Fusobacterial head and neck infections in children

Fusobacterial head and neck infections in children

International Journal of Pediatric Otorhinolaryngology 79 (2015) 953–958 Contents lists available at ScienceDirect International Journal of Pediatri...

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International Journal of Pediatric Otorhinolaryngology 79 (2015) 953–958

Contents lists available at ScienceDirect

International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl

Review Article

Fusobacterial head and neck infections in children Itzhak Brook * Department of Pediatrics, Georgetown University School of Medicine, USA

A R T I C L E I N F O

A B S T R A C T

Article history: Received 25 March 2015 Received in revised form 28 April 2015 Accepted 29 April 2015 Available online 8 May 2015

Fusobacterium species are increasingly recognized as a cause of head and neck infections in children. These infections include acute and chronic otitis, sinusitis, mastoiditis, and tonsillitis; peritonsillar and retropharyngeal abscesses; Lemierre syndrome; post-anginal cervical lymphadenitis; and periodontitis. They can also be involved in brain abscess and bacteremia associated with head and neck infections. This review describes the clinical spectrum of head and neck fusobacterial infection in children and their management. ß 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Fusobacteria Children Abscess Antibiotics Resistance

Contents 1. 2. 3. 4. 5.

6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bacteremia and Lemierre syndrome (postanginal sepsis) . 5.1. Head and neck infections . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Pulmonary Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Osteoarticular infections. . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. 5.5. Central nervous system infections . . . . . . . . . . . . . . . . . . . Abscesses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Wound Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Antimicrobial susceptibility of Fusobacterial species . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Fusobacterium species inhabits the oropharynx, gastrointestinal tract, and female genital tract and are important potential

* Correspondence to: 4431 Albemarle St NW, Washington, DC 20016, USA. Tel.: +1 202 744 8211. E-mail address: [email protected] http://dx.doi.org/10.1016/j.ijporl.2015.04.045 0165-5876/ß 2015 Elsevier Ireland Ltd. All rights reserved.

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pathogens in children [1]. These organisms are increasingly recognized as a cause of head and neck infections in pediatric patients. These include acute and chronic otitis, sinusitis, mastoiditis, and tonsillitis; peritonsillar and retropharyngeal abscesses; Lemierre syndrome; post-anginal cervical lymphadenitis; periodontitis; and bacteremia and brain abscess complicating these infections [2–7]. This review outlines the clinical spectrum of fusobacterial head and neck infection in children and their clinical management.

