Arcanobacterium haemolyticum

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MICROBIOLOGY

Arcanobacterium haemolyticum was first described by MacLean et al. in 1946 (26) as a pathogen in cases of exudative pharyngitis and soft-tissue infections. In 1982 the previously named Corynebacterium haemolyticum was included in a new genus to reflect major differences in cell wall components and chemotaxonomic characters, the genus Arcanobacterium (10). Currently, there are nine identified species within this genus of which A. haemolyticum, A. pyogenes, and A. bernardiae have been recovered from clinical specimens (16).

It is a catalase-negative, aerobic, beta-haemolytic, nonmotile, irregular gram-positive to gram-variable rod that may be misidentified as Streptococcus species, Corynebacterium species, or A. pyogenes. Microscopic morphology differentiates A. haemolyticum from Streptococcus species; beta-haemolysis and absence of catalase from Corynebacterium species; and failure to ferment xylose, and reverse CAMP-test from A. pyogenes.

Growth is enhanced in a blood enriched medium at 37ºC in the presence of 5-10% CO2. Haemolysis is best observed in a CO2-enriched atmosphere, and on media with human or horse blood.

A. haemolyticum exists in a smooth and rough biotypes (7). The smooth biotype predominates in wound infections and the rough biotype in respiratory tract infections.

EPIDEMIOLOGY

Man is the primary environmental reservoir. Although it has been identified as a commensal of the human pharyngeal flora, isolation from the nasopharyngeal microbiota of asymptomatic patients is infrequently reported.

As a cause of pharyngitis the general prevalence is 0.4-1.4%, with a peak of 2.5% in patients aged 15-18 years (8,25). In a recent study it represent 0.35 of all pharyngeal samples and 1.1% of all positive pharyngeal samples. The mean patient age was 16 years (range, 4-32 years), and the highest rate of positivity was during spring (18). In 9 of 55 episodes the patients were coinfected with other organisms, 4 with group A beta-haemolytic streptococci, 4 with group C beta-haemolytic streptococci, and 1 with Epstein-Barr virus (18).

CLINICAL MANIFESTATIONS

A. haemolyticum remains most commonly associated with upper respiratory and skin and soft-tissue infections. Systemic infections are exceedingly rare.

This organism has been isolated in throat swabs from patients with pharyngitis and/or tonsillitis, and recurrent throat infections. Clinical features of patients with pharyngitis caused by A. haemolyticum are indistinguishable from those caused by Streptococcus pyogenes. The spectrum of clinical presentation ranges from a mild respiratory illness to a diphtheria-like disease. Infection is most common in adolescents and young adults with a sore throat (8, 25).

The cutaneous manifestations of A. haemolyticum pharyngitis are the most salient features of the infection. These manifestations appear unique to pharyngeal infection and have not been described in association with infection in other body sites. Between one third and one half or even more of patients with A. haemolyticum pharyngitis develop a blanching, erythematous, macular, papular rash, frequently described as scarlatiniform (18, 19).

This organism has been implicated as a cause of cutaneous and soft tissue infections including chronic ulceration, wound infection, soft tissue abscess and cellulitis (12, 32). In skin infections, it is frequently isolated in association with other microorganisms including Bacteroides spp., Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, group GStreptococcus, and Fusobacterium necrophorum (12, 32). Therefore, the pathogenic significance is difficult to interpret.

Lemierre disease, caused by A. haemolyticum alone or associated to F. necrophorum, has been reported (14, 24). It has been implicated rarely in systemic and deep-seated infections, including endocarditis, bacteremia, severe sepsis, osteomyelitis, meningitis, brain abscess, and pneumonia (2, 15, 21, 31, 32, 33, 34, 35). These conditions occur mainly in patients with underlying predisposing diseases like diabetes, alcoholism, or malignant neoplasms. Patients with bacteremia can be classified into two main groups: an older population with underlying immunosupresive conditions (usually malignancy) or with known risk factors for infectious diseases such as diabetes, and a younger population with no known risk factors.

LABORATORY DIAGNOSIS

Although A. haemolyticum is a beta-haemolytic organism, the haemolysis is less well defined than that of beta-hemolytic streptococci and may be overlooked in cultures with heavy growth of commensal throat flora. The colony size and degree of hemolysis vary considerably with the types of blood cells, medium bases, and atmosphere used. There are significant differences with regard to the impact of atmosphere, time of incubation, and culture media for isolation. In a study the authors concluded that after 48 hours of incubation trypticase soy agar with 5% horse blood in 5% CO2 was the best medium (17).

