Streptococcus intermedius and Other Streptococcus anginosus Group Species in Pediatric Cranial and Intracranial Pyogenic Infections

Streptococci have been classified as a diverse group of more than 100 currently recognized gram-positive species based on their α-hemolytic, β-hemolytic and nonhemolytic properties. Historically, Streptococcus pyogenes and Streptococcus pneumoniae were the first to attract attention due to their virulent pyogenic action. Τhe “viridans group streptococci” species, which remain when β-hemolytic streptococci, enterococci and pneumococci are excluded, have been human commensals of low pathogenic potential in immunocompetent individuals.1,2 The viridans group streptococci consists of 6 groups, that is, Streptococcus mutans group, Streptococcus salivarius group, Streptococcus bovis group, Streptococcus mitis group, Streptococcus sanguinis group and Streptococcus anginosus group (SAG); the latter has been the cause of long debate.1–4 The initial name of the group was “milleri” but the term SAG proposed by Kawamura is currently the most widely accepted.4 SAG consists of 3 distinct species, Streptococcus anginosus, Streptococcus intermedius and Streptococcus constellatus, which share phenotypic similarities, being microaerophilic, catalase-negative, gram-positive cocci, and having also been categorized as β-hemolytic, α-hemolytic and nonhemolytic.1 These heterogeneous, hemolytic and biochemical features have commonly led to misidentification of these strains.1–4 Pathogenicity of SAG Species in Pediatric Patients The members of SAG are frequently found in various oral structures and tissues. S. intermedius and S. constellatus are often associated with dental plaque and periodontal diseases, while S. anginosus colonizes the mucosal membranes of the oral cavity. All species, spreading from the oral cavity, can also colonize the throat, the nasopharynx, the gastrointestinal and the genitourinary tracts.2–4 Until 1990s SAG was considered to be a rare cause of infection outside the oral cavity. For many years, the literature on SAG consisted of case reports of SAG infections, mostly in immunocompromised adults.1,2,4 This has dramatically changed, and SAG isolates have been recognized not only as oral, gastrointestinal and genitourinary tract commensals, but also as pathogens causing pyogenic infections, which range from minor (eg, sinusitis) to more severe ones involving the head and neck regions, the lungs, the abdomen and the soft tissue.1,2,4 The mechanisms of infection outside the oral cavity and their tissue specificity and pathogenicity are not well understood, and only a relatively limited number of studies have described the putative virulence factors that could be involved in their interaction with the human immune defense.1,3,4 It appears that, similar to other members of the Streptococcus family, the presence of a capsule in certain SAG strains and the production of enzymes such as hyaluronidase, deoxyribonuclease and chondroitin sulfatase are responsible for SAG virulence.2–4 The retrospective design of the studies investigating SAG, the uncertainty of its identification, the methods used to differentiate among the 3 SAG members that are often reported as “total group,” the dismissal of SAG as part of the commensal oral flora and the overlap of their clinical presentation have hampered the assessment of the clinical significance of each species in suppurative disease.2–4 Recently, awareness about the clinical significance of SAG bacteria has increased worldwide.4–9 In pediatric patients, the prevalence of each SAG species reported from different anatomical sites varies. In a study of 133 children, where SAG bacteria were further classified into the 3 distinct species of the group, S. anginosus was the most prevalent (39%), while S. constellatus (34%) and S. intermedius (27%) followed.10 The 3 SAG species were not distributed equally across infection sites. S. intermedius was more frequently associated with head and neck infections than S. anginosus and S. constellatus. Conversely, both S. anginosus and S. constellatus were more likely to be cultured from intra-abdominal infections, especially appendicitis, than S. intermedius.10 In a retrospective single-center study conducted from January 2008 to March 2015, 48 cases of S. intermedius infection in patients under 19 years of age were identified. In 52% of patients, the infected site included the head, neck and upper chest area; this finding explains why the pathogenic role of the viridans streptococci in cultures can be underestimated since their growth is often discarded as oral cavity contamination.11 In a recent study of 40 children diagnosed with S. intermedius infection, 17 suffered a head and neck, including a neck soft tissue infection, and 15 an intra-abdominal infection.12 Clinical Importance of S. intermedius and Other SAG Species in Suppurative Complications of Bacterial Sinusitis and Otitis Media A recent review of clinical reports on SAG infections stressed the importance of S. intermedius as the culprit in the formation of suppurative infections, including abscesses.3,4 The expression of hydrolytic enzymes by S. intermedius appears to be responsible for tissue liquefaction and pus formation, while higher hyaluronidase concentrations are observed in deeper abscesses. Biofilm formation is also dependent on the activity of hyaluronidase and autoinducer-2 that controls quorum-sensing communication. Intermedilysin and sialidase A, 2 important virulence determinants, are not found in the other members of the SAG group. Intermedilysin creates pores in membranes of red blood cells allowing for cell destruction. Sialidase A contributes to