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2. Epidemology Fusobacterial infections and their invasive and disseminated complications have different age related patterns: in children they usually originate from the middle ear and cervical lymph nodes; in adolescents from the throat and tonsils; in adults from the sinuses, carious teeth and periodontium, and in older adults from the gastrointestinal or genitourinary tracts [5–7]. The recently observed increase in reports about recovery of Fusobacterial species in head and neck infections in children may be due to the decrease in the number of tonsillectomies, increased utilization of corticosteroids for infectious mononucleosis, decreased empiric administration of antibiotics for sore throat, otitis and sinusitis, improvement in blood culture methodologies and techniques for isolation and identification of anaerobic organisms, and usage of molecular diagnostic methods such as polymerase chain reaction (PCR) for the identification of Fusobaterium spp. [2– 4]. Precise estimates, however, of the true incidence of isolation of Fusobaterium spp. in head and neck infections have been complicated by the difficulties in recovery of anaerobic bacteria, and the required use of special methods of specimen transportation and cultivation needed for their isolation. 3. Microbiology Fusobacteria are strict anaerobic gram-negative, thin, long, filamentous, nonmotile, and nonsporulating. The genus Fusobacterium is a heterogenous group of 13 species. The clinically important group members are Fusobacterium necrophorum, Fusobacterium nucleatum, Fusobacterium gonidiaformans, Fusobacterium naviforme, Fusobacterium mortiferum, and Fusobacterium varium [8–10]. More than half of fusobacterial infections are polymicrobial, and unlike other Gram negative anaerobic bacteria Fusobacteriae can invade the human host as primary pathogens [2,3]. Studies in animals demonstrated Fusobacteriae increased virulence in the presence of other gastrointestinal and oral aerobic and anaerobic flora organisms [11]. 4. Pathogenesis Underlying host factors can predispose children to fusobacterial infection. A molecular thrombophilic predisposition was observed in children with invasive infection [12–15], and a single nucleotide polymorphism in the toll-like receptor 5 gene was found in an affected child [12]. Because Fusobacteria are part of the normal flora of the oral cavity they can cause a contiguous, polymicrobial infection adjacent to these sites, as well as distant locations [1]. These infections are characterized by blood vessel invasion, inflammation, and thrombosis. Compromised blood supply or tissue injury follows accidental or surgical trauma can facilitate low oxidation– reduction potential which enhances fusobacterial bacterial growth [2]. Fusobacterial virulence factors include the production of lipopolysaccharide capsule [16], leukocidins, lipases, DNAases, hemolysins, hemagglutinins, neutrophil-cytotoxic factors, deoxyribonuclease [17–19], and the ability to aggregate platelets (F. necrophorum) [4,7,9], and produce proteolytic enzymes, that enhance invasion [20]. Fusobacteria (mostly by F. nucleatum) can produce the enzyme beta-lactamase, which protects these organisms as well as other co-pathogens against beta-lactam antibiotics [19]. Fusobacteria can enhance the growth of other anaerobic and aerobic organisms as was demonstrated in animal studies [11,21]. Fusobacterial infections often occurs as a result of disruption of the normal mucocutaneous barrier that leads to tissue invasion.

This may occur in Epstein–Barr virus pharyngitis [22] or in mucositis due to chemotherapy and neutropenia. F. necrophorum is second only to the Group A beta hemolytic streptococci (GABHS) amongst bacterial pathogens causing sore throat [23,24]. Tissue adhesion and invasion by F. necrophorum may be dependent on viral co-infection [25,26]. 5. Clinical manifestations Fusobacterial infection is often localized but can also be invasive. Fusobacterium species are associated with a variety of clinical infections that are age dependent, with a bimodal occurrence in adolescents and the elderly [27,28]. When adequate methods are used for cultivation and isolation of anaerobic bacteria, fusobacterial infections are often found to be polymicrobial, where the number of isolates of 5–10 organisms per site. The type of co-pathogens depends on the body site and the circumstances leading to the infection [2]. 5.1. Bacteremia and Lemierre syndrome (postanginal sepsis) About 3% of all cases of anaerobic bacteremia and 5% of all anaerobic infections in children are caused by Fusobacterium spp. [27–29]. The majority of the infections are caused by F. necrophorum and F. nucleatum. Bacteremia in children is generally associated with a primary focus of infection in the head, neck, or upper respiratory tract [27]. Primary parapharyngeal infection usually spreads to the blood vessels causing a local septic thrombophlebitis and subsequent septic embolization, leading to necrotizing pneumonia or involvement of multiple viscera or joints. This clinical syndrome was described by Lemierre as postanginal sepsis [30,31]. F. necrophorum is the most common species causing Lemierre syndrome. Other Fusobacteria include F. nucleatum, F. gonidiaforum and F. varium. Other isolates recovered alone or in combination include pigmented Prevotella, Bacteroides and Peptostreptococcus spp. [30]. The most common symptoms and clinical findings of Lemierre syndrome are: sore throat, fever, rigors (a distinctive feature of this disease), neck mass and pain, trismus, tenderness along the neck vasculature, malaise, anorexia, chest pain, shortness of breath, cough, and prostration [4,6,7,13,31]. It usually occurs in a previously healthy adolescent male who develops sore throat, followed by fevers and rigors on the fourth or fifth day, and painful swelling in the neck (often wrongly attributed to lymphadenopathy) [4,6,7,13]. Metastatic foci of infection usually occur in the lungs, but also can emerge in muscles, bones, joints, liver, spleen, skin, and endocardium [32]. Isolation of Fusobacterium spp. from blood should lead to investigation for primary and metastatic foci of infection. Primary infection has been associated with lymphadenitis or infectious mononucleosis and can be trivial in nature and easily overlooked. 5.2. Head and neck infections Fusobacterium is implicated in approximately half of anaerobic infections of the head and neck, including gingival and dental infections, [32] chronic tonsillitis, [33] chronic sinusitis, [34] acute, [35,71] and chronic otitis media, [36,37] mastoiditis, [38–40] and parapharyngeal [41,42] and mouth floor infections. F. nucleatum is the most commonly isolated species. Fusobacterial sinusitis can be dangerous, especially because contiguous spread through tissue planes can take place [22]. Fusobacterium spp. were recovered from 4 to 8% of children with chronic otitis media [36,37] and from 8% with chronic mastoiditis [38].