A. haemolyticum does not produce catalase. Esculin, gelatin, urea, and casein are not hydrolyzed. Acid is produced from glucose, lactose, maltose, and fructose but not from xylose, mannitol, or mannose. It produces DNase and is resistant to bacitracin (<10 mm of inhibition zone diameter with 0.04 U disks). Inhibition of the hemolytic zone of Staphylococcus aureus (reverse CAMP test) is useful in its identification. A cross-reaction with group B-streptococci antiserum could be observed.

Incubation for 72 hours reveals the organism’s colony features: circular, discoid, opaque, and whitish pinpoint colonies, 0.5 mm in diameter, with a narrow zone of complete hemolysis on sheep or horse blood agar.

There are commercial systems useful for the diagnosis such as API Coryne (bioMérieux, France) (20). With the use of a 7-McFarland inoculum the results are more optimal (18). MALDI-TOF is a rapid and accurate system for its identification (36).

PATHOGENESIS

A. haemolyticum produces uncharacterized hemolytic agent(s) and two biochemically defined extracellular products, a neuraminidase, and a phospholipase D genetically and functionally similar to Corynebacterium pseudotuberculosis phospholipase D. This phospholipase is a lipid-hydrolyzing enzyme that is damaging to mammalian cell membranes, enhances bacterial adhesion and promotes host cell necrosis following invasion, and therefore, may be important in the disease pathogenesis (1, 23). Recently a cholesterol-dependent cytolysin, designated arcanolysin, has been identified, and may be a virulence determinant (22).

The evidence of the pathogenicity of A. haemolyticum was documented by clinical comparisons of culture-positive patients with pharyngitis vs. that of healthy, matched controls; patients with a throat infection or an exanthema, harboring A. haemolyticum, also produce antibodies to this organism during the acute infection (27).

SUSCEPTIBILITY IN VITRO AND IN VIVO

In 2006 the Clinical and Laboratory Standards Institute (CLSI) (9), and in 2014 the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (13) defined standardized methods for susceptibility of Corynebacterium that could be used with A. haemolyticum. In vitro testing of A. haemolyticum isolated from human infections shows that it was generally susceptible to penicillins, cephalosporins, carbapenems, macrolides, clindamycin, rifampin, glycopeptides, gentamicin and ciprofloxacin, but resistant to trimethoprim-sulfamethoxazole (1, 5, 6). Resistance to tetracycline has been described in 34% of the isolates (18). Reported MICs of penicillin G were between 0.03 and 0.25 mg/l (1, 3). Erythromycin (MIC90, 0.06 mg/l) and clindamycin (MIC90, 0.06 mg/l) shows in general excellent activity (1, 5). Isolates resistant to vancomycin, macrolides, penicillin V, and fluoroquinolones have been reported (1, 30).

Bactericidal tests, however, have shown most isolates of A. haemolyticum to be tolerant to penicillin, which may lead to treatment failures (28). Strains of A. haemolyticum were highly susceptible to the bactericidal action of gentamicin (28). Results of time-kill experiments showed that A. haemolyticum was killed slowly by penicillin while gentamicin caused rapid killing (28). In a study by Österlund (29) to explain failures in treatments with penicillin despite in vitro susceptibility, the 12 strains of A. haemolyticum tested were internalized by Hep-2 cells. Four strains were able to survive intracellularly for 4 days, thus creating intracellular reservoirs of bacteria. Erythromycin, a macrolide that penetrates well intracellularly, killed these bacteria.

E-test results of susceptibility were in good agreement with those given by the CLSI agar dilution method (4).

ANTIMICROBIAL THERAPY

The optimum antibiotic therapy for infections with A. haemolyticum has yet to be determined.

The course of untreated A. haemolyticum pharyngitis is poorly described. A standardized treatment protocol has not been developed. Resolution of symptoms within 3 days after initiation of penicillin therapy has been reported, but reports of clinical and microbiological failures also exist (3). Österlund has proposed that the mechanism of penicillin treatment failure could be the survival of intracellularly residing bacteria (29). For pharyngitis, erythromycin should be the considered the antibiotic of first choice and penicillin G, an alternative.

Recommendations for invasive infection are based on clinical experience, on the site of infection, and in vitro susceptibility studies (31, 33). The treatment regimens reported include penicillin, with or without gentamicin, as well as erythromycin. Most cases responded well to intravenously administered penicillin. First-line therapy with intravenous penicillin is optimal due to low rates of resistance in this organism, the rapid bactericidal effects of this agent, and their ability to achieve adequate tissue concentrations for use in a variety of systemic infections. However, in seriously ill patients, penicillin G in combination with gentamicin might be preferable.

Macrolides (eg. erythromycin, azithromycin) are a reasonable second-line option, although these agents are bacteriostatic and distributed extensively into the tissues, which may limit their effectiveness in cases of bacteremia. Alternative therapies include vancomycin, fluoroquinolones, and clindamycin. Broad spectrum beta-lactam antibiotics as well as clindamycin and macrolides should be equally good choices. In cases where the site of infection may prevent adequate drug penetration, such as endocarditis and osteomyelitis, macrolides or clindamycin in combination with rifampin might be preferable to beta-lactam antibiotics.

