1203CHAPTER 150 Diphtheria and Other Corynebacterial Infections

E. casseliflavus, have intrinsic low-level resistance to vancomycin

due to the presence of the VanC operon in the chromosome.

High-level resistance to aminoglycosides (of which gentamicin

and streptomycin are the only two tested by clinical laboratories)

abolishes the synergism observed between cell wall–active agents

and the aminoglycoside. This important phenotype is routinely

sought by the clinical laboratory in isolates from serious infections (Tables 149-1 and 149-2). Genes encoding aminoglycosidemodifying enzymes are usually the cause of high-level resistance to

these compounds and are widely disseminated among enterococci,

decreasing the options for the treatment of severe enterococcal

infections. Additionally, ribosomal methyltransferases, enzymes

that methylate rRNA and, as a consequence, disrupt the binding

site for aminoglycosides, can also lead to high-level resistance.

Resistance to daptomycin has now been well documented in both

E. faecalis and E. faecium. Daptomycin exerts its action by complexing with calcium and binding to phosphatidylglycerol in the

bacterial membrane. After binding, daptomycin forms oligomers,

with recent data suggesting that it displaces enzymes important

for cell envelope synthesis (MurG and PlsX) and that it can form

a complex with lipid II molecules critical for cell-wall synthesis,

among other effects on the membrane. Resistance to this antibiotic

in enterococci arises via two main pathways. The first involves

mutations in genes that coordinate the cell-wall and cell-membrane

stress response, most commonly a three-component system designated LiaFSR (for lipid II interfering antibiotics). These mutations

lead to activation of the system, with increased expression of an

extracellular protein known as LiaX capable of binding daptomycin

and enhancing the signaling response. In clinical isolates, mutations in LiaFSR may lead to tolerance (loss of bactericidal activity)

usually in isolates with MICs near the daptomycin breakpoint (i.e.,

3–4 mg/L). The second pathway involves changes in genes involved

in phospholipid metabolism. It is thought that mutations priming

the stress response system occur first, with the subsequent accrual

of phospholipid changes leading to a fully resistant phenotype.

Prior exposure to daptomycin has been identified as a risk factor

for the emergence of daptomycin-resistant E. faecium in cancer

patients. Resistance in the absence of exposure to the drug has also

been well described, possibly due to the similarity of this antibiotic

to antimicrobial peptides of the innate immune system. Thus, careful consideration of patient characteristics, bacterial phenotype,

and daptomycin dose is warranted, and it is advisable to obtain

infectious diseases consultation in complicated VRE infections.

The oxazolidonones (linezolid and tedizolid) act by binding to

the ribosome and inhibiting the binding of aminoacyl-tRNAs, thus

preventing protein synthesis. Resistance to this class of antibiotics

is usually due to alterations of the binding site, either via mutations

in the 23S rRNA genes or the presence of an rRNA methylase.

Since enterococci carry multiple copies of the gene encoding the

23S rRNA, prolonged exposure to oxazolidonones can select for

increasing levels of resistance by favoring propagation of the resistance allele via recombination. Changes in accessory ribosomal

proteins have also been associated with linezolid resistance and may

act to mitigate the fitness defects of mutations in the rRNA. More

concerning is the emergence of plasmid-borne resistance genes,

which can be readily transferred between enterococcal strains.

Several of these genes were first recognized in bacterial isolates of

animal origin, likely under the selective pressure of antibiotics such

as florfenicol. The cfr (chloramphenicol-florfenicol resistance) gene

encodes an rRNA methylase that modifies the 23S rRNA, leading

to increases in the MIC of linezolid. Tedizolid tends to exhibit lower

MICs in the presence of cfr; however, animal models suggest some

variants of the enzyme may compromise the activity of this drug.

Two other transmissible resistance genes, optrA and poxtA, encode

a ribosomal protection factor that has been implicated in linezolid

resistance in enterococcal strains of human and animal origin.

While still relatively rare to encounter in clinical practice, these

determinants have been identified across the globe and could be an

emerging source of resistance.

Tigecycline retains activity in the presence of typical tetracycline

resistance determinants, including drug efflux pumps and ribosomal protection factors. However, resistance has been documented

and appears to be related to changes in the S10 ribosomal protein,

which is situated near the binding site for the drug.

■ FURTHER READING

Bouza E et al: The NOVA score: A proposal to reduce the need for

transesophageal echocardiography in patients with enterococcal bacteremia. Clin Infect Dis 60:528, 2015.