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F. necrophorum was associated with 25 pediatric cases of acute otitis media [35]. Eleven (44%) had uncomplicated otitis media, two had acute mastoiditis (40%); and four (16%) had otogenic variant of Lemierre syndrome associating acute mastoiditis, suppurative thrombophlebitis of the lateral and/ or cavernous sinuses, meningitis syndrome, and sometimes distant septic metastasis or extensive osteolysis of the temporal bone. Fusobacterium spp were also isolated from children with acute mastoiditis [39,40]; F. necrophorum was the most frequently recovered species. In an Israeli report [40] of seven children with acute mastoiditis caused by F. necrophorum, four had an epidural abscess, three had evidence of osteomyelitis beyond the mastoid bone, and four had imaging evidence of sinus vein thrombosis. All seven children underwent cortical mastoidectomy with insertion of ventilatory tubes and two had multiple surgical interventions. Two children had recurrent episodes of mastoiditis due to other pathogens. Pharyngitis [23,24], tonsillitis [43], and peritonsillar abscess [41,44], are the most common fusobacterial infection. Fusobacterial pharyngitis is often recurring, persisting and does not respond to typically-prescribed antimicrobials. Significantly higher antibodies levels to F. nucleatum and Prevotella intermedia were found in the serum sample of patients with non-GABHS pharyngo-tonsillitis (P < 0.001) and GABHS tonsillitis (P < 0.05), as compared with the levels of antibodies in these patients at the beginning of their illness and in controls [45]. These findings suggest a possible pathogenic role for these organisms in acute non-GABHS and GABHS tonsillitis. That anaerobes including Fusobacterium spp. play a role in chronic sinusitis is supported by the detection of antibodies (IgG) to two anaerobic organisms commonly recovered from sinus aspirates (F. nucleatum and Prevotella intermedia) [46]. Antibody levels to these organisms decreased in the patients who responded to therapy but did decline not in those who did not respond to antimicrobial therapy. Over three fourth of tonsil surgically removed from children with recurrent tonsillitis harbor beta-lactamase producing bacteria (BLPB) including Fusobacterium spp. [47–50]. Free betalactamase enzyme was detected in the core of most of those excised tonsils [51]. It is postulated based on in vitro, animal studies, that the inactivation of penicillin by BLPB, can protect GABHS and allows it to survive [49]. Antibiotics that are effective against GABHS and are also resistant to the enzyme beta-lactamase achieve a higher success rates in eradication of acute and recurrent GABHS pharyngotonsillitis. These antibiotics included clindamycin, lincomycin, macrolides, cephalosporins, and the combination of amoxicillin and clavulanate [45,51–55]. Fusobacterium spp. were found in 15 of 16 (94%) peritonsillar abscesses [41] and in all 14 retropharyngeal abscesses [42]. The predominate Fusobacteria were F. nucleatum, F. necrophorum, and Fusobacterium gonidiaformans. GABHS was recovered only from about a quarter of the abscesses. Kjærulff et al. [56] explored the role of F. necrophorum in acute tonsillitis in Denmark [58]. One hundred acute tonsillitis patients and 100 healthy controls aged 15–40 years were included in the study. The prevalence of F. necrophorum was (non-significantly) higher among acute tonsillitis patients (16%) compared to healthy individuals (9%) (P = 0.199). This trend was border significant for patients aged 15–29 years (24 vs 9%) (P = 0.050). Significantly, more F. necrophorum-positive patients were men (75%) compared to patients growing other bacteria (17%) or mixed oral flora (27%) (P < 0.001). The authors concluded that F. necrophorum is possibly a significant and prevalent pathogen in acute tonsillitis among teenagers and young adults.