ADJUNCTIVE THERAPY

Surgery and drainage are indicated for some soft tissue infections (15).

ENDPOINTS FOR MONITORING THERAPY

For cutaneous infection, clinical signs of resolution are probably more important than bacteriologic monitoring. For invasive infections and bacteremia, however, a poor clinical response is an indication for repeat cultures; antibiotics with intracellular penetration may be preferred if cultures remain positive.

VACCINES

There are no vaccines available.

REFERENCES

1. Almuzara MN, de Mier C, Barberis CM, Mattera J, Famiglietti A, Vay C. Arcanobacterium haemolyticum identification and susceptibility to nine antimicrobial agents. Clin Microbiol Infect 2002;8:828-9. [PubMed]

2. Alós JI, Barros C, Gómez-Garcés JL. Endocarditis caused by Arcanobacterium haemolyticum. Eur J Clin Microbiol Infect Dis 1995;14:1085-88. [PubMed ]

3. Banck G, Nyman M. Tonsillitis and rash associated with Corynebacterium haemolyticum. J Infect Dis 1986;154:1037-40.[PubMed]

4. Carlson P. Comparison of the E test and agar dilution methods for susceptibility testing of Arcanobacterium haemolyticum. Eur J Clin Microbiol Infect Dis 2000;19:891-3. [PubMed ]

5. Carlson P, Kontiainen S, Renkonen OV. Antimicrobial susceptibility of Arcanobacterium haemolyticum. Antimicrob Agents Chemother 1994;38:142-3. [PubMed ]

6. Carlson P, Korpela J, Walder M, Nyman M. Antimicrobial susceptibilities and biotypes of Arcanobacterium haemolyticum blood isolates. Eur J Clin Microbiol Infect Dis 1999;18:915-7. [PubMed ]

7. Carlson P, Lounatmaa K, Kontiainen S. Biotypes of Arcanobacterium haemolyticum. J Clin Microbiol 1994;32:1654-57.[PubMed ]

8. Carlson P, Renkonen OV, Kontiainen S. Arcanobacterium haemolyticum and streptococcal pharyngitis. Scand J Infect Dis 1994;26:283-7. [PubMed ]

9. Clinical and Laboratory Standards Institute (CLSI). Methods for antimicrobial dilution and disk susceptibility testing of infrequenly isolated or fastidious bacteria; approved guideline. CLSI document M45-A. CLSI, Pennsylvania, USA. 2006.

10. Collins MD, Jones D, Schofield GM. Reclassification of Corynebacterium haemolyticum in the genus Arcanobacterium gen. nov. as Arcanobacterium haemolyticum nom. rev., comb. nov. J Gen Microbiol 1982;128:1279-81. [PubMed ]

11.Cuevas WA, Songer JG. Arcanobacterium haemolyticum phospholipase D is genetically and functionally similar to Corynebacterium pseudotuberculosis phospholipase D. Infect Immun 1993;61:4310-6. [PubMed ]

12. Dobinsky S, Noesselt T, Rücker A, Maerker J, Mack D. Three cases of Arcanobacterium haemolyticum associated with abscess formation and cellulitis. Eur J Clin Microbiol Infect Dis 1999;18:804-6. [PubMed ]

13. European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Breakpoint_table_v_4.0.pdf

14. Fernández-Suárez A, Benítez JM, Vidal AM, Iglesias JM. Lemierre's syndrome and septicaemia caused solely by Arcanobacterium haemolyticum in a young immunocompetent patient. J Med Microbiol. 2009;58:1645-8. [PubMed]

15. Ford JG, Yeatts RP, Givner LB. Orbital cellulitis, subperiosteal abscess, sinusitis, and septicemia caused by Arcanobacterium haemolyticum. Am J Ophthalmol 1995;120:261-2. [PubMed ]

16. Funke G, Bernard KA. Coryneform Gram-positive rods. In: Versalovic J, Carroll K, Funke G, Jorgensen JH, Landry ML, Warnock DW. Manual of Clinical Microbiology, 10th ed. 2011. ASM Press.