Garcia-Solache M, Rice L: The enterococcus: A model of adaptablility to its environment. Clin Microbiol Rev 32:e00058, 2019.

Khan A et al: Antimicrobial sensing coupled with cell membrane

remodeling mediates antibiotic resistance and virulence in Enterococcus faecalis. Proc Natl Acad Sci USA 116:26925, 2019.

Lebreton F et al: Tracing the enterococci from Paleozoic origins to the

hospital. Cell 169:849, 2017.

Satlin MJ et al: Development of daptomycin susceptibility breakpoints

for Enterococcus faecium and revision of the breakpoints for other

enterococcal species by the Clinical and Laboratory Standards Institute. Clin Infect Dis 70:1240, 2020.

DIPHTHERIA

Diphtheria is a nasopharyngeal and skin infection caused by Corynebacterium diphtheriae. Toxigenic strains of C. diphtheriae produce a

protein toxin that causes systemic toxicity, myocarditis, and polyneuropathy. The toxin is associated with the formation of pseudomembranes in the pharynx during respiratory diphtheria. While toxigenic

strains most frequently cause pharyngeal diphtheria, nontoxigenic

strains commonly cause cutaneous disease.

■ ETIOLOGY

C. diphtheriae is a gram-positive bacillus that is unencapsulated, nonmotile, and nonsporulating. The organism was first identified microscopically in 1883 by Klebs and a year later was isolated in pure culture

by Löffler in Robert Koch’s laboratory. The bacteria have a characteristic

club-shaped bacillary appearance and typically form clusters of parallel rays, or palisades, that are referred to as “Chinese characters.” The

specific laboratory media recommended for the cultivation of C. diphtheriae rely upon tellurite, colistin, or nalidixic acid for the organism’s

selective isolation from other autochthonous pharyngeal microbes. C.

diphtheriae may be isolated from individuals with both nontoxigenic

(tox–

) and toxigenic (tox+) phenotypes. Uchida and Pappenheimer

demonstrated that corynebacteriophage beta carries the structural gene

tox, which encodes diphtheria toxin, and that a family of closely related

corynebacteriophages are responsible for toxigenic conversion of tox– C.

diphtheriae to the tox+ phenotype. Moreover, lysogenic conversion from

a nontoxigenic to a toxigenic phenotype has been shown to occur in situ.

Growth of toxigenic strains of C. diphtheriae under iron-limiting conditions leads to the optimal expression of diphtheria toxin and is believed

to be a pathogenic mechanism during human infection. Less commonly,

diphtheria-like disease may be caused by Corynebacterium ulcerans and

Corynebacterium pseudotuberculosis, which express the same toxin and

are considered members of the C. diphtheriae group (discussed below).

■ EPIDEMIOLOGY

While in many regions diphtheria has been controlled in recent years

with effective vaccination, there have been sporadic outbreaks in the

150 Diphtheria and Other

Corynebacterial Infections

William R. Bishai, John R. Murphy

1204 PART 5 Infectious Diseases

United States and Europe. Diphtheria is still common in the Caribbean,

Latin America, and the Indian subcontinent, where mass immunization programs are not enforced. Large-scale epidemics of diphtheria

have occurred in the post–Soviet Union independent states. Additional

outbreaks have recently been reported in Africa and Asia. In temperate

regions, respiratory diphtheria occurs year-round but is most common

during winter months.

C. diphtheriae is transmitted via the aerosol route, usually during

close contact with an infected person. There are no significant reservoirs other than humans. The incubation period for respiratory diphtheria is 2–5 days, but disease onset has occurred as late as 10 days after

exposure. Prior to the vaccination era, most individuals over the age of

10 were immune to C. diphtheriae; infants were protected by maternal

IgG antibodies but became susceptible after ~6 months of age. Thus,

the disease primarily affected children and nonimmune young adults.

