novel strategies to prevent or attenuate the course of clostridial

infections in both civilians and military personnel. Vaccination against

exotoxins important in pathogenesis would be of great benefit in developing nations and could also be used safely in at-risk populations such

as the elderly, patients with diabetes who may require lower-limb surgery due to trauma or poor circulation, and those undergoing intestinal

surgery. Moreover, a hyperimmune globulin would be a valuable tool

for prophylaxis in victims of acute traumatic injury or for attenuation

of the spread of infection in patients with established gas gangrene.

CLINICAL SYNDROMES

Life-threatening clostridial infections range from intoxications (e.g.,

food poisoning, tetanus) to necrotizing enteritis/colitis, bacteremia,

myonecrosis, and toxic shock syndrome (TSS). Tetanus and botulism

are discussed in Chaps. 152 and 153, respectively. Colitis due to

C. difficile is discussed in Chap. 134.

1221CHAPTER 154 Gas Gangrene and Other Clostridial Infections

■ ENTERIC CLOSTRIDIAL INFECTIONS

C. perfringens type A is one of the most common bacterial causes of foodborne illness in the United States and Canada. The foods typically implicated include improperly cooked meat and meat products (e.g., gravy) in

which residual spores germinate and proliferate during slow cooling or

insufficient reheating. Illness results from the ingestion of food containing at least ~108

 viable vegetative cells, which sporulate in the alkaline

environment of the small intestine, producing C. perfringens enterotoxin

in the process. The diarrhea that develops within 7–30 h of ingestion of

contaminated food is generally mild and self-limiting; however, in the

very young, the elderly, and the immunocompromised, symptoms are

more severe and occasionally fatal. Enterotoxin-producing C. perfringens has been implicated as an etiologic agent of persistent diarrhea in

elderly patients in nursing homes and tertiary-care institutions and has

been considered to play a role in antibiotic-associated diarrhea without

pseudomembranous colitis.

C. perfringens strains associated with food poisoning possess the

gene (cpe) coding for enterotoxin, which acts by forming pores

in host cell membranes. C. perfringens strains isolated from

non-food-borne diseases, such as antibiotic-associated and sporadic

diarrhea, carry cpe on a plasmid that may be transmitted to other

strains. Several methods have been described for the detection of

C. perfringens enterotoxin in feces, including cell culture assay (Vero

cells), enzyme-linked immunosorbent assay, reversed-phase latex

agglutination, and polymerase chain reaction (PCR) amplification of

cpe. Each method has its advantages and limitations.

Enteritis necroticans (gas gangrene of the bowel) is a fulminating

clinical illness characterized by extensive necrosis of the intestinal

mucosa and wall. Cases can occur sporadically in adults or as epidemics in people of all ages. Enteritis necroticans is caused by α toxin– and

β toxin–producing strains of C. perfringens type C; β toxin is located

on a plasmid and is mainly responsible for pathogenesis. This lifethreatening infection causes ischemic necrosis of the jejunum. In

Papua New Guinea during the 1960s, enteritis necroticans (known in

that locale as pigbel) was found to be the most common cause of death

in childhood; it was associated with pig feasts and occurred both sporadically and in outbreaks. Intramuscular immunization against the β

toxin resulted in a decreased incidence of the disease in Papua New

Guinea, although the condition remains common. Enteritis necroticans has also been recognized in the United States, the United Kingdom, Germany (where it is known as darmbrand), and other developed

nations; especially affected are adults who are malnourished or who

have diabetes, alcoholic liver disease, or neutropenia.

Necrotizing enterocolitis, a disease resembling enteritis necroticans

but associated with C. perfringens type A, has been found in North

■ CLOSTRIDIAL WOUND CONTAMINATION

Of open traumatic wounds, 30–80% reportedly are contaminated with

clostridial species. In the absence of devitalized tissue, the presence of

clostridia does not necessarily lead to infection. In traumatic injuries,

clostridia are isolated with equal frequency from both suppurative

and well-healing wounds. Thus, diagnosis and treatment of clostridial

infection should be based on clinical signs and symptoms and not

solely on bacteriologic findings.