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Other studies identified F. necrophorum subspecies funduliforme in 10–21% of cases of persistent sore throat or tonsillitis [23,43,57]. A study from Finland detected F. nucleatum and F. necrophorum from 26% and 38% of peritonsillar abscesses, respectively. GABHS was recovered from 45% of abscesses [43]. Studies from Denmark isolated F. necrophorum in 21–23% of 1848 peritonsillar abscesses [26,58]. F. necrophorum was significantly more prevalent than GABHS among patients aged 15–24 years (P < 0.001). In contrast, GABHS was significantly more frequently recovered among children aged 0–9 years and adults aged 30–39 years compared with F. necrophorum (P < 0.001 and P = 0.017 respectively) [59]. Similar to postanginal sepsis, peritonsillar abscess can be associated with Epstein–Barr virus pharyngitis or chronic or recurrent pharyngitis of any etiology. A history of pharyngitis not responding to antibacterial therapy along with a persistent fever, sore throat, and toxic appearance with asymmetrical tonsillar enlargement is often found in those with a peritonsillar abscess. Fusobacterium is most commonly isolated as part of the polymicrobial flora in the abscess [60]. Elevated levels of serum antibody to F. nucleatum and P. intermedia have been found in patients with peritonsillar cellulitis and abscess [61]. Fusobacterial sinusitis can lead to meningitis and brain abscesses in older children and adults [62–65]. Brain abscesses, however, occur more often secondary to periodontal disease with bloodstream infection [66,67]. Otogenic disseminated fusobacterial infection frequently causes intracranial complications, including meningitis [27,35,67–72] and vascular thrombosis [27,72], and can rarely lead to internal jugular dissemination [73]. 5.3. Pulmonary Infections Pulmonary infections are often a complication of fusobacterial upper respiratory tract infection, through septic pulmonary emboli from neck infections. It can also be caused by aspiration of oral flora in predisposed individuals (such as those with poor dental hygiene, seizure disorders, neurologic impairment, or swallowing dysfunction). The spectrum of pulmonary infections includes aspiration pneumonia, necrotizing pneumonia, pleural empyema, and lung abscess. F. nucleatum is the most commonly recovered fusobacterial species [74,75]. 5.4. Osteoarticular infections Fusobacterium spp. can be isolated from about 40% of anaerobic bone and joint infections [27,28]. Many of these infections originate from hematogenous spread from head and neck infections including odontogenic ones. The most commonly involves joints are the knee, hip, ankle, shoulder, elbow, sacroiliac, and sternoclavicular [67,76,77]. Bone infections often affects the facial bones, the vertebrae, pubic bone, or extremities [78–80]. F. necrophorum and F. nucleatum are the most common isolates [80]. Infection can be prolonged and complicated, leading to inanition and cachexia requiring nutritional support [22]. Aspiration or biopsy of the involved bone or joint, and recovery of the isolates from blood culture are the optimal diagnostic methods. 5.5. Central nervous system infections Central nervous system infection by Fusobacterium spp. often occur following metastatic infection due to postanginal sepsis or as a complication of chronic otitis, mastoiditis or sinusitis [81]. Although uncomplicated meningitis has been observed, multiple brain abscesses with areas of infarction are typical. Isolation or visualization on bacterial staining of fusiform like bacteria from cerebrospinal fluid should prompt imaging studies to evaluate the