The development of diphtheria antitoxin in 1898 by von Behring

and of the diphtheria toxoid vaccine in 1924 by Ramon led to the

near-elimination of diphtheria in Western countries. The annual

incidence rate in the United States peaked in 1921, with 206,000 cases

(191 cases per 100,000) and 15,520 deaths. In contrast, since 1980,

the annual figure in the United States has been fewer than 5 cases per

100,000, with only 2 cases reported from 2004 through 2017. Nevertheless, pockets of colonization persist in North America, and groups

or individuals who resist vaccination remain at risk. Immunity to

diphtheria induced by childhood vaccination gradually decreases in

adulthood. An estimated 30% of men 60–69 years old have antitoxin

titers below the protective level. In addition to older age and lack of

vaccination, risk factors for diphtheria outbreaks include alcoholism,

low socioeconomic status, crowded living conditions, and Native

American ethnic background. An outbreak of diphtheria in Seattle,

Washington, between 1972 and 1982 comprised 1100 cases, most of

which were cutaneous. During the 1990s in the states of the former

Soviet Union, a much larger diphtheria epidemic included more than

140,000 cases and more than 4000 deaths; at its peak in 1995, more

than 50,412 cases were reported. Clonally related toxigenic C. diphtheriae strains of the ET8 complex were associated with this outbreak.

Beginning in 1998, this epidemic was controlled by mass vaccination

programs, and between 2000 and 2009 the diphtheria incidence fell by

>95%, with high-burden countries such as Latvia reporting fewer than

10 cases. During the epidemic, the incidence rate was high among individuals between 16 and 50 years of age. The epidemic was attributed

to multiple factors, including socioeconomic instability, migration,

deteriorating public health programs, unnecessary contraindications to

vaccination, low-dose vaccine formulations, frequent vaccine and antitoxin shortages, delayed implementation of vaccination and treatment

in response to cases, public mistrust, and lack of awareness.

Since 2010, significant outbreaks of diphtheria and diphtheriarelated mortality have continued to be reported from many developing countries, including the Dominican Republic, Nigeria, India,

Laos, Thailand, Indonesia, and Brazil. Statistics collected by the

World Health Organization indicated that 7321 diphtheria cases were

reported in 2014, but many more cases are likely to have gone unreported. Although 86% of the global population has been adequately

vaccinated, only 28% of countries have successfully vaccinated >80%

of individuals in all districts.

Cutaneous diphtheria is usually a secondary infection that follows

a primary skin lesion due to trauma, allergy, or autoimmunity. Most

often, these isolates lack the tox gene and thus do not express diphtheria toxin. In tropical latitudes, cutaneous diphtheria is more common

than respiratory diphtheria. In contrast to respiratory disease, cutaneous diphtheria is not reportable in the United States. Nontoxigenic

strains of C. diphtheriae have been associated with pharyngitis in

Europe, causing outbreaks among men who have sex with men and

persons who use illicit IV drugs.

■ PATHOGENESIS AND IMMUNOLOGY

Diphtheria toxin produced by tox+ strains of C. diphtheriae is the primary virulence factor in clinical disease. The toxin is synthesized in

precursor form; is released as a 535-amino-acid, single-chain protein;

and, in sensitive species (e.g., guinea pigs and humans, but not mice

or rats), has a 50% lethal dose of ~100 ng/kg of body weight. The

toxin is produced in the pseudomembranous lesion and is taken up in

the bloodstream, from which it is distributed to all organ systems in

the body. Once bound to its cell surface receptor (a heparin-binding

epidermal growth factor–like precursor), the toxin is internalized by

receptor-mediated endocytosis and enters the cytosol from an acidified

early endosomal compartment. In vitro, the toxin may be separated

into two chains by digestion with serine proteases: the N-terminal A

fragment and the C-terminal B fragment. Delivery of the A fragment

into the eukaryotic cell cytosol results in irreversible inhibition of

protein synthesis by NAD+-dependent ADP-ribosylation of elongation

factor 2. The eventual result is the death of the cell.

In 1926, Ramon at the Institut Pasteur found that formalinization

of diphtheria toxin resulted in the production of a nontoxic but highly

immunogenic diphtheria toxoid. Subsequent studies showed that

immunization with diphtheria toxoid elicited antibodies that neutralized the toxin and prevented most disease manifestations. In the 1930s,

mass immunization of children and susceptible adults with diphtheria

toxoid commenced in the United States and Europe.

Individuals with a diphtheria antitoxin titer of >0.01 U/mL are at

low risk of disease. In populations where a majority of individuals have

protective antitoxin titers, the carrier rate for toxigenic strains of C.

diphtheriae decreases and the overall risk of diphtheria among susceptible individuals is reduced. Nevertheless, individuals with nonprotective titers may contract diphtheria through either travel or exposure to

individuals who have recently returned from regions where the disease

is endemic.