■ POLYMICROBIAL INFECTIONS INVOLVING

CLOSTRIDIA

Clostridial species may be found in polymicrobial infections also

involving microbial components of the indigenous flora. In these

infections, clostridia often appear in association with non-spore-forming anaerobes and facultative or aerobic organisms. Head and neck

infections, conjunctivitis, brain abscess, sinusitis, otitis, aspiration

pneumonia, lung abscess, pleural empyema, cholecystitis, septic arthritis, and bone infections all may involve clostridia. These conditions

are often associated with severe local inflammation but may lack the

characteristic systemic signs of toxicity and rapid progression seen in

other clostridial infections. In addition, clostridia are isolated from

~66% of intraabdominal infections in which the mucosal integrity of

the bowel or respiratory system has been compromised. In this setting,

C. ramosum, C. perfringens, and C. bifermentans are the most commonly

isolated species. Their presence does not invariably lead to a poor outcome. Clostridia have been isolated from suppurative infections of the

female genital tract (e.g., ovarian or pelvic abscess) and from diseased

gallbladders. Although the most frequently isolated species is C. perfringens, gangrene is not typically observed; however, gas formation in

the biliary system can lead to emphysematous cholecystitis, especially

in diabetic patients. C. perfringens in association with mixed aerobic

and anaerobic microbes can cause aggressive life-threatening type I

necrotizing fasciitis or Fournier’s gangrene.

The treatment of mixed aerobic/anaerobic infection of the abdomen, perineum, or gynecologic organs should be based on Gram’s

staining, culture, and antibiotic sensitivity information. Reasonable

empirical treatment consists of ampicillin or ampicillin/sulbactam

combined with either clindamycin or metronidazole (Table 154-1).

Broader gram-negative coverage may be necessary if the patient has

recently been hospitalized or treated with antibiotics. Such coverage

can be obtained by substituting ticarcillin/clavulanic acid, piperacillin/

sulbactam, or a penem antibiotic for ampicillin or by adding a fluoroquinolone or an aminoglycoside to the regimen. Empirical treatment

should be given for 10–14 days or until the patient’s clinical condition

improves.

TABLE 154-1 Treatment of Clostridial Infections

CONDITION ANTIBIOTIC TREATMENT PENICILLIN ALLERGY ADJUNCTIVE TREATMENT/NOTE

Wound

contamination

None — Treatment should be based on clinical signs and symptoms as listed

below and not solely on bacteriologic findings.

Polymicrobial

anaerobic infections

involving clostridia

(e.g., abdominal wall,

gynecologic)

Ampicillin (2 g IV q4h)

plus

Clindamycin (600–900 mg IV

q6–8h)

plus

Ciprofloxacin (400 mg IV q6–8 h)

Vancomycin (1 g IV q12h)

plus

Metronidazole (500 mg IV q6h)

plus

Ciprofloxacin (400 mg IV q6–8h)

Empirical therapy should be initiated.

Therapy should be based on Gram’s stain and culture results and

on sensitivity data when available. Add gram-negative coverage if

indicated (see text).

Clostridial sepsis Penicillin (3–4 mU IV q4–6h)

plus

Clindamycin (600–900 mg IV

q6–8h)

Clindamycin alone

or

Metronidazole (as above)

or

Vancomycin (as above)

Transient bacteremia without signs of systemic toxicity may be

clinically insignificant.

Gas gangrenea Penicillin G (4 mU IV q4–6 h)

plus

Clindamycin (600–900 mg IV

q6–8h)

Cefoxitin (2 g IV q6h)

plus

Clindamycin (600–900 mg IV q6–8h)

Emergent surgical exploration and thorough debridement are

extremely important.

Hyperbaric oxygen therapy may be considered after surgery and

antibiotic initiation.

a

C. tertium is resistant to penicillin, cephalosporins, and clindamycin. Appropriate antibiotic therapy for C. tertium infection is vancomycin (1 g q12h IV) or metronidazole

(500 mg q8h IV).

1222 PART 5 Infectious Diseases

America in previously healthy adults. It is also a serious gastrointestinal disease of low-birth-weight (premature) infants hospitalized

in neonatal intensive care units. The etiology and pathogenesis of

this disease have remained enigmatic for more than four decades.

Pathologic similarities between necrotizing enterocolitis and enteritis

necroticans include the pattern of small-bowel necrosis involving the

submucosa, mucosa, and muscularis; the presence of gas dissecting the

tissue planes; and the degree of inflammation. In contrast to enteritis

necroticans, which most commonly involves the jejunum, necrotizing

enterocolitis affects the ileum and frequently the ileocecal valve. Both

diseases may manifest as intestinal gas cysts, although this feature is

more common in necrotizing enterocolitis. The sources of the gas,

which contains hydrogen, methane, and carbon dioxide, are probably

the fermentative activities of intestinal bacteria, including clostridia.