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extent of brain involvement and administration of appropriate therapy [82,83]. An Israeli report of 27 children with Fusobacterial infections described high frequency of neurologic symptoms at presentation. The most common ones were seizures in a 9 (33%), 5 (19%) had abnormal neurological examination, with various degrees of decreased level of consciousness [84]. One child with mastoiditis, sub-periosteal abscess, and bilateral lateral sinus thrombosis had hypotension and was comatose [84]. 5.6. Abscesses Fusobacterium spp. can be recovered from dental [33] parapharyngeal, retropharyngeal, [42,85] peritonsillar, [41] intracranial, [79,81] visceral, hepatic, [86] splenic, [86] subphrenic, [87] perirectal, [88] pilonidal, [89] pelvic, illeopsoas [90], and vulvovaginal abscesses [27]. Fusobacterial abscesses in the soft tissue of the limbs, breasts, lungs, and parotid gland have been reported. Infections are characteristically polymicrobial. 5.7. Wound Infections Because Fusobacterium is frequently isolated from infected human bite wounds [91]. Poorly debrided burn wounds can also be complicated by fusobacterial infection. F. necrophorum has recovered from orofacial gangrene (cancrum oris or noma) [92– 94], and tropical ulcer [95]. 6. Antimicrobial susceptibility of Fusobacterial species Resistance of Fusobacterium spp. to beta-lactam antibiotics has been increasing. F nucleatum resistance is primarily through the produce of penicillinases. A multicenter survey found penicillin resistance for 9% of Fusobacterium spp. [96]. F. varium and F. mortiferum show increased resistance to penicillins through other mechanisms. The combination of penicillins and beta-lactamase inhibitors, are effective against Fusobacterium spp. However, resistance to amoxicillin-clavulanate was noted (up to 11%) [97]. Many Fusobacterium spp. are resistant to cephalosporins by virtue of cephalosporinase production [98]. However, cefoxitin and cefotetan remain active against Fusobacterial species. The macrolides have poor efficacy against fusobacteria [99]. Azithromycin is the most active macrolide against Fusobacterium spp. including those resistant to erythromycin [100]. Tetracycline has variable activity; and no resistance was found against tigecycline [97,101]. Resistance to moxifloxacin was noted in 10– 25% of Fusobacterium spp., and metronidazole resistance was rare (<1%) [97]. However, recent studies illustrated 9% of F. nucleatum to resist metronidazole [102]. Combinatorial effects were observed between amoxicillin and metronidazole on some F. nucleatum strains [103]. Clindamycin has lost some of its activity against anaerobic gram-positive bacilli [104]. Resistance to clindamycin was also noted for Fusobacterium spp. (8–31%). However, in some countries with antimicrobial stewardship it remains active against Fusobacterial species [105]. The carbapenems ertapenem and doripenem are generally effective against Fusobacterium spp. However resistance to meropenem (8%) and imipenem (4%) was noted [97]. Linezolid is active against F. nucleatum, as well as other Fusobacterium spp. [99]. 7. Management Optimal management of fusobacterial infections includes surgical intervention and drainage whenever appropriate and antimicrobial therapy. Surgical debridement of devitalized tissue