17. García de la Fuente C, Campo-Esquisabel AB, Unda F, Ruíz de Alegría C, Benito N, Martínez-Martínez L. Comparison of different culture media and growth conditions for recognition of Arcanobacterium haemolyticum. Diagn Microbiol Infect Dis 2008;61:232-4. [PubMed]

18. García-de-la-Fuente C, Ruiz De Alegría C, Cano ME, Campo AB, Unda F, Agüero J, Martínez-Martínez L. Phenotypic and molecular characterization of Arcanobacterium haemolyticum isolated from clinical samples. Diagn Microbiol Infect Dis. 2012;72:1-7. [PubMed]

19. Gaston DA, Zurowski SM. Arcanobacterium haemolyticum pharyngitis exanthem. Arch Dermatol 1996;132:61-4.[PubMed ]

20. Gavin SE, Leonard SB, Briselden AM, Coyle MB. Evaluation of the rapid CORYNE identification system for Corynebacterium species and other coryneforms. J Clin Microbiol 1992;30:1692-5. [PubMed]

21. Hedman K, Brauner A. Septicaemia caused by Arcanobacterium haemolyticum smooth type in an immunocompetent patient. J Med Microbiol. 2012;61:1328-9. [PubMed]

22. Jost BH, Lucas EA, Billington SJ, Ratner AJ, McGee DJ. Arcanolysin is a cholesterol-dependent cytolysin of the human pathogen Arcanobacterium haemolyticum. BMC Microbiol. 2011;11:239. [PubMed]

23. Lucas EA, Billington SJ, Carlson P, McGee DJ, Jost BH. Phospholipase D promotes Arcanobacterium haemolyticum adhesion via lipid raft remodeling and host cell death following bacterial invasion. BMC Microbiol. 2010;10:270. [PubMed]

24. Lundblom K, Jung K, Kalin M. Lemierre syndrome caused by co-infection by Arcanobacterium haemolyticum and Fusobacterium necrophorum. Infection. 2010;38:427-9. [PubMed]

25. Mackenzie A, Fuite LA, Chan FT, King J, Allen U, MacDonald N, Diaz-Mitoma F. Incidence and pathogenicity of Arcanobacterium haemolyticum during a 2-year study in Ottawa. Clin Infect Dis 1995;21:177-81. [PubMed ]

26. MacLean PD, Liebow AA, Rosenberg AA. A hemolytic corynebacterium resembling Corynebacterium ovis and Corynebacterium pyogenes in man. J Infect Dis 1946;79:69-90. [PubMed ]

27. Nyman M, Alugupalli KR, Strömberg S, Forsgren A. Antibody response to Arcanobacterium haemolyticum infection in humans. J Infect Dis 1997;175:1515-18. [PubMed ]

28. Nyman M, Banck G, Thore M. Penicillin tolerance in Arcanobacterium haemolyticum. J Infect Dis 1990;161:261-5.[PubMed ]

29. Österlund A. Are penicillin treatment failures in Arcanobacterium haemolyticum pharyngotonsillitis caused by intracellularly residing bacteria? Scand J Infect Dis 1995;27:131-4. [PubMed ]

30. Power EG, Abdulla YH, Talsania HG, Spice W, Aathithan S, French GL. vanA genes in vancomycin-resistant clinical isolates of Oerskovia turbata and Arcanobacterium (Corynebacterium) haemolyticum. J Antimicrob Chemother 1995;36:595-606. [PubMed]

31. Skov RL, Sanden AK, Danchell VH, Robertsen K, Ejlertsen T. Systemic and deep-seated infections caused by Arcanobacterium haemolyticum. Eur J Clin Microbiol Infect Dis 1998;17:578-82. [PubMed ]

32. Tan TY, Ng SY, Thomas H, Chan BK. Arcanobacterium haemolyticum bacteraemia and soft-tissue infections: case report and review of the literature. J Infect. 2006;53:e69-74. [PubMed]

33. Therriault BL, Daniels LM, Carter YL, Raasch RH. Severe sepsis caused by Arcanobacterium haemolyticum: A case report and review of the literature. Ann Pharmacother 2008;42:1696-702. [PubMed]

34. Van Loo IH, van den Wildenberg WJ, van Huijstee PJ, Roukema JA, Apperloo AJ, Peeters MF. Pelvic abscess caused by Arcanobacterium haemolyticum mimicking a soft tissue tumour. J Med Microbiol 2007;56:1684-6. [PubMed]

35. Vargas J, Hernandez M, Silvestri C, Jiménez O, Guevara N, Carballo M, Rojas N, Riera J, Alayo E, Fernández M, Rodriguez-Morales AJ, Silva M. Brain abscess due to Arcanobacterium haemolyticum after dental extraction. Clin Infect Dis 2006;42:1810-1.[PubMed]

36. Vila J, Juiz P, Salas C, Almela M, de la Fuente CG, Zboromyrska Y, Navas J, Bosch J, Agüero J, de la Bellacasa JP, Martínez-Martínez L. Identification of clinically relevant Corynebacterium spp., Arcanobacterium haemolyticum, and Rhodococcus equi by matrix-assisted laser desorption ionization-time of flight mass spectrometry. J Clin Microbiol. 2012;50:1745-7. [PubMed]