Epidemiologic data support an important role for C. perfringens or

other gas-producing microorganisms (e.g., C. neonatale, certain other

clostridia, or Klebsiella species) in the pathogenesis of necrotizing

enterocolitis.

Patients with suspected clostridial enteric infection should undergo

nasogastric suction and receive IV fluids. Pyrantel is given by mouth,

and the bowel is rested by fasting. Benzylpenicillin (1 mU) is given

IV every 4 h, and the patient is observed for complications requiring

surgery. Patients with mild cases recover without surgical intervention.

However, if surgical indications are present (gas in the peritoneal cavity, absent bowel sounds, rebound tenderness, abdominal rigidity), the

mortality rate ranges from 35 to 100%; a fatal outcome is due in part to

perforation of the intestine.

As pigbel continues to be a common disease in Papua New Guinea,

consideration should be given to the use of a C. perfringens type C

β toxoid vaccine in local areas. Two doses given 3–4 months apart are

preventive.

■ CLOSTRIDIAL BACTEREMIA

Clostridium species are important causes of bloodstream infections.

Molecular epidemiologic studies of anaerobic bacteremia have identified C. perfringens and C. tertium as the two most frequently isolated

species; these organisms cause up to 79 and 5%, respectively, of clostridial bacteremias. Occasionally, C. perfringens bacteremia occurs in the

absence of an identifiable infection at another site. When associated

with myonecrosis, bacteremia has a grave prognosis.

C. septicum is also commonly associated with bacteremia. This species is isolated only rarely from the feces of healthy individuals but may

be found in the normal appendix. More than 50% of patients whose

blood cultures are positive for this organism have some gastrointestinal

anomaly (e.g., diverticular disease) or underlying malignancy (e.g.,

carcinoma of the colon). In addition, a clinically important association

of C. septicum bacteremia with neutropenia of any origin—and, more

specifically, with neutropenic enterocolitis involving the terminal

ileum or cecum—has been observed. Patients with diabetes mellitus,

severe atherosclerotic cardiovascular disease, or anaerobic myonecrosis

(gas gangrene) also may develop C. septicum bacteremia. C. septicum

has been recovered from the bloodstream of cirrhotic patients, as have

C. perfringens, C. bifermentans, and other clostridia. Infections of the

bloodstream by C. sordellii and C. perfringens have been associated

with TSS.

Bloodstream infection by C. tertium, either alone or in combination

with C. septicum or C. perfringens, can be found in patients with serious underlying disease such as malignancy or acute pancreatitis, with

or without neutropenic enterocolitis; the frequency has not been systematically studied. C. tertium may present special problems in terms

of both identification and treatment. This organism may stain gramnegative; is aerotolerant; and is resistant to metronidazole, clindamycin, and cephalosporins.

Other clostridia from the C. clostridioforme group (including

C. clostridioforme, C. hathewayi, and C. bolteae) can cause bacteremia.

The clinical importance of recognizing clostridial bacteremia—

especially that due to C. septicum—and starting appropriate treatment

immediately (Table 154-1) cannot be overemphasized. Patients with

this condition usually are gravely ill, and infection may metastasize

to distant anatomic sites, resulting in spontaneous myonecrosis (see

next section). Alternative methods to identify bacteremia-causing

clostridial species, such as PCR or other rapid diagnostic tests, are not

currently available. Anaerobic blood cultures and Gram’s stain interpretation remain the best diagnostic tests at this point.

■ CLOSTRIDIAL SKIN AND SOFT TISSUE

INFECTIONS

Histotoxic clostridial species such as C. perfringens, C. histolyticum,

C. septicum, C. novyi, and C. sordellii cause aggressive necrotizing

infections of the skin and soft tissues. These infections are attributable

in part to the elaboration of bacterial proteases, phospholipases, and

cytotoxins. Necrotizing clostridial soft tissue infections are rapidly

progressive and are characterized by marked tissue destruction, gas

in the tissues, and shock; they frequently end in death. Severe pain,

crepitus, brawny induration with rapid progression to skin sloughing,

violaceous bullae, and marked tachycardia are characteristics found in

the majority of patients.

