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AUTHOR AND EDITOR INFORMATION

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Author: Kyle L Horner, MD, MS, Staff Physician, Department of Dermatology, Penn State Milton S Hershey Medical Center

Kyle L Horner is a member of the following medical societies: American Academy of Dermatology, American Medical Association, and Washington State Medical Association

Coauthor(s): Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle; Kord Honda, MD, Fellow in Dermatopathology, Division of Dermatology, Department of Medicine, University of Cincinnati; Richard Miller, MD, Chief, Infectious Disease Section, VA Medical Center; Associate Professor, Department of Medicine, Division of Infectious Diseases, University of Washington

Editors: Robin Travers, MD, Professor, Department of Dermatology, Boston University School of Medicine; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Paul Krusinski, MD, Director of Dermatology, Professor, Department of Internal Medicine, Fletcher Allen Health Care, University of Vermont; Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center

Author and Editor Disclosure

Synonyms and related keywords: A haemolyticum, C haemolyticum, Corynebacterium haemolyticum, C pyogenes, Corynebacterium pyogenes, pharyngitis, cutaneous infections, infections, secretive bacteria, pharyngeal infection

INTRODUCTION

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Background

The bacterium now named Arcanobacterium haemolyticum was first described in 1946 as the pathogenic agent causing pharyngitis and cutaneous infections among US service members and indigenous peoples of the South Pacific.1 As a result of its close resemblance to Corynebacterium pyogenes, some investigators believed the bacterium to be a mutant of this species and appended a subspecies name, C pyogenes subsp hominis.

Based on its peptidoglycan, fatty acid, and DNA characteristics, the bacterium was renamed and reclassified as the first member of the genus Arcanobacterium, which means "secretive bacteria.2" Since its original description, the spectrum of diseases caused by A haemolyticum has been expanded to include invasive infections, including sepsis and osteomyelitis. The importance of A haemolyticum to dermatology lies in the characteristic rash associated with pharyngeal infection. Interestingly, the cutaneous manifestations of A haemolyticum infection apparently were not reported in the dermatologic literature until 1996.3

Pathophysiology

A haemolyticum is a pleomorphic, facultatively anaerobic, nonmotile, nonsporulating, non–acid-fast, hemolytic gram-positive rod. However, the organism can demonstrate a variable response to Gram staining if examined after 24 hours of growth.1, 4 The at least 70 known strains are divided into smooth and rough biotypes.5 The smooth biotype predominates in wound infections, and the rough biotype predominates in respiratory tract infections.6

The composition of the cell wall is based on lysine, and its fatty acids are primarily straight and monounsaturated.7 A haemolyticum ferments dextrose, maltose, lactose, galactose, and glycerol. It coagulates milk and causes liquefaction of gelatin. The bacterium does not reduce nitrates or produce indole.1

A haemolyticum infection has rarely been reported in animals, and its pathogenicity in animals has not been well documented.8, 9 Humans are believed to be its main environmental reservoir, although, usually, A haemolyticum is not a respiratory colonizer.

Since its original description, A haemolyticum has been occasionally isolated in patients with sepsis, osteomyelitis, septic arthritis, cellulitis, wound infections, venous ulcers, skin abscesses, peritonsillar abscesses, cavitary pneumonia, pyothorax, paronychia, omphalitis, otitis media, endocarditis, sinusitis, orbital cellulitis, canaliculitis, meningitis, brain abscesses, diabetic soft tissue infections, and spontaneous bacterial peritonitis.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29
 
Many of the patients are immunocompromised (eg, from cancer, diabetes). A haemolyticum is sometimes a copathogen with other bacteria, including with Fusobacterium necrophorum in one case of Lemierre disease.30

Although A haemolyticum has been implicated in a wide spectrum of diseases, it has been most commonly associated with pharyngitis. Several investigators reported A haemolyticum as the sole or dominant pathogen in patients presenting with pharyngitis. These studies are limited because the investigators did not look for concomitant infection by viruses or atypical bacteria.

