Continuing Education Activity

Arcanobacterium haemolyticum is a gram-positive, facultative bacillus known for causing pharyngitis with a distinctive "sandpaper" scarlatiniform rash in children and young adults. Although it is rarely isolated due to limited routine testing, A haemolyticum can cause various infections, including soft tissue, endocarditis, bacteremia, and septicemia, particularly in older or immunosuppressed patients. Both viruses and bacteria can cause acute pharyngitis, highlighting the need to include A haemolyticum in the differential diagnosis list and differentiate it from Streptococcus pyogenes due to their similar clinical presentation.

Delays in diagnosing A haemolyticum infections stem from the clinical similarities with S pyogenes, leading to potential misinterpretations of the scarlatiniform rash as either the scarlet fever rash or a viral exanthem. In addition, A haemolyticum is more challenging to isolate in culture, contributing to diagnostic challenges. Prompt recognition and treatment with antibiotics, such as penicillins, macrolides, or tetracyclines, and supportive care are crucial for favorable patient outcomes, leaving no long-term sequelae. This activity reviews the evaluation and management of A haemolyticum infection, with emphasis on differential diagnosis and proper laboratory testing for accurate identification and treatment. This activity also highlights the crucial role of an interprofessional healthcare team in providing comprehensive care to patients affected by A haemolyticum infections.

Objectives:

• Identify the clinical manifestations and risk factors associated with Arcanobacterium haemolyticum infections.

• Screen patients with suspected Arcanobacterium haemolyticum infections using appropriate diagnostic tests and laboratory methods.

• Select appropriate antimicrobial agents based on antimicrobial susceptibility testing results for Arcanobacterium haemolyticum infections.

• Collaborate with interprofessional healthcare teams, including infectious disease specialists, for complex cases of Arcanobacterium haemolyticum infections or when antimicrobial management needs clarification.

Introduction

Arcanobacterium haemolyticum, formerly known as Corynebacterium haemolyticum, is a gram-positive, facultative, anaerobic, catalase-negative, β-hemolytic bacillus known for its ability to inhibit hemolysis of Staphylococcus aureus in the Christie-Atkins-Munch-Peterson (CAMP) test and to enhance hemolysis of Streptococcus agalactiae in the reverse CAMP test.[1][2] The initial cases reported with this pathogen in 1946 involved acute pharyngitis and ulcerative skin lesions among American soldiers in the Pacific Islands.[3] 

Most infections caused by A haemolyticum have been related to head and neck infections, such as acute pharyngitis and sinusitis, primarily in children and adolescents, and skin and soft-tissue infections, mainly in immunocompromised populations. However, A haemolyticum can also rarely cause other types of infections, including bacteremia, endocarditis, osteomyelitis, severe sepsis, brain abscesses, and pneumonia.[4][5][6] 

Distinguishing the cause of acute pharyngitis between viruses and bacteria can be challenging without culture confirmation. S pyogenes is the most common cause of acute pharyngitis, whereas A haemolyticum has an incidence of up to 2.5%.[7][8] However, the clinical presentation of both these bacteria can be almost indistinguishable. Therefore, A haemolyticum should always be included in the differential diagnosis of acute pharyngitis to ensure accurate diagnosis and appropriate treatment. 

The clinical manifestations of A haemolyticum pharyngitis include sore throat, fever, and a pruritic "sandpaper" scarlatiniform rash, which may be confused with S pyogenes pharyngitis and its scarlet fever rash.[7][9][10] Delays in diagnosing A haemolyticum infections occur due to similarities in clinical presentation between S pyogenes and A haemolyticum, as well as the potential misinterpretation of the scarlatiniform rash as either the scarlet fever rash or a viral exanthem. Delays can also occur because the β-hemolysis caused by A haemolyticum can take 48 to 72 hours to manifest, compared to up to 24 hours for S pyogenes, and this delay may go unnoticed.[2] In addition, A haemolyticum is more challenging to isolate in culture, contributing to diagnostic challenges.[2] Prompt recognition and treatment with antibiotics such as penicillins, macrolides, or tetracyclines, along with supportive care, are crucial for achieving favorable patient outcomes without long-term sequelae.

