Microbiology and Antimicrobial Management of Head and Neck Infections in Children

Microbiology and Antimicrobial Management of Head and Neck Infections in Children

Advances in Pediatrics 55 (2008) 305–325 ADVANCES IN PEDIATRICS Microbiology and Antimicrobial Management of Head and Neck Infections in Children Itz...

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Advances in Pediatrics 55 (2008) 305–325

ADVANCES IN PEDIATRICS Microbiology and Antimicrobial Management of Head and Neck Infections in Children Itzhak Brook, MD, MSc Departments of Pediatrics and Medicine, Georgetown University School of Medicine, 4431 Albemarle Street, NW, Washington DC 20016, USA

T

he management of upper respiratory tract infections (URTI) and head and neck infections in children includes an accurate clinical and bacteriologic diagnosis followed by an initial empiric antimicrobial therapy that may be adjusted once culture results are available. The increasing antimicrobial resistance of many bacterial pathogens has made the treatment of these infections more difficult [1,2]. This review summarizes the aerobic and anaerobic microbiology and antimicrobials therapy for acute and chronic URTI and other head and neck infections in children.

THE PREDOMINANT AEROBIC AND ANAEROBIC BACTERIA Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the major aerobic pathogens recovered in acute URTI (Table 1). Their resistance to antimicrobials has significantly increased in the past 2 decades. Endogenous oropharyngeal anaerobes commonly are recovered in chronic URTI and head and neck infections, some of which are serious and life threatening (Tables 1 and 2) [3]. Anaerobes are difficult to isolate and often are overlooked. Furthermore, their exact role is difficult to ascertain from the medical literature because of the inconsistent methodologies used for their isolation and identification in many studies. Their isolation and identification requires appropriate methods of collection, transportation, and cultivation of specimens [4–6]. Treatment of anaerobic infection is complicated by the slow growth of these organisms, their polymicrobial nature, and the growing resistance of anaerobic bacteria to antimicrobials. An important mechanism of resistance of aerobic (Staphylococcus aureus, H influenzae, and M catarrhalis) and anaerobic (anaerobic gram-negative bacilli

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Table 1 Aerobic and anaerobic bacteria isolated in upper respiratory tract infections Type of infection Otitis media: acute

Otitis media: chronic and mastoiditis

Peritonsillar and retropharyngeal abscess Recurrent tonsillitis

Suppurative thyroiditis Sinusitis: acute

Sinusitis: chronic

Cervical lymphadenitis

Aerobic and facultative organisms S pneumoniae H influenzaea M catarrhalisa S aureusa E colia K pneumoniaea P aeruginosaa Peptostreptococcus spp S pyogenes S aureusa S pneumoniae S pyogenes H influenzaea S aureusa S pyogenes S aureusa H influenzaea S pneumoniae M catarrhalisa S aureusa S pneumoniae H influenzae S aureusa Mycobacterium spp

Postoperative infection disrupting oral mucosa

Staphyloccus sppa Enterobacgeriaceaea Streptococcus sppa

Deep neck species

Streptococcus spp Staphylococcus sppa

Odontogenic complications

Streptococcus spp Staphylococcus sppa

Oropharyngeal: Vincent’s angina Necrotizing ulcerative gingivitis

Streptococcus spp

a

Staphylococcus sppa

Anaerobic organism Peptostreptococcus spp

Pigmented Prevotella and Porphyromonas spp Bacteroides sppa Fusobacterium sppa Fusobacterium sppa Pigmented Prevotella and Porphyromonas sppa Fusobacterium sppa

Pigmented Prevotella and Porphyromonas sppa Peptostreptococcus spp Fusobacterium sppa Pigmented Prevotella and Porphyromonas sppa Pigmeted Prevotella and Porphyromonas sppa Peptostreptococcus spp Fusobacterium sppa Bacteroides sppa Pigmented Prevotella and Porphyromonas sppa Peptostreptococcus spp Bacteroides sppa Fusobacterium sppa Peptostreptococcus sppa Pigmented Prevotella and Porphyromonas sppa Peptostreptococcus spp F necrophoruma Spirochetes, P intermidia Fusobacterium spp

Organisms that have the potential of producing b-lactamase.