and incision and drainage of an abscess have paramount importance. In the absence of abscess drainage the infection including bacteremia may persist and lead to complications. Most patients respond adequately to proper antimicrobial therapy; and suppuration can be prevented by early and proper therapy. However, once an abscess has formed surgical drainage is needed. Ultrasonography or computed tomography scan can be used to detect suppuration. Progressive induration, edema, and clinical manifestations of toxicity are also an indication for drainage. Administration of a prolonged and high dose antimicrobial therapy is important in the treatment of Lemierre syndrome to insure cure and prevent local and systemic extension of the infection. A poor therapeutic response to treatment of Lemierre syndrome may require the use of anticoagulation, rather than for a change in antibiotics. However, the use of these agents is controversial [107]. Because this syndrome is an endovascular infection, surgical draining of purulent collection (empyema, septic arthritis, and soft-tissue abscess) is required. Ligation and resection of the internal jugular vein is unnecessary in most patients [106,107]. Antimicrobials should be directed at the eradication of the predominant pathogens. Therapy should be individualized, when possible, by collecting appropriate specimens from the infected site that are cultured for aerobic and anaerobic bacteria. The choice of the proper antimicrobials depends on the antimicrobial susceptibility of the etiologic agent(s). Broad antimicrobial coverage is required to cover all potential aerobic and anaerobic pathogens, including Staphylococcus aureus, hemolytic streptococci, and beta-lactamase producing anaerobic gram-negative bacilli. Many of the anaerobic gram-negative bacteria recovered in these infections can produce beta-lactamase [2]. These include pigmented Prevotella and Porphyromonas as well as Fusobacterium spp. Penicillin or amoxicillin are appropriate therapy for non-betalactamase-producing Fusobacterium spp. However, because fusobacterial infections typically are polymicrobial and may include other beta-lactamase and non-beta-lactamase-producing anaerobic, facultative, and aerobic organisms, broader spectrum or multiple agents are frequently necessary [97,108]. Clindamycin or a penicillin plus a beta-lactamase inhibitor combination frequently can be used as single therapy for dental, oropharyngeal, or pulmonary infection. Metronidazole plus a third-generation cephalosporin (with or without penicillin) can be used for central nervous system infection. Clindamycin, cefoxitin, chloramphenicol, carbapenems (e.g., imipenem, meropenem, doripenem, ertapenem), the combination of a beta-lactam antibiotic/beta lactamase inhibitor (e.g., ampicillin-sulbactam, amoxicillin-clavulanate and piperacillin-tazobactam), or metronidazole plus a macrolide, will provide adequate coverage for anaerobic (including fusobacteria) as well as aerobic bacteria. A penicillinase-resistant penicillin (e.g., nafcillin) or firstgeneration cephalosporin is generally adequate when the infection occurs is caused only by staphyloccoci. Treatment of methicillinresistant staphylococci mandates the administration of effective agents (i.e., vancomycin or linezolid). The duration of therapy is usually prolonged and is dependent on the site of infection, adequacy of surgical intervention, and multiple host factors. 8. Conclusions Fusobacterium species are important pathogens in pediatric head and neck infections and their complications. These infections include acute and chronic otitis, sinusitis, mastoiditis, and tonsillitis; peritonsillar and retropharyngeal abscesses; Lemierre syndrome; post-anginal cervical lymphadenitis; and periodontitis.