Characteristic pathologic findings of diphtheria include mucosal

ulcers with a pseudomembranous coating composed of an inner band

of fibrin and a luminal band of neutrophils. Initially white and firmly

adherent, in advanced diphtheria the pseudomembranes turn gray or

even green or black as necrosis progresses. Mucosal ulcers result from

toxin-induced necrosis of the epithelium accompanied by edema,

hyperemia, and vascular congestion of the submucosal base. A significant fibrinosuppurative exudate from the ulcer develops into the

pseudomembrane. Ulcers and pseudomembranes in severe respiratory

diphtheria may extend from the pharynx into medium-sized bronchial

airways. Expanding and sloughing membranes may result in fatal airway obstruction.

APPROACH TO THE PATIENT

Diphtheria

Diphtheria, although rare in the United States and other developed

countries, should be considered when a patient has severe pharyngitis, particularly when there is difficulty swallowing, respiratory

compromise, or signs of systemic disease (e.g., myocarditis or generalized weakness). The leading causes of pharyngitis are respiratory viruses (rhinoviruses, influenza viruses, parainfluenza viruses,

coronaviruses, adenoviruses; ~25% of cases), group A streptococci

(15–30%), group C streptococci (~5%), atypical bacteria such as

Mycoplasma pneumoniae and Chlamydia pneumoniae (15–20% in

some series), and other viruses such as herpes simplex virus (~4%)

and Epstein-Barr virus (<1% in infectious mononucleosis). Less

common causes are acute HIV infection, gonorrhea, fusobacterial infection (e.g., Lemierre’s syndrome), thrush due to Candida

albicans or other Candida species, and diphtheria. The presence

of a pharyngeal pseudomembrane or an extensive exudate should

prompt consideration of diphtheria (Fig. 150-1).

■ CLINICAL MANIFESTATIONS

Respiratory Diphtheria The clinical diagnosis of diphtheria is

based on the constellation of sore throat; adherent tonsillar, pharyngeal, or nasal pseudomembranous lesions; and low-grade fever.

In addition, diagnosis requires the isolation of C. diphtheriae or histopathologic isolation of compatible gram-positive organisms. The

1205CHAPTER 150 Diphtheria and Other Corynebacterial Infections

FIGURE 150-1 Respiratory diphtheria due to toxigenic C. diphtheriae producing

exudative pharyngitis in a child displaying a pseudomembrane extending from

the uvula to the pharyngeal wall. The characteristic white pseudomembrane is

caused by diphtheria toxin–mediated necrosis of the respiratory epithelial layer,

producing a fibrinous coagulative exudate. Submucosal edema adds to airway

narrowing. The pharyngitis is acute in onset, and respiratory obstruction from the

pseudomembrane may occur in severe cases. Inoculation of pseudomembrane

fragments or submembranous swabs onto Löffler’s or tellurite selective medium

reveals C. diphtheriae. (Photograph courtesy of the Centers for Disease Control and

Prevention and Immunization Action Coalition, used by permission.)

FIGURE 150-2 Cutaneous diphtheria due to nontoxigenic C. diphtheriae on the

lower extremity. (From the Centers for Disease Control and Prevention, Public

Health Image Library [PHIL]. #1941.)

Centers for Disease Control and Prevention (CDC) recognizes confirmed respiratory diphtheria (laboratory proven or epidemiologically

linked to a culture-confirmed case) and probable respiratory diphtheria

(clinically compatible but not laboratory proven or epidemiologically

linked). Carriers are defined as individuals who have positive cultures

for C. diphtheriae and who either are asymptomatic or have symptoms

but lack pseudomembranes. Most patients seek medical care for sore

throat and fever several days into the illness. Occasionally, weakness,

dysphagia, headache, and voice change are the initial manifestations.

Neck edema and difficulty breathing are evident in more advanced

cases and carry a poor prognosis.

The systemic manifestations of diphtheria stem from the effects of

diphtheria toxin and include weakness as a result of neurotoxicity and

cardiac arrhythmias or congestive heart failure due to myocarditis.

Most commonly, the pseudomembranous lesion is located in the tonsillopharyngeal region. Less commonly, the lesions are located in the

larynx, nares, and trachea or bronchial passages. Large pseudomembranes are associated with severe disease and a poor prognosis. A few

patients develop massive swelling of the tonsils and present with “bullneck” diphtheria, which results from edema of the submandibular and

paratracheal region and is further characterized by foul breath, thick

speech, and stridorous breathing. The diphtheritic pseudomembrane

is gray or whitish and sharply demarcated. Unlike the exudative lesion

associated with streptococcal pharyngitis, the pseudomembrane in

diphtheria is tightly adherent to the underlying tissues. Attempts to dislodge the membrane may cause bleeding. Hoarseness suggests laryngeal diphtheria, in which laryngoscopy may be diagnostically helpful.