Patients from whom A haemolyticum is cultured develop specific antibody responses to the bacteria.31 Furthermore, the bacteria gradually disappear from the oropharynx as the symptoms subside.1 These studies suggest that A haemolyticum is a pathogenic organism in some adults with pharyngitis. However, in experimental studies conducted on humans, 325,000 A haemolyticum organisms were inoculated into each tonsil of 7 healthy volunteers. No organisms could be recovered 1 hour later, but cultures performed 24-48 hours after inoculation showed a predominant growth of A haemolyticum, which persisted for 4-6 weeks.1 None of these patients developed symptomatic disease.

Pharyngitis caused by A haemolyticum must be differentiated from the more prevalent pharyngitis caused by streptococcal organisms. A haemolyticum may be missed on routine throat cultures because of the use of rapid group A streptococcal antigen assays and the use of special culture media for optimal isolation of group A streptococcal species. Most cultures for pharyngitis are evaluated at 24 hours, at which point A haemolyticum colonies are very small and demonstrate minimal hemolysis, and the cultures may be discarded.

Epidemiologic contact studies indicate that the infection is likely spread through an unknown route by human contact with people who are infected.32 A haemolyticum is rarely recovered in healthy individuals.33, 34

The mechanism responsible for adherence of A haemolyticum to the pharyngeal mucosa is not known. In vitro experiments have shown that A haemolyticum does have the ability to invade HEp-2 cells (immortalized upper respiratory tract epithelial cells) and survive there for 4 days, thus creating an intracellular reservoir of bacteria.35

The pathophysiology of the rash is also unknown; however, the hypothesis that the rash is caused by a bacterial exotoxin is reasonable. Phospholipase D, neuraminidase, and a hemolysin have been identified as extracellular toxins secreted by A haemolyticum.36

Frequency

United States

A haemolyticum has been isolated from the pharynx in 0.4% of adult patients with pharyngitis in the United States.32 When specifically sought in throat swab cultures, A haemolyticum is found responsible for 0.5-2.5% of bacterial pharyngitis cases, especially among adolescents.37

International

In Canada and Finland, A haemolyticum pharyngitis has a similar incidence to that found in the United States. In Israel, the Czech Republic, and Sweden, A haemolyticum was cultured from the pharynx of people with pharyngitis with frequencies of 0.2%, 0.75%, and 2% of patients, respectively.38, 39, 40, 41, 34

Mortality/Morbidity

Rarely, a patient with pharyngitis caused by A haemolyticum is hospitalized because of an inability to swallow. Cases of peritonsillar abscess have been reported, requiring drainage in 5 patients.42, 43, 32 Sepsis developed in 4 patients with pharyngitis; A haemolyticum was isolated from blood cultures of these patients.44, 45, 46, 47 Sepsis and pulmonary abscess with tonsillitis developed in 1 patient.44 No deaths have been reported resulting from pharyngitis caused by A haemolyticum, although A haemolyticum caused the death of 2 patients with endocarditis.14, 26

Race

No known racial susceptibility to the disease has been reported.

Sex

In 1 study, a higher rate of pharyngitis caused by A haemolyticum was reported in females than in males, in which the male-to-female ratio was 1:1.6, while another study reported a higher rate in males compared with females, in which the male-to-female ratio was 1.3:1.48, 33

Age

Pharyngitis caused by A haemolyticum most commonly affects adolescents and young adults aged 10-30 years, with the maximum incidence occurring among those aged 15-18 years.38


CLINICAL

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History

The most common symptoms include the following32, 33:

  • Sore throat (97-100%)
  • Pruritus (33%)
  • Nonproductive cough (33%)

Physical

Physical examination findings include fever (40-64%), pharyngeal erythema (97-100%), tonsillar exudate (70%), lymphadenopathy (41-48%), and rash (0-75%). The fever ranges from 37.6-40°C.32, 41