Etiology

A haemolyticum is a catalase-negative, aerobic, β-hemolytic, nonmotile, branching, gram-positive bacillus, which is considered a part of the normal flora of the skin and nasopharynx. Transmission most likely occurs through direct person-to-person spread via droplets. The presence of A haemolyticum in the throats of household contacts suggests household transmission.[10]

A haemolyticum has 2 biotypes—smooth and rough. The smooth biotypes are more commonly associated with soft-tissue infections and form even colonies on growth media, which are β-hemolytic and β-glucuronidase negative, and are capable of fermenting sucrose and trehalose. On the other hand, rough biotypes, characterized by non-hemolytic activity, β-glucuronidase positivity, and the inability to ferment sucrose and trehalose, form uneven colonies on growth media. Pharyngitis is more commonly associated with rough-type colonies.[11][12]

A haemolyticum forms β-hemolytic colonies with a characteristic morphology of gram-positive bacilli. Optimal growth occurs at 37 ºC on blood agar in the presence of 5% to 10% CO₂. Hemolysis is most apparent on human or horse blood media; however, if sheep agar is used, growth may be slower and take up to 72 hours.[13] Slower growth may go unnoticed unless the microbiology laboratory is informed to observe the culture for an extended period. Identification of A haemolyticum is confirmed by a negative catalase test and a positive reverse CAMP test.[13]

An additional challenge in diagnosis occurs during the initial appearance of the organism on culture media, as it may be misidentified as other bacteria. Specifically, due to its morphology, it can be mistaken for normal flora or misidentified as Corynebacterium species, Streptococcus species, or A pyogenes. The presence of β-hemolysis and a negative catalase test differentiates it from Corynebacterium species. In addition, it is distinguished from A pyogenes by its inability to ferment xylose and a positive reverse CAMP test, while its microscopic morphology distinguishes it from Streptococcus species.[12]

Epidemiology

A haemolyticum is a part of the normal skin and pharyngeal flora. The burden of disease caused by A haemolyticum is not precisely known or underreported mainly because it is not routinely considered in the differential diagnosis and/or microbiological methods are not routinely performed. A haemolyticum causes acute pharyngitis and other head and neck infections, particularly in healthy children and adolescents. The incidence of A haemolyticum in pediatric populations with acute pharyngitis ranges from 0.5% to 2.5%.[7][8] The highest incidence was reported in the subgroup of individuals aged 15 to 18.[7]

A haemolyticum causes skin and soft tissue infections in older or immunocompromised patients, including individuals with type 2 diabetes.[1][14] In patients with cutaneous symptoms, A haemolyticum infections present as chronic skin ulcers, abscesses, or cellulitis, which can be coinfected with other gram-positive bacteria such as S aureus, C diphtheriae, or Streptococcus species.[5] In addition, cases of osteomyelitis have also been reported to originate from cutaneous A haemolyticum infections.[14] 

Rarely, A haemolyticum infection may become more invasive and lead to conditions such as brain abscesses, pneumonia, infective endocarditis, pyothorax, and bacteremia.[15][16][17][18] Special populations, including individuals with type 2 diabetes, cancers, or any form of immunosuppression, may be at a higher risk of developing bacteremia due to A haemolyticum infection.[19] 

History and Physical

A comprehensive history and physical examination are essential for patients with a sore throat and fever. Given the wide range of differential diagnoses, many infections cannot be distinguished based solely on clinical examination and history. Non-streptococcal pharyngitis caused by A haemolyticum primarily affects individuals aged 15 to 25.[20] The severity of the spectrum of illness varies from mild pharyngitis to diphtheria-like illness. Typical manifestations include pharyngitis, pharyngeal erythema, and pharyngeal exudate, present in nearly all cases. Fever is commonly observed, and approximately two-thirds of cases present with tender bilateral anterior cervical or submandibular adenopathy.

An erythematous rash is present in many cases, mostly likely due to a toxin similar to that which causes scarlet fever in S pyogenes pharyngitis.[20] This rash manifests as diffuse erythematous blanching papules, often described as "sandpaper-like" and may be pruritic. The rashes typically start on the distal extremities and spread centrally, primarily affecting the neck, chest, and back while sparing the face, palms, and soles. Pharyngitis usually precedes the rash by 1 to 4 days and lasts for 2 to 5 days.[20] Clinically, symptoms can be indistinguishable from the rash of scarlet fever due to S pyogenes, although features such as strawberry tongue or Pastia lines are absent.[9][7] Furthermore, some cases of A haemolyticum infection can have complications such as Lemierre syndrome.[21]

Patients with skin and soft tissue infections are more likely to be older and to have underlying diseases. A haemolyticum skin and soft tissue infections manifest as chronic skin ulcers, abscesses, or cellulitis. Although less common, reports of A haemolyticum infections can be invasive, leading to brain abscesses, pneumonia, infective endocarditis, pyothorax, and bacteremia.[15][16][17][18] Immunosuppression may increase the risk of systemic infections such as meningitis and bacteremia.[1][4][19]

Evaluation

Diagnostic challenges should be considered when testing for A haemolyticum due to several factors. Clinicians often rely on rapid streptococcal antigen tests to differentiate it from the most common cause of acute pharyngitis, S pyogenes. However, even if these tests are negative, they may not rule out S pyogenes completely, as these tests do not identify A haemolyticum. Thus, further testing may be required based on the level of suspicion. 