the direct interbacterial and host-bacterial interactions.4 Although acute bacterial sinusitis is usually a mild disease, extension of the infection to adjacent tissue may occur, causing, anteriorly, Pott's puffy tumor (due to the particularities of pneumatization and venous drainage of the frontal sinus of children and young adolescents), laterally, orbital cellulitis (potentially with abscess) and, intracranially, epidural/subdural empyema, meningitis, cerebritis and/or brain abscess and venous sinus thrombosis.3–9,13 SAG species, especially S. intermedius, have been reported to cause significantly more severe intracranial complications and neurological disorders than other bacteria in pediatric patients with bacterial sinusitis.5,9 Otogenic extension of infection to the mastoid may occasionally progress through the periosteum (periostitis) with subsequent involvement of the surrounding structures, resulting in severe extratemporal and intracranial complications.5,7 Although the incidence of suppurative intracranial complications, particularly otogenic, has declined markedly with the widespread use of antibiotics in the late 20th century, the danger of potentially devastating events of neurological morbidity and mortality remains5; of note, the literature on otogenic infectious intracranial complications is substantially more scarce than its sinogenic counterpart.7,13 SAG Species Involvement in Polymicrobial, Aerobic and Anaerobic, Head and Neck Infections Anaerobes are considered to be important contributors to abscess formation and polymicrobial infections.3,4,6,14 SAG species often act synergistically with aerobic and anaerobic bacteria to cause tissue necrosis, abscess formation and other more severe infections, including those of the head and neck.3,5,6,12 Coexistence of anaerobes has always been postulated in many suppurative infections, including brain abscesses, but it has been difficult to recover those organisms by means of conventional anaerobic cultures.4,6,9,14 Notably, there are reports indicating that among the 3 SAG species, S. intermedius was the most frequently identified sole pathogen in purulent material.5,11 In a study conducted from 2019 to 2022, 31 patients were identified with intracranial subdural and/or epidural empyema and concurrent sinus involvement. Intracranial sampling was performed in all patients, while 15 patients also underwent sinus sampling. S. intermedius was the most common pathogen in the intracranial samples. Mixed organisms were obtained from 13 patients (42%), identified either by culture or polymerase chain reaction (PCR). The use of PCR techniques in the identification of additional organisms, predominantly anaerobes, increased the diagnostic yield by 57%. Of 15 patients who also underwent sinus sampling only 1 (7%) demonstrated identical organisms in both sampling sites; of note, 50% of sinus samples did not identify the main intracranially cultured pathogen.9 In a retrospective study of 95 cases of pediatric complicated sinusitis and acute otitis media caused by SAG, S. intermedius emerged as the most prevalent species (80%) followed by S. constellatus (12.6%) and S. anginosus (7.4%). Overall, 50.5% of cases were polymicrobial with an additional 1–4 organisms isolated per case. Anaerobic copathogens were identified in 22 of 86 anaerobic cultures performed (25.6%); the most identified anaerobes were Prevotella and Peptostreptococcus spp.5 Identification of SAG Isolates by Classical and Molecular Methods Traditionally, cultures of specimens obtained, such as blood, cerebrospinal fluid and pus, have been used to identify SAG species. Due to the lack of reliable phenotypic differences among the members of the SAG, those streptococci have been rarely identified up to the species level in clinical microbiological laboratories.3 Studies using automated basic and/or molecular methods to identify SAG infections have contributed substantially to the clinical awareness of these pathogens.3,9,15 Innovative technology such as real-time PCR targeting the cpn60 and 16S ribosomal ribonucleic acid (rRNA) genes was introduced to identify SAG isolates.16 Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry has also been used in clinical laboratories to identify SAG; however, difficulties in the identification of S. intermedius have been reported.3,4 The application of next-generation sequencing (NGS) has greatly augmented the detection of pathogens by providing their quick identification in culture-negative specimens. 16S rRNA Sanger sequencing can detect 1 organism at a time, whereas NGS can identify multiple organisms simultaneously.15 Revolutionary applications of NGS such as whole-genome sequencing (cultured isolates) and 16S rRNA metagenomics studies (direct sequencing in clinical samples) have proven to be extremely useful in the detection of SAG isolates as well as other bacteria, that is, anaerobes or aerobes in mixed infections.3,4,12,15 Pediatric Intracranial Infections and SAG Involvement in the COVID-19 Pandemic Many studies conducted during the first months of SARS-CoV-2 pandemic have noticed a decline of invasive bacterial infections and hospitalizations due to nonpharmacological (interventional) measures implemented to contain virus spread. Some studies conducted after the first year of the pandemic have already reported evidence of a return and rebound of invasive bacterial infections after the relaxation of nonpharmacological measures. In September 2022, The Centers for Disease Control and Prevention evaluated the fluctuation of hospitalizations due to brain abscesses and epidural/subdural empyemas associated with Streptococcus species in the United States, between