  • Pharyngitis: The pharyngeal exudate is patchy and gray-to-white. It is difficult to scrape off. Although the appearance of the posterior aspect of the pharynx is similar to that of scarlet fever, no associated hemorrhagic macules on the palate or findings on the tongue are present.32
  • Exanthem: The exanthem has been described only in patients with pharyngitis, not in patients with infection of other sites.
    • It usually develops 1-4 days after the pharyngitis, although occasionally, it is the initial manifestation of the infection.
    • It has been described as erythematous (see Media File 1), pruritic, urticarial, scarlatiniform, and maculopapular.
    • It usually begins on the extensor surfaces of the extremities, where it is most severe (see Media Files 2-3). Over the next 2-3 days, it spreads centrally to the neck and the trunk.
    • It almost always spares the face (see Media File 4), the palms, and the soles, and the abdomen and the buttocks are relatively spared.
    • It usually persists longer than 48 hours, and mild desquamation may occur during resolution.32
    • No long-term sequelae have been noted.
    • Although the onset of rash and the constitutional symptoms are similar to those of scarlet fever, the rash in scarlet fever is centrifugal and has prominent Pastia lines. In both conditions, desquamation may occur during resolution of the rash.
  • Lymphadenopathy: Patients may develop anterior cervical or submandibular lymphadenopathy that is bilateral, tender, and 1-1.5 cm in size.

Causes

No risk factors are known for A haemolyticum infection. Although purely speculative, Parija et al22 suggested in 2005 that close contact with animals such as cows and buffaloes and handling or consumption of unpasteurized milk might put patients at risk. A recent investigation did isolate a strain of A haemolyticum (DSM 20595T) from preputial swabs of European bison (Bison bonasus) bulls with balanoposthitis.49


DIFFERENTIALS

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Cutaneous Manifestations of HIV Disease
Enteroviral Infections
Scarlet Fever
Syphilis

Other Problems to be Considered

Epstein-Barr virus infection
Mucocutaneous lymph node syndrome
Toxoplasmosis
Toxic shock syndrome
Diphtheria
Kawasaki disease
Mycoplasma pneumoniae infection
Vincent angina
Yersinia enterocolitica infection
Acute HIV type 1 infection
Influenza virus infection
Adenovirus infection
Coronavirus infection
Parainfluenza infection
Rhinovirus infection
Coxsackie virus infection
Secondary syphilis
Gonorrheal pharyngitis


WORKUP

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Lab Studies

  • A complete blood cell count can show a white blood cell count of 7,100-23,000 cells/µL, with polymorphonuclear leukocytosis and a mean level of 13,000 cells/µL.32, 33
  • Monospot and antistreptolysin O titers are negative (unless concomitant infection is present), and help to distinguish A haemolyticum infection from infectious mononucleosis and scarlet fever.
  • Kits are available to identify A haemolyticum, such as the bioMérieux ANI card and the bioMérieux Coryne strip (a miniaturized test strip format), but are infrequently used in clinical laboratories.30
    • The diagnosis is most often made by culturing the pharyngeal swab on 5% blood agar plates (preferably rabbit or human blood agar, although sheep blood agar works if read at 48 h) at 37°C with 5% carbon dioxide for 24-48 hours. Because most throat cultures are plated on sheep blood agar and read at 24 hours, the slow-growing colonies of A haemolyticum may be missed.50
    • At 48 hours, the bacteria produce nonpigmented 1-mm diameter colonies surrounded by a 3- to 5-mm diameter zone of hemolysis. Transmitted light may reveal a small dark dot at the center of each colony.22
  • If the clinician suspects this diagnosis, the laboratory should be notified because special media, longer incubation times, and further investigations are required for isolation and identification.

Imaging Studies

  • No imaging studies are recommended. Radiography, CT scanning, or MRI can be used in special circumstances when A haemolyticum is suspected in peritonsillar abscesses, osteomyelitis, sinusitis, pulmonary infections, or central nervous system lesions.