Cutaneous Diphtheria This dermatosis is characterized by punched-out ulcerative lesions with necrotic sloughing or

pseudomembrane formation (Fig. 150-2). The diagnosis requires cultivation of C. diphtheriae from lesions, which most commonly occur on

the lower and upper extremities, head, and trunk.

Infections Due to Non-diphtheriae Corynebacterium Species

and Nontoxigenic C. diphtheriae Non-diphtheriae species of

Corynebacterium and related genera (discussed below) as well as nontoxigenic strains of C. diphtheriae itself have been found in bloodstream

and respiratory infections, often in individuals with immunosuppression or chronic respiratory disease. These organisms can cause disease

manifestations and should not necessarily be dismissed as colonizers.

Other Clinical Manifestations C. diphtheriae causes rare cases

of endocarditis and septic arthritis, most often in patients with preexisting risk factors, such as abnormal cardiac valves, injection drug use,

or cirrhosis.

■ COMPLICATIONS

Airway obstruction poses a significant early risk in patients presenting

with advanced diphtheria. Pseudomembranes may slough and obstruct

the airway or may advance to the larynx or into the tracheobronchial

tree. Children are particularly prone to obstruction because of their

small airways.

Polyneuropathy and myocarditis are late toxic manifestations of

diphtheria. During a diphtheria outbreak in the Kyrgyz Republic in

1999, myocarditis was found in 22% and neuropathy in 5% of 676

hospitalized patients. The mortality rate was 7% among patients

with myocarditis as opposed to 2% among those without myocardial

manifestations. The median time to death in hospitalized patients was

4.5 days. Myocarditis is typically associated with arrhythmias and

dilated cardiomyopathy.

Polyneuropathy is seen 3–5 weeks after the onset of diphtheria and

has a slow indolent course. However, patients may develop severe and

prolonged neurologic abnormalities. The disorders typically occur in

the mouth and neck, with lingual or facial numbness as well as dysphonia, dysphagia, and cranial nerve paresthesias. More ominous signs

include weakness of respiratory and abdominal muscles and paresis

of the extremities. Sensory manifestations and sensory ataxia also are

observed. Cranial nerve dysfunction typically precedes disturbances of

the trunk and extremities because of proximity to the site of infection.

Autonomic dysfunction also is associated with polyneuropathy and can

lead to hypotension. Polyneuropathy is typically reversible in patients

who survive the acute phase.

Other complications of diphtheria include pneumonia, renal failure,

encephalitis, cerebral infarction, pulmonary embolism, and serum

sickness from antitoxin therapy.

1206 PART 5 Infectious Diseases

■ DIAGNOSIS

The diagnosis of diphtheria is based on clinical signs and symptoms

plus laboratory confirmation. Respiratory diphtheria should be considered in patients with sore throat, pharyngeal exudates, and fever.

Other symptoms may include hoarseness, stridor, or palatal paralysis.

The presence of a pseudomembrane should prompt strong consideration of diphtheria. Once a clinical diagnosis of diphtheria is made,

diphtheria antitoxin should be obtained and administered as rapidly

as possible.

Laboratory diagnosis of diphtheria is based either on cultivation of

C. diphtheriae or toxigenic C. ulcerans from the site of infection or on

the demonstration of local lesions with characteristic histopathology.

Corynebacterium pseudodiphtheriticum, a nontoxigenic organism, is

a common component of the normal throat flora and does not pose a

significant risk. Throat samples should be submitted to the laboratory

for culture with the notation that diphtheria is being considered. This

information should prompt cultivation on special selective medium

and subsequent biochemical testing to differentiate C. diphtheriae

from other nasopharyngeal commensal corynebacteria. All laboratory

isolates of C. diphtheriae, including nontoxigenic strains, should be

submitted to the CDC.

A diagnosis of cutaneous diphtheria requires laboratory confirmation since the lesions are not characteristic and are indistinguishable

from other dermatoses. Diphtheritic ulcers occasionally—but not

consistently—have a punched-out appearance (Fig. 150-2). Patients in

whom cutaneous diphtheria is identified should have the nasopharynx

cultured for C. diphtheriae. The laboratory medium for cutaneous

diphtheria specimens is the same as that used for respiratory diphtheria: Löffler’s or Tinsdale’s selective medium in addition to nonselective medium such as blood agar. As has been mentioned, respiratory

diphtheria remains a notifiable disease in the United States, whereas

cutaneous diphtheria is not.