[AGNB]) organisms is the production of the enzyme b-lactamase. b-lactamase– producing bacteria (BLPB) not only can protect themselves from b-lactam antibiotics but also can shield other penicillin-susceptible organisms from the activity of these agents [7].

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Table 2 Anaerobic bacteria most frequently encountered in upper respiratory tract infections and head and neck infections Organism Gram-positive cocci Peptostreptococcus spp Microaerophilic streptococcia Gram-positive bacilli Actinomyces spp P acnes Bifidobacterium spp Clostridium spp C perfringens C difficile C ramosum Gram-negative bacilli B fragilis group Pigmented Prevotella and Porphyromonas spp P oralis P oris-buccae F nucleatum F necrophorum a

Infectious site Respiratory tract, deep neck, and soft tissue infections Sinusitis, brain abscesses Intracranial abscesses, chronic mastoiditis, head and neck infections Infections associated with foreign body COM, CL Soft tissue infection Colitis, antibiotic-associated diarrheal disease Soft tissue infections Chronic otitis and sinusitis (rare) Orofacial and deep neck infections, periodontitis Orofacial infections Orofacial infections Orofacial, deep neck, and respiratory tract infections, brain abscesses, bacteremia Bacteremia

Not obligate anaerobes.

MICROBIOLOGY AND ANTIMICROBIAL MANAGEMENT OF SPECIFIC INFECTIONS Dental infections Gingivitis Microbiology. The healthy gingival sulcus contains relatively few organisms, usually streptococci and actinomyces. The development of gingivitis is associated with a significant increase in gram-negative anaerobes (Fusobacterium nucleatum, Prevotella intermedia, and Bacteroides spp), spirochetes, and motile rods (see Table 1). Nercotizing ulcerative gingivitis, previously called acute nercotizing ulcerative gingivitis, trench mouth, or Vincent’s infection, is caused by synergistic infection between unusually large spirochetes and fusobacteria [8,9], which are part of the normal oropharyngeal flora. The bacteria associated with the infection are fairly constant and include oral Treponemes and Selenomonas spp and P intermidia and Fusobacterium spp. Antimicrobial management. Management of nercotizing ulcerative gingivitis includes gentle de´bridement, good oral hygiene, and adequate nutrition. Rinsing the mouth with warm normal saline or 3% peroxide solution may be helpful. Analgesics may be required after initial de´bridement. Therapeutically, the various drugs that are active against anaerobes in general, including penicillin G, are effective.

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Other antimicrobials used successfully in the treatment of this infection include clindamycin, amoxicillin-clavulanate, and metronidazole plus erythromycin [10]. Periodontitis Microbiology. All forms of periodontitis and periodontal abscesses are polymicrobial aerobic-anaerobic bacterial infection. Periodontal disease develops usually because of two events in the oral cavity: an increase in bacterial quantity of AGNB and a change in the balance of bacterial types from harmless to diseasecausing bacteria. Among the bacteria most implicated in periodontal disease and bone loss are Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Other bacteria associated with periodontal disease are Bacteroides forsythus, Treponema denticola, Treponema sokranskii, and P intermedia [11]. The most prevalent organisms in chronic periodontitis and periodontal abscess include P intermedia, B forsythus, Actinomyces spp, Capnocytophaga spp, and Peptostreptococcus micros. Aggressive periodontitis is now recognized as a contagious infection that can be passed between family members. A actinomycetemcomitans and P gingivalis are believed to play a major role in this infection. Antimicrobial management. Therapy for perodontitis should include root de´briding and drainage of the infected root and surgically resecting inflamed periodontal tissues [12]. Although penicillin remains the drug of choice, successful therapy with penicillin has decreased [13]. This has been associated with the increasing recovery of BLPB. Other antimicrobials that are resistant to the enzyme b-lactamase would be superior in such a setting. Systemic therapy with tetracyclines has been effective. The rapid emergence of tetracyclineresistant aerobic and anaerobic bacteria, however, limits their efficacy. Furthermore, using tetracyclines for patients under 7 years of age is not recommended. Metronidazole has been shown to have comparable or superior activity to penicillin in treating periodontal infection [14]. Treatment of periodontal abscess includes drainage of puss and de´bridement. Antimicrobial therapy similar to the one used for Vincent‘s infection is necessary whenever local or systemic spread is present. Extraction of the involved tooth may be necessary if antibiotic therapy fails [10]. Otitis media Acute otitis media Microbiology. S pneumoniae, H influenzae, and M catarrhalis are the principal etiologic agents in bacterial acute otitis media (AOM) accounting for approximately 80% of the bacterial isolates [15]. Of special concern is the increased rate of isolation of penicillin-resistant strains of S pneumoniae [16] and amoxicillin-resistant H influenzae [16,17] from infected ears. The incidence of such strains reached 50% in some areas. S pneumoniae has consistently been found more commonly, irrespective of age group, but its predominance has decreased after the introduction of the pneumococcal conjugate vaccine in 2000, where the frequency of isolation of H influenzae increased [18].