A haemolyticum forms β-hemolytic colonies characterized by gram-positive to gram-variable, weakly acid-fast, non-facultative anaerobic bacilli. These bacteria grow optimally in blood or serum-enriched medium at 37 ºC with 5% to 10% CO₂. A haemolyticum can be further identified by being catalase-negative, oxidase-negative, indole-negative, and urease-negative but positive in the reverse CAMP test.[13]

Clinical microbiology laboratories can often miss the diagnosis of A haemolyticum due to the rapid β-hemolysis exhibited by streptococci when plated on sheep agar within 24 hours. In contrast, A haemolyticum hemolysis occurs slowly over 48 to 72 hours. Hemolysis is most accurately observed on human or horse blood media.[13] Slower growth of A haemolyticum may go unnoticed in routine cultures unless the microbiology laboratory is informed to extend the observation period. Without this notification, cultures are often discarded prematurely before sufficient incubation time.[1][22] Therefore, clinicians must collaborate with their laboratory if there is suspicion that A haemolyticum is responsible for pharyngitis.

Furthermore, during the initial growth on the culture medium, A haemolyticum may be misidentified as other bacteria due to morphological similarities. Specifically, it can be confused with normal flora or misidentified as Corynebacterium species, Streptococcus species, or A pyogenes. Differential identification involves the presence of β-hemolysis and a negative catalase test, distinguishing it from Corynebacterium species. In addition, failure to ferment xylose and a positive reverse CAMP test differentiate it from A pyogenes, while microscopic morphology aids in distinguishing it from Streptococcus species.[12] 

A haemolyticum is currently included in the majority of matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry databases, which can rapidly diagnose the bacterium if this technology is available in the laboratory.[23]

Treatment / Management

Antimicrobial resistance is a significant concern when managing infections, particularly when administering empirical treatment. Unfortunately, data on antimicrobial susceptibility testing for A haemolyticum are limited. Existing information is derived from a few published studies, many of which are dated and employ diverse diagnostic methods, complicating result comparisons.[1][12][24] 

Studies indicate that most A haemolyticum strains are susceptible to penicillins, tetracyclines, and macrolides but resistant to trimethoprim-sulfamethoxazole.[1][25] However, reports of varied resistance to tetracyclines, macrolides, clindamycin, and penicillin exist.[1][12] Penicillin and macrolides are commonly prescribed antimicrobials for treatment. Conducting antimicrobial susceptibility testing is crucial when culture is available to ensure treatment efficacy and tailor it according to susceptibility results if necessary. 

Differential Diagnosis

Acute pharyngitis is a common infection caused by various bacteria, such as S pyogenes, Mycoplasma pneumoniae, and Neisseria gonorrhea. Viruses, such as Epstein-Barr virus, cytomegalovirus, measles, and coronaviruses, including SARS-CoV-2, also contribute to the differential diagnosis. The presence of a scarlatiniform rash may make it indistinguishable from scarlet fever.

A haemolyticum can be differentiated from S pyogenes in the laboratory by a negative Streptococcus species and catalase test and a positive reverse CAMP test. Severe upper respiratory infections may also cause diphtheria-like symptoms, which are characterized by a gray membrane overlying the tonsil or epiglottis.[26] Failure to grow A haemolyticum on tellurite enables differentiation from C diphtheriae.[27]

Prognosis

A haemolyticum pharyngitis typically resolves within 7 to 10 days. Complications are rare, and complete resolution is the norm for those treated with appropriate antibiotics. 

Complications

Although complications associated with A haemolyticum are rare, they have been reported, which include Lemierre syndrome, brain abscesses, endocarditis, and bacteremia. Delayed recognition and treatment of the infection may contribute to persistent infection or complications, leading to poor outcomes and increased mortality rates, especially among patients with severe comorbidities.[15][19][18][28]

Consultations

Consultation with an infectious disease specialist can be beneficial in coordinating care with the clinical microbiology laboratory.

Deterrence and Patient Education

Droplet and contact precautions are crucial infection prevention measures that can effectively reduce the risk of disease transmission. Patients should receive education on methods to minimize transmission, such as regular handwashing, covering the mouth when coughing, avoiding sharing utensils, and practicing social distancing while symptomatic. Early detection and the appropriate selection of antimicrobials typically lead to symptom resolution. Supportive care for A haemolyticum infections includes ensuring adequate fluid intake and rest and using nonsteroidal anti-inflammatory drugs as needed. 

Enhancing Healthcare Team Outcomes

Effective coordination among clinicians, clinical laboratory microbiologists, and pharmacists is crucial in ensuring successful interprofessional communication during the treatment of patients with A haemolyticum infections. Clinicians should communicate with the laboratory to ensure proper handling of pharyngeal culture specimens when considering this diagnosis. Consultation with infectious disease specialists may be necessary to facilitate communication between the laboratory and pharmacy. This coordinated approach is vital for achieving positive clinical outcomes in patients with A haemolyticum pharyngitis.