TREATMENT

Diphtheria

DIPHTHERIA ANTITOXIN

Prompt administration of diphtheria antitoxin is critical in the

management of respiratory diphtheria. Diphtheria antitoxin, a

horse antiserum, is effective in reducing the extent of local disease

as well as the risk of complications of myocarditis and neuropathy.

Rapid institution of antitoxin therapy is also associated with a significant reduction in mortality risk. Because diphtheria antitoxin

cannot neutralize cell-bound toxin, prompt initiation is important.

This product, which is no longer commercially available in the

United States, can be obtained from the CDC Emergency Operations Center at 770-488-7100 (website: www.cdc.gov/diphtheria/dat

.html) after first contacting the state health department. The current

protocol for the use of diphtheria antitoxin involves a test dose to

rule out immediate hypersensitivity. Patients who demonstrate

hypersensitivity require desensitization before a full therapeutic

dose of antitoxin is administered.

Given that the world supply of equine anti–diphtheria toxin

is limited, a human monoclonal antibody with the potential to

provide a safer alternative to equine antitoxin therapy is being

developed.

ANTIMICROBIAL THERAPY

Antibiotics are used in the management of diphtheria primarily

to prevent transmission to susceptible contacts. Antibiotics also

prevent further toxin production and reduce the severity of local

infection. Recommended treatment options for patients with respiratory diphtheria are as follows:

• Erythromycin, 500 mg IV q6h (for children: 40–50 mg/kg

per day IV in two or four divided doses) until the patient can

swallow comfortably; then 500 mg PO qid to complete a 14-day

course

• Procaine penicillin G, 600,000 U IM q12h (for children: 12,500–

25,000 U/kg IM q12h) until the patient can swallow comfortably;

then oral penicillin V, 125–250 mg qid to complete a 14-day

course

A clinical study in Vietnam found that penicillin was associated

with a more rapid resolution of fever and a lower rate of bacterial

resistance than erythromycin; however, relapses were more common in the penicillin group. Erythromycin therapy targets protein

synthesis and thus offers the presumed benefit of stopping toxin

synthesis more quickly than a cell wall–active β-lactam agent.

Alternative therapeutic agents for patients who are allergic to penicillin or cannot take erythromycin include rifampin and clindamycin. Other reasonable antibiotics are clarithromycin, azithromycin,

linezolid, and vancomycin, although they have not been studied in

comparison to the agents above.

Eradication of C. diphtheriae should be documented after antimicrobial therapy is complete. A repeat throat culture 2 weeks

later is recommended. For patients in whom the organism is not

eradicated after a 14-day course of erythromycin or penicillin,

an additional 10-day course followed by repeat culture is recommended. Drug-resistant strains of C. diphtheriae exist, and several

reports have described multidrug-resistant strains, predominantly

in Southeast Asia. Drug resistance should be considered when

efforts at pathogen eradication fail.

Cutaneous diphtheria should be treated as described above

for respiratory disease. Individuals infected with toxigenic strains

should receive antitoxin. It is important to treat the underlying

cause of the dermatoses in addition to the superinfection with

C. diphtheriae.

Patients who recover from respiratory or cutaneous diphtheria

should have antitoxin levels measured. If diphtheria antitoxin has

been administered, this test should be performed 6 months later.

Patients who recover from respiratory or cutaneous diphtheria

should receive the appropriate vaccine to ensure the development

of protective antibody titers.

MANAGEMENT STRATEGIES

Patients in whom diphtheria is suspected should be hospitalized

in respiratory isolation rooms, with close monitoring of cardiac

and respiratory function. A cardiac workup is recommended to

assess the possibility of myocarditis. In patients with extensive

pseudomembranes, an anesthesiology or an ear, nose, and throat

consultation is recommended because of the possible need for tracheostomy or intubation. In some settings, pseudomembranes can

be removed surgically. Treatment with glucocorticoids has not been

shown to reduce the risk of myocarditis or polyneuropathy.