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Other organisms that less frequently cause AOM include group A b-hemolytic streptococci (GABHS), S aureus, Turicella otitidis, Allioicoccus otitis, Chlamydia spp, Staphylococcus epidemidis, and various aerobic gram-negative bacilli [19] (eg, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus spp). Aerobic gram-negative bacilli and staphylococci are implicated as dominant etiologic agents in otitis media of the neonate. Even among very young infants, S pneumoniae and H influenzae constitute the most common etiologic agents. Viruses were recovered in the middle ear fluid of 14.3% of children [20]. Anaerobes were recovered from 5% to 15% of acutely infected ears [21] and 42% of culture-positive aspirates of serous otitis media [22]. Peptostreptococcus spp and Propionibacterium acnes were predominant in acute and serous otitis and AGNB also were recovered in serous otitis media. Persistent otitis media can become chronic. Antimicrobial management. Antimicrobials are administered to eradiate the pathogens, prevent recurrences and complications, and facilitate recovery. Although spontaneous resolution is common and may occur in approximately three quarters of patients, it is impossible to predict who requires antimicrobials to improve [23]. The current guidelines by the American Academy of Pediatrics and American Academy of Family Physicians for treatment of AOM offer an observation option in children between ages 6 month and 2 years who have uncertain diagnosis and nonsevere illness and those over 2 years who do not have severe illness or who have uncertain diagnosis [24]. The duration of therapy is controversial. Although most physicians use 10 days of therapy, a shorter course of 5 to 7 days can be given to children older than 2 years, those who do not attend daycare, and those who have no history of recurrences or other serious medical problem [23]. The growing resistance to amoxcillin of H influenzae and M catarrhalis, through the production of blactamase, and S pneumoniae and H influenzae, through changes in the protein binding site, have increased the risk for antimicrobial failure. Increasing the dose of amoxicillin to 90 mg/kg per day overcomes S pneumoniae penicillin resistance. The combination of amoxicillin plus clavulanic acid is effective against penicillin-resistant aerobic and anaerobic bacteria. The second-generation (cefuroxime) and extended-spectrum cephalosporins (cefdinir and cefpedoxime) also are effective in the treatment, mostly because of their effectiveness against H influenzae and M catarrhalis and intermediately penicillin-resistant S pneumoniae [25]. The growing resistance of S pneumoniae to macrolides (approximately 35%) and the poor pharmacokintics of azithromycin for H influenzae make these agents less effective. The anaerobes recovered in AOM are susceptible to penicillins and the other antibiotics commonly used to treat AOM. Trimethoprim-sulfamethoxazole (TMP/SMX), however, is effective against only 50% of peptostreptococci, the major anaerobe isolated in AOM. Chronic otitis media and cholestatoma Microbiology. The most common isolated aerobes are P aeruginosa and S aureus. Anaerobes were isolated from approximately 50% of the patients who had

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chronic suppurative otitis media [3,4,26,27] and those who had infected cholesteatoma [28,29]. The predominant anaerobes isolated are AGNB and Peptostreptococcus spp. Anaerobes generally are isolated, mixed with aerobic bacteria, and the number of isolates per specimen ranged between 2 and 6. Many of these organisms can produce b-lactamase that might have contributed