Clostridial Myonecrosis (Gas Gangrene) •  TRAUMATIC GAS

GANGRENE C. perfringens myonecrosis (gas gangrene) is one of the

most fulminant gram-positive bacterial infections of humans. Even

with appropriate antibiotic therapy and management in an intensive

care unit, tissue destruction can progress rapidly. Gas gangrene is

accompanied by bacteremia, hypotension, and multiorgan failure and

is invariably fatal if untreated. Gas gangrene is a true emergency and

requires immediate surgical debridement.

The development of gas gangrene requires an anaerobic environment and contamination of a wound with spores or vegetative

organisms. Devitalized tissue, foreign bodies, and ischemia reduce

locally available oxygen levels and favor outgrowth of vegetative cells

and spores. Thus, conditions predisposing to traumatic gas gangrene

include crush-type injury, laceration of large or medium-sized arteries,

and open fractures of long bones that are contaminated with soil or

bits of clothing containing the bacterial spores. Gas gangrene of the

abdominal wall and flanks follows penetrating injuries such as knife

or gunshot wounds that are sufficient to compromise intestinal integrity, with resultant leakage of the bowel contents into the soft tissues.

Proximity to fecal sources of bacteria is a risk factor for cases following

hip surgery, adrenaline injections into the buttocks, or amputation of

the leg for ischemic vascular disease. In the last decade, cutaneous gas

gangrene caused by C. perfringens, C. novyi, and C. sordellii has been

described in the United States and northern Europe among persons

injecting black-tar heroin subcutaneously.

The incubation period for traumatic gas gangrene can be as short as

6 h and is usually <4 days. The infection is characterized by the sudden

onset of excruciating pain at the affected site and the rapid development of a foul-smelling wound containing a thin serosanguineous

discharge and gas bubbles. Brawny edema and induration develop and

give way to cutaneous blisters containing bluish to maroon-colored

fluid. Such tissue later may become liquefied and slough. The margin

between healthy and necrotic tissue often advances several inches per

hour despite appropriate antibiotic therapy, and radical amputation

remains the single best life-saving intervention. Shock and organ failure frequently accompany gas gangrene; when patients become bacteremic, the mortality rate exceeds 50%.

Diagnosis of traumatic gas gangrene is not difficult because the

infection always begins at the site of significant trauma, is associated

with gas in the tissue, and is rapidly progressive. Gram’s staining of

drainage or tissue biopsy is usually definitive, demonstrating large

gram-positive (or gram-variable) rods, an absence of inflammatory

cells, and widespread soft tissue necrosis.

SPONTANEOUS (NONTRAUMATIC) GAS GANGRENE Spontaneous gas

gangrene generally occurs via hematogenous seeding of normal muscle

with histotoxic clostridia—principally C. perfringens, C. septicum, and

C. novyi and occasionally C. tertium—from a gastrointestinal tract

portal of entry (as in colonic malignancy, inflammatory bowel disease,

diverticulitis, necrotizing enterocolitis, cecitis, or distal ileitis or after

gastrointestinal surgery, including colonoscopic polypectomy). These

1223CHAPTER 154 Gas Gangrene and Other Clostridial Infections

gastrointestinal pathologies permit bacterial access to the bloodstream;

consequently, aerotolerant C. septicum can proliferate in normal tissues. Patients surviving bacteremia or spontaneous gangrene due to

C. septicum should undergo aggressive diagnostic studies to rule out

gastrointestinal pathology.

Additional predisposing host factors include leukemia, lymphoproliferative disorders, cancer chemotherapy, radiation therapy, and AIDS.

Cyclic, congenital, or acquired neutropenia also is strongly associated

with an increased incidence of spontaneous gas gangrene due to

C. septicum; in such cases, necrotizing enterocolitis, cecitis, or distal

ileitis is common, particularly among children.

The first symptom of spontaneous gas gangrene may be confusion

followed by the abrupt onset of excruciating pain in the absence of

trauma. These findings, along with fever, should heighten suspicion

of spontaneous gas gangrene. However, because of the lack of an

obvious portal of entry, the correct diagnosis is frequently delayed or

missed. The infection is characterized by rapid progression of tissue

destruction with demonstrable gas in the tissue (Fig. 154-2). Swelling

increases, and bullae filled with clear, cloudy, hemorrhagic, or purplish

fluid appear. The surrounding skin has a purple hue, which may reflect

vascular compromise resulting from the diffusion of bacterial toxins

into surrounding tissues. Invasion of healthy tissue rapidly ensues, with

quick progression to shock and multiple-organ failure. Mortality rates

in this setting range from 67 to 100% among adults; among children,

the mortality rate is 59%, with the majority of deaths occurring within

24 h of onset.