■ PROGNOSIS

The mortality rate for diphtheria is 5–10% but may approach 20%

among children <5 years old and adults >40 years of age. Fatal

pseudomembranous diphtheria typically occurs in patients with

nonprotective antibody titers and in unimmunized patients. The

pseudomembrane may actually increase in size from the time it is first

noted. Risk factors for death include bullneck diphtheria; myocarditis

with ventricular tachycardia; atrial fibrillation; complete heart block;

an age of >60 years or <6 months; alcoholism; extensive pseudomembrane elongation; and laryngeal, tracheal, or bronchial involvement.

Another important predictor of fatal outcome is the interval between

the onset of local disease and the administration of antitoxin. Cutaneous diphtheria has a low mortality rate and is rarely associated with

myocarditis or peripheral neuropathy.

■ PREVENTION

Vaccination Sustained campaigns for vaccination of children and

adequate boosting vaccination of adults are responsible for the exceedingly low incidence of diphtheria in most developed nations. Currently,

diphtheria toxoid vaccine is coadministered with tetanus vaccine (with

or without acellular pertussis). DTaP (full-level diphtheria toxoid,

1207CHAPTER 150 Diphtheria and Other Corynebacterial Infections

tetanus toxoid, and acellular pertussis vaccine) is currently recommended for children up to the age of 6; DTaP replaced the earlier

whole-cell pertussis vaccine DTP in 1997. Tdap is a tetanus toxoid,

reduced diphtheria toxoid, and acellular pertussis vaccine formulated

for adolescents and adults. Tdap was licensed for use in the United

States in 2005 and is recommended for children ≥7 years old and for

adults. It is recommended that all adults (i.e., persons >19 years old)

receive a single dose of Tdap if they have not received it previously,

regardless of the interval since the last dose of Td (tetanus and reduceddose diphtheria toxoids, adsorbed). Tdap vaccination is a priority for

health care workers, pregnant women, adults anticipating contact with

infants, and adults not previously vaccinated for pertussis. Adults who

have received acellular pertussis vaccine should continue to receive

decennial Td booster vaccinations. The vaccine schedule is detailed

in Chap. 123.

Prophylaxis Administration to Contacts Close contacts

of diphtheria patients should undergo throat culture to determine

whether they are carriers. After samples for throat culture are obtained,

antimicrobial prophylaxis should be considered for all contacts, even

those whose cultures are negative. The options are 7–10 days of oral

erythromycin or one dose of IM benzathine penicillin G (1.2 million

units for persons ≥6 years of age or 600,000 units for children <6 years

of age).

Contacts of diphtheria patients whose immunization status is

uncertain should receive the appropriate diphtheria toxoid–containing

vaccine. The Tdap vaccine (rather than Td) is now the booster vaccine

of choice for adults who have not recently received an acellular pertussis–containing vaccine. Carriers of C. diphtheriae in the community

should be treated and vaccinated when identified.

OTHER CORYNEBACTERIAL AND

RHODOCOCCUS INFECTIONS

Nondiphtherial corynebacteria, referred to as diphtheroids or coryneforms, are frequently considered colonizers or contaminants; however,

they have been associated with invasive disease, particularly in immunocompromised patients. Importantly, even though they are termed

nondiphtherial corynebacteria, C. ulcerans and C. pseudotuberculosis

may produce diphtheria toxin and therefore cause severe human

illness. These organisms have been isolated from the bloodstream,

especially in association with catheter infection, endocarditis, prosthetic valve infection, meningitis, brain abscess, osteomyelitis, and

peritonitis. Risk factors include indwelling intravenous or peritoneal

catheters and neurosurgical shunts. Patients infected with these organisms are often immunosuppressed or have significant medical comorbidities. The nondiphtherial coryneforms are a collection of bacteria

that are taxonomically grouped together in the genus Corynebacterium

on the basis of their 16S rDNA signature nucleotides. Despite the

shared rDNA signatures, these isolates are quite diverse. For example, their guanine-cytosine content ranges from 45 to 70%. Several

nondiphtheroid corynebacteria, including Corynebacterium jeikeium

and Corynebacterium urealyticum, are associated with resistance to

multiple antibiotics. Rhodococcus equi is associated with necrotizing

pneumonia and granulomatous infection, particularly in immunocompromised individuals.

■ MICROBIOLOGY AND LABORATORY DIAGNOSIS

These organisms are non-acid-fast, catalase-positive, aerobic or facultatively anaerobic rods. Their colonial morphologies on blood agar

vary widely; some species are small and α-hemolytic (similar to lactobacilli), whereas others form large white colonies (similar to yeasts).

Many nondiphtherial coryneforms require special media, such as

Löffler’s, Tinsdale’s, or tellurite medium. These cultivation idiosyncrasies have led to a complex taxonomic categorization of the organisms.

■ EPIDEMIOLOGY

Humans are the natural reservoirs for several nondiphtherial coryneforms, including C. xerosis, C. pseudodiphtheriticum, C. striatum,

C. minutissimum, C. jeikeium, C. urealyticum, and Arcanobacterium

haemolyticum. Animal reservoirs including milk are responsible for

carriage of C. ulcerans and C. pseudotuberculosis. Soil is the natural

reservoir for R. equi.

■ CLINCAL MANIFESTATIONS

C. ulcerans This organism causes a diphtheria-like illness and produces both diphtheria toxin and a dermonecrotic toxin. The organism

is a commensal in horses and cattle and has been isolated from cow’s

milk. In contrast to diphtheria, this infection is considered a zoonosis,

and cases have been traced to contact with animal carriers, including

dogs and pigs. C. ulcerans causes exudative pharyngitis, primarily during summer months, in rural areas, and among individuals exposed to

animals. Treatment with antitoxin and antibiotics should be initiated

when respiratory C. ulcerans is identified, and a contact investigation

(including throat cultures to determine the need for antimicrobial prophylaxis and, in unimmunized contacts, administration of the appropriate diphtheria toxoid–containing vaccine) should be conducted.

The organism grows on Löffler’s, Tinsdale’s, and tellurite agars as well

as blood agar. In addition to exudative pharyngitis, cutaneous disease

due to C. ulcerans has been reported. C. ulcerans is susceptible to a wide

panel of antibiotics. Erythromycin and other macrolides appear to be

the first-line agents.

C. pseudotuberculosis Infection caused by C. pseudotuberculosis

is an important animal pathogen (most notably of sheep) that rarely

causes human disease. C. pseudotuberculosis causes suppurative granulomatous lymphadenitis and an eosinophilic pneumonia syndrome

among individuals who handle sheep; horses, cattle, goats, deer, and

raw milk also have been implicated. Surgical excision of affected lymph

nodes should be performed when feasible, and successful treatment

with erythromycin or tetracycline has been reported. Some strains

express diphtheria toxin and produce a diphtheria-like disease, which

should be treated with antitoxin.

C. jeikeium (Group JK) Originally described in American hospitals, C. jeikeium infection was subsequently reported in Europe. After a

1976 survey of diseases caused by nondiphtherial corynebacteria, CDC

group JK emerged as an important opportunistic pathogen among

neutropenic and HIV-infected patients. The organism has now been

designated a separate species. C. jeikeium forms small, gray to white,

glistening, nonhemolytic colonies on blood agar. It lacks urease and

nitrate reductase and does not ferment most carbohydrates. The predominant syndrome associated with C. jeikeium is sepsis, sometimes

with associated pneumonia, endocarditis, meningitis, osteomyelitis, or

epidural abscess. Risk factors for C. jeikeium infection include hematologic malignancy, neutropenia from comorbid conditions, prolonged

hospitalization, exposure to multiple antibiotics, and skin disruption.

There is evidence that C. jeikeium is part of the inguinal, axillary, genital, and perirectal flora of hospitalized patients.

Broad-spectrum antimicrobial therapy appears to select for colonization. The organisms appear as gram-positive coccobacillary forms

slightly resembling streptococci. C. jeikeium is resistant to the majority

of antibiotic classes except oxazolidinones (e.g., linezolid) and glycopeptides (e.g., vancomycin). Effective therapy involves removal of the

infectious source, whether a catheter, prosthetic joint, or prosthetic

valve. Efforts have been made to prevent C. jeikeium infection with

strict institution of infection control protocols for high-risk patients,

particularly those in intensive care units.

C. urealyticum (Group D2) Identified as a urease-positive

nondiphtherial Corynebacterium in 1972, C. urealyticum is an opportunistic pathogen causing sepsis and urinary tract infection. C. urealyticum appears to be the etiologic agent of a severe urinary tract

syndrome known as alkaline-encrusted cystitis, a chronic inflammatory

bladder infection associated with deposition of ammonium magnesium phosphate on the surface and walls of ulcerating lesions in the

bladder. In addition, C. urealyticum has been associated with pneumonia, peritonitis, endocarditis, osteomyelitis, and wound infection.

It is similar to C. jeikeium in its resistance to most antibiotics except

oxazolidinones and glycopeptides. Vancomycin therapy has been used

successfully in severe infections.