January 2016 and August 2022. Among intracranial purulent infections with 1 or more identified microorganisms, S. intermedius emerged as the most prevalent causative agent (46.1%), whereas the remaining pathogens included S. anginosus (18.4%) and S. constellatus (9.2%).14 In the recently updated analysis of extended hospitalization data through March 2023 from 37 hospitals in 19 states and the District of Columbia, a higher-than-expected number of pediatric intracranial infections beginning in August 2021, with a large peak during winter 2022–2023 was noted.17 Authors from Connecticut Children's Medical Center at Hartford in the United States reported that, at an institutional level, there was an approximately 3-fold increase in cases of sinusitis and otitis media-related intracranial infections during the COVID-19 pandemic, beginning in mid-2021 and peaking in the winter of 2022–2023. Surgically-obtained wound cultures yielded a variety of organisms; S. constellatus/anginosus/intermedius were more prevalent during the COVID-19 period than in the pre-COVID one (87.5% vs. 0%, P < 0.001), and this was also the case with Parvimonas micra (62.5% vs. 0%, P = 0.007).8 Speculative mechanisms of SARS-CoV-2 predisposing to pyogenic intracranial infections include disruption of respiratory microbiota, modulation of the innate or adaptive immune systems at the mucosal interface, and alteration of the bacterial milieu and that of respiratory viruses in the respiratory tract due to social distancing. Although there is insufficient evidence regarding the mechanism(s) that contributed to the increase of suppurative complications of sinogenic and otogenic infections during the pandemic, the role of SAG strains was highlighted.8,14 SAG Susceptibility to Antibiotics Streptococcal strains that belong to SAG are reported to be almost entirely susceptible to penicillin, ampicillin, ceftriaxone and cefotaxime, but according to some case series there is some resistance to macrolides, clindamycin and/or tetracyclines. In a study of 78 SAG isolates, collected in Poland during 1996–2012, 100% susceptibility in β-lactams was noted, as expected; however, 7 SAG isolates (9%) were resistant to erythromycin and 40 (51%) to tetracyclines.18 In the Houston study, all SAG isolates were susceptible to ampicillin, ceftriaxone and vancomycin.5 The Centers for Disease Control and Prevention performed antimicrobial susceptibility testing on all 18 available Streptococcus specimens (16 S. intermedius and 2 S. constellatus). Both S. constellatus isolates were intermediately resistant to ampicillin but susceptible to other antimicrobials tested. Of the 16 S. intermedius isolates, 9 were pan-susceptible, 1 was resistant to tetracycline only and 4 displayed minimal inhibitory concentration 1.5 μg/mL against vancomycin, which was slightly above the clinical breakpoint for susceptibility (≤1 μg/mL); these were also susceptible to other antimicrobials tested, while 2 isolates were resistant to multiple antibiotics (erythromycin, clindamycin and tetracycline) and intermediately resistant to quinupristin-dalfopristin; 1 isolate also displayed minimal inhibitory concentration 1.5 μg/mL against vancomycin. No close genetic relatedness of the 15 sequenced S. intermedius isolates from different patients was identified.14 The combination of a third- or fourth-generation cephalosporin and metronidazole has been the usual treatment of choice.5,8,9,14,19 Patients are usually maintained on intravenous antibiotics until they have completed 2–6 weeks5,6,8 according to the clinical severity of the infection, especially when intracerebral extension is proven or suspected. Irrespective of susceptibility-based coverage of SAG isolates, additional empiric treatment for copathogens such as anaerobes is favored in severe cases.6,9,14 Staphylococcus aureus has been reported as copathogen more frequently in extracranial rather than in intracranial infection.5,9 The possibility of mixed infection, frequently with pathogens difficult to be timely identified, must be considered.9,14 It has been suggested that vancomycin should be added in areas of the world where methicillin-resistant S. aureus is not uncommon, for example, in North America, especially when severe infections are empirically treated.14,19 Severity of infection, treatment failure and unnecessary use of antibiotics also need to be taken into account in the therapeutic regimen. Many studies have confirmed the critical role of surgical management of SAG infections, particularly those of the head and neck. In a recent study in the United Kingdom, among 14 children who suffered sinogenic intracranial empyema due to a SAG isolate, 64% required reoperation, mostly due to the reaccumulation of empyema and/or inadequate source control; conversely, only 13% needed such intervention among 23 children in whom SAG streptococci were not isolated (odds ratio 11.5, P = 0.003).20 CONCLUSIONS The increasing number of reports of life-threatening infections caused by SAG before and after the COVID-19 pandemic highlights their clinical importance. Advanced molecular and sampling techniques have made the precise identification of the SAG species possible, that is, S. intermedius, S. constellatus and S. anginosus, thus broadening our knowledge regarding their association with a variety of invasive suppurative sinogenic and otogenic infections in adults and children alike; however, larger studies are needed. The evolution of NGS techniques, in combination with machine learning and more user-friendly software, will greatly augment epidemiologic surveillance, clinical awareness and ultimately successful management of these potentially dangerous infections.