PATHOGENESIS OF GAS GANGRENE In traumatic gas gangrene, organisms are introduced into devitalized tissue. It is important to recognize

that, for C. perfringens and C. novyi, trauma must be sufficient to

interrupt the blood supply and thereby to establish an optimal anaerobic environment for growth of these species. These conditions are not

strictly required for the more aerotolerant species such as C. septicum

and C. tertium, which can seed normal tissues from gastrointestinal

lesions. Once introduced into an appropriate niche, the organisms

proliferate locally and elaborate exotoxins.

The major C. perfringens extracellular toxins implicated in gas

gangrene are α toxin and θ toxin. A lethal hemolysin that has both

phospholipase C and sphingomyelinase activities, α toxin has been

implicated as the major virulence factor of C. perfringens: immunization of mice with the C-terminal domain of α toxin provides protection

against lethal challenge with C. perfringens, and isogenic α toxin–

deficient mutant strains of C. perfringens are not lethal in a murine

model of gas gangrene. Recently, a human single-chain recombinant

antibody to α toxin that has significant preventive and therapeutic

efficacy in mice has been developed.

It has been shown in experimental models that the severe pain, rapid

progression, marked tissue destruction, and absence of neutrophils in

C. perfringens gas gangrene are attributable in large part to α toxin–

induced occlusion of blood vessels by heterotypic aggregates of platelets and neutrophils. The formation of these aggregates, which occurs

within minutes, is largely mediated by α toxin’s ability to activate the

platelet adhesion molecule gpIIb/IIIa (Fig. 154-3); the implication is

that platelet glycoprotein inhibitors (e.g., eptifibatide, abciximab) may

be therapeutic for maintaining tissue blood flow.

C. perfringens θ toxin (perfringolysin O [PFO]) is a member of

the thiol-activated cytolysin family known as cholesterol-dependent

cytolysins, which includes streptolysin O from group A Streptococcus,

pneumolysin from Streptococcus pneumoniae, and several other toxins.

Cholesterol-dependent cytolysins bind as oligomers to cholesterol in

host cell membranes. At high concentrations, these toxins form ringlike pores resulting in cell lysis. At sublytic concentrations, θ toxin

hyperactivates phagocytes and vascular endothelial cells. θ toxin–

mediated activation of the macrophage inflammasome, with production of interleukin 1β, has also been reported.

Cardiovascular collapse and end-organ failure occur late in the

course of C. perfringens gas gangrene and are largely attributable to

both direct and indirect effects of α and θ toxins. In experimental

models, θ toxin causes markedly reduced systemic vascular resistance

but increased cardiac output (i.e., “warm shock”), probably via induction of endogenous mediators (e.g., prostacyclin, platelet-activating

factor) that cause vasodilation. This effect is similar to that observed

in gram-negative sepsis. In sharp contrast, α toxin directly suppresses

myocardial contractility; the consequence is profound hypotension due

to a sudden reduction in cardiac output. The roles of other endogenous

mediators, such as cytokines (e.g., tumor necrosis factor, interleukin 1,

interleukin 6) and vasodilators (e.g., bradykinin) have not been fully

elucidated.

C. septicum produces three main toxins—α toxin (lethal, hemolytic,

necrotizing activity), β toxin (DNase), and γ toxin (hyaluronidase)—as

FIGURE 154-2 Radiograph of patient with spontaneous gas gangrene due to

C. septicum, demonstrating gas in the affected arm and shoulder.

GpIIbIIIa

CD11b/CD18

Fibrinogen

P-selectin

PSGL-1

Carbohydrates

Platelet

Leukocyte

FIGURE 154-3 Schematic illustration of the molecular mechanisms of

C. perfringens toxin–induced platelet/neutrophil aggregates. Homotypic aggregates

of platelets (not shown) and heterotypic aggregates of platelets and leukocytes

are due to α toxin–induced activation of the platelet fibrinogen receptor gpIIb/IIIa

and upregulation of leukocyte CD11b/CD18. Binding of fibrinogen (red) bridges the

connection between these adhesion molecules on adjacent cells. An auxiliary role

for α toxin–induced upregulation of platelet P-selectin and its binding to leukocyte

P-selectin glycoprotein ligand 1 (PSGL-1) or other leukocyte surface carbohydrates

also has been demonstrated.