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Gal, Fusobacterium necrophorum as the cause of recurrent sore throat: comparison of isolates from persistent sore throat syndrome and Lemierre’s disease, J. Infect. 51 (2005) 299–305. [24] J.A. Amess, W. O’Neill, C.N. Giollariabhaigh, J.K. Dytrych, A six-month audit of the isolation of Fusobacterium necrophorum from patients with sore throat in a district general hospital, Br. J. Biomed. Sci. 64 (2007) 63–65. [25] S. Ramirez, T.G. Hild, C.N. Rudolph, J.R. Sty, S.C. Kehl, P. Havens, et al., Increased diagnosis of Lemierre syndrome and other Fusobacterium necrophorum infections at a children’s hospital, Pediatrics 112 (2003) e380–e385. [26] L. Hagelskjaer Kristensen, J. Prag, Human necrobacillosis, with emphasis on Lemierre’s syndrome, Clin. Infect. Dis. 31 (2000) 524–532. [27] I. Brook, Fusobacterial infections in children, J. Infect. 28 (1994) 155–165. [28] A.M. Bourgault, F. Lamothe, P. Dolce, et al., Fusobacterium bacteremia: clinical experience with 40 cases, Clin. Infect. Dis. 25 (Suppl 2) (1997) 181–183. [29] I. Brook, Bacteremia due to anaerobic bacteria in newborns, J. Perinatol. 10 (1990) 351–356. [30] J. Goldhagen, B.A. Alford, L.H. Prewitt, L. Thompson, M.K. Hostetter, Suppurative thrombophlebitis of the internal jugular vein: report of three cases and review of the pediatric literature, Pediatr. Infect. Dis. J. 7 (1988) 410–414. [31] T. Riordan, Human infection with Fusobacterium necrophorum (necrobacillosis), with a focus on Lemierre’s syndrome, Clin. Microbiol. Rev. 20 (2007) 622–659. [32] I. Brook, E.H. Frazier, M.E. Gher, Aerobic and anaerobic microbiology of periapical abscess, Oral Microbiol. Immunol. 6 (1991) 123–125. [33] I. Brook, P.A. Foote, J. Slots, Immune response to Fusobacterium nucleatum, Prevotella intermedia and other anaerobes in children with acute tonsillitis, J. Antimicrob. Chemother. 39 (1997) 763–769.

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[34] I. Brook, Management of bacterial rhinosinusitis in children, Eur. Respir. Dis. 8 (2012) 56–60. [35] A. Le Monnier, A. Jamet, E. Carbonnelle, et al., Fusobacterium necrophorum middle ear infections in children and related complications: report of 25 cases and literature review, Pediatr. Infect. Dis. J. 27 (2008) 613–617. [36] M. Cunningham, E. Guardiani, H.J. Kim, I. Brook, Otitis media, Future Microbiol. 7 (2012) 733–753. [37] I. Brook, Role of anaerobic bacteria in chronic otitis media and cholesteatoma, Int. J. Pediatr. Otorhinolaryngol. 31 (1995) 153–157. [38] I. Brook, Aerobic and anaerobic bacteriology of chronic mastoiditis in children, Am. J. Dis. Child. 135 (1981) 478–479. [39] P. Gorphe, A. de Barros, O. Choussy, D. Dehesdin, J.P. Marie, Acute mastoiditis in children: 10 years experience in a French tertiary university referral center, Eur. Arch. Otorhinolaryngol. 269 (2012) 455–460. [40] H. Yarden-Bilavsky, E. Raveh, G. Livni, O. Scheuerman, J. Amir, E. 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Yocum, Immune response to Fusobacterium nucleatum and Prevotella intermedia in patients with chronic maxillary sinusitis, Ann. Otol. Rhinol. Laryngol. 108 (1999) 293–295. [47] I. Brook, P. Yocum, E.M. Friedman, Aerobic and anaerobic bacteria in tonsils of children with recurrent tonsillitis, Ann. Otol. Rhinol. Laryngol. 90 (1981) 261– 263. [48] I.H. Kielmovitch, G. Keleti, C.D. Bluestone, E.R. Wald, C. Gonzales, Microbiology of obstructive tonsillar hypertrophy and recurrent tonsillitis, Arch. Otolaryngol. Head Neck Surg. 115 (1989) 721–725. [49] I. Brook, Role of beta-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection, Rev. Infect. Dis. 6 (1984) 601–607. [50] I. Brook, The role of anaerobic bacteria in tonsillitis, Int. J. Pediatr. Otorhinolaryngol. 69 (2005) 9–19. [51] I. Brook, P. Yocum, Quantitative measurement of beta-lactamase level in tonsils of children with recurrent tonsillitis, Acta Otolaryngol. Scand. 98 (1984) 446–460. [52] I. Brook, R. 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