Other Tests

  • No other tests are routinely recommended.

Procedures

  • No procedures are indicated.

Histologic Findings

Skin biopsy specimens of the exanthem typically reveal edema in the superficial dermis with a mixed perivascular infiltrate consisting of lymphocytes and smaller numbers of neutrophils, eosinophils, and plasma cells. The infiltrate is without antibody or fibrin deposition. Organisms are not observed in skin biopsy specimens.51, 32


TREATMENT

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Medical Care

Without antibiotic therapy, symptoms from pharyngeal infection last from a few days to 2 weeks. With antibiotic therapy, patients have symptoms for an average of 3 days.32 Whether antimicrobial therapy prevents late sequelae of infection is not known. However, the fact that the organism's prevalence may be increasing and because some of infections may be serious, antibiotic therapy is recommended.52

Surgical Care

Patients who develop a peritonsillar abscess require incision and drainage in addition to antibiotics.

Consultations

Consult an otolaryngologist to drain any suspected peritonsillar abscesses.

Diet

No specific dietary recommendations are indicated for this disease.

Activity

Patients can perform their normal activities.


MEDICATION

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No controlled trials of antimicrobial therapy have been conducted for pharyngitis caused by A haemolyticum. Many patients with pharyngitis have been treated with 1 dose of intramuscular penicillin or 7-10 days of erythromycin or oral penicillin.32 Antibiotic sensitivity testing reveals that most strains are resistant to trimethoprim-sulfamethoxazole; tetracycline resistance has been observed in 30% of strains tested.53, 4 A recent isolate was also resistant to ciprofloxacin.27 Virtually all strains of A haemolyticum studied so far are sensitive to erythromycin, azithromycin, and clindamycin.4 The majority of isolates are susceptible to penicillin, although tolerance has been reported. Accordingly, macrolides are now considered the drugs of choice.34, 33, 32

Penicillin treatment failures also may be related to the ability of A haemolyticum to invade HEp-2 cells (immortalized upper respiratory epithelial cells) and survive there for 4 days, thus creating an intracellular reservoir of bacteria.35 Macrolides achieve much higher intracellular concentrations than penicillin.35, 54, 55

More serious systemic infections have been treated successfully with high-dose intravenous beta-lactams (eg, penicillin, ampicillin, amoxicillin, cefuroxime, cefotaxime). Vancomycin is also an acceptable choice for serious infections; however, one strain carries the vanA gene, which is resistant to vancomycin.56 Antibiotic selection should be based on antibiotic sensitivity testing because no clinical trials of treatment of systemic infections have been conducted.

Drug Category: Antibiotics

Although antibiotic therapy decreases the duration of symptoms, whether it prevents sequelae of pharyngeal infection is not known.32, 1

Drug NameErythromycin (E.E.S, E-Mycin, Eryc, Eryc-Tab, Erythrocin)
DescriptionInhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, arresting RNA-dependent protein synthesis. For treatment of staphylococcal and streptococcal infections.
In children, age, weight, and severity of infection determine proper dosage. When bid dosing is desired, half of total daily dose may be taken q12h. For more severe infections, double dose. While no controlled studies have been performed, erythromycin has been effective in case series and most strains are susceptible.
Adult Dose250 mg PO q6h for 10 d
Pediatric Dose30-50 mg/kg/d PO divided q6h for 10 d; not to exceed 2 g/d
ContraindicationsDocumented hypersensitivity; hepatic impairment
InteractionsCoadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsCaution in liver disease; estolate formulation may cause cholestatic jaundice; adverse GI effects are common (administer doses pc); discontinue if nausea, vomiting, malaise, abdominal colic, or fever develop

Drug NameAzithromycin (Zithromax)
DescriptionActs by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Treats mild-to-moderate microbial infections. Shorter course and qd dosing make this a good alternative for patients who are sensitive to penicillin.
Adult Dose500 mg PO qd for 4-5 d
Pediatric Dose12 mg/kg/d PO qd for 5 d; not to exceed 500 mg
ContraindicationsDocumented hypersensitivity; hepatic impairment; do not administer with pimozide
InteractionsMay increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsSite reactions can occur with intravenous route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzyme levels and cause cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, geriatric, or debilitated patients

Drug NameClindamycin (Cleocin)
DescriptionSemisynthetic antibiotic produced by 7(S)-chloro-substitution of 7(R)-hydroxyl group of parent compound lincomycin. Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Widely distributes in the body without penetration of CNS. Protein bound and excreted by the liver and kidneys.
Oral or parenteral antibiotic for anaerobic or susceptible streptococcal, pneumococcal, or staphylococcal species. Considered to have good absorption into bloodstream in both oral and parental forms.
Adult Dose150-450 mg PO q8h
1.2-2.7 g IV/IM q8h
Pediatric DoseNeonates: Not established
Infants and children: 15-25 mg/kg/d PO q8h; 25-40 mg/kg/d IV/IM q8h
ContraindicationsDocumented hypersensitivity; regional enteritis, ulcerative colitis, hepatic impairment, antibiotic-associated colitis
InteractionsIncreases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects; antidiarrheals may delay absorption
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsAdjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile


FOLLOW-UP

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Further Inpatient Care

  • Occasionally, a patient who appears very ill with pharyngitis caused by A haemolyticum (ie, unable to swallow, illness is severe) may require admission for administration of parenteral antibiotics.
  • Admit patients with systemic infections caused by A haemolyticum to administer parenteral antibiotics and manage their infection in a way similar to that of a patient with bacteremia or focal abscess.

Deterrence/Prevention

  • Although epidemiologic contact studies suggest that the disease is spread from human to human, the exact mechanism of spread has not been determined. However, it is not unreasonable to suggest that judicious handwashing and avoiding shared utensils and food may help to prevent the spread of the disease.

Complications

  • Peritonsillar abscess has been reported in 5 patients. The patients presented with severe sore throat and fever (37.3-40.1°C). After drainage, resolution occurred in all patients.42, 43, 32
  • Sepsis, with isolation of A haemolyticum from blood cultures, has occurred in patients with pharyngitis.44, 45, 46, 47

Prognosis

  • The natural course of pharyngitis caused by A haemolyticum is resolution within a few days to 2 weeks.1
  • Antibiotics have been shown to eradicate A haemolyticum from the oropharynx and to resolve symptoms within 3 days.32
  • Whether antibiotic therapy prevents complications in patients with pharyngitis is not known.


MISCELLANEOUS

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Medical/Legal Pitfalls

  • Failure to clinically distinguish pharyngitis caused by A haemolyticum from scarlet fever is a pitfall. Diagnosis is differentiated by the results of bacterial pharyngeal culture.

Special Concerns

  • The authors would like to thank Jan Hirschmann for his critical review of this article and Richard Miller, MD, for graciously providing the images.


MULTIMEDIA

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Media file 1:  Rash associated with pharyngitis caused by Arcanobacterium haemolyticum. Note the erythematous nature of the rash.
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Media type:  Photo

Media file 2:  The rash associated with pharyngitis caused by Arcanobacterium haemolyticum is most prominent on the extremities. Note the rash on the upper limbs.
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Media type:  Photo

Media file 3:  The rash associated with pharyngitis caused by Arcanobacterium haemolyticum is most prominent on the extremities. Note the rash on the lower limbs.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  Photo

Media file 4:  Rash associated with pharyngitis caused by Arcanobacterium haemolyticum. Note the significant involvement of the extremities and the relative sparing of the face.
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Media type:  Photo


REFERENCES

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Arcanobacterium Haemolyticum excerpt

Article Last Updated: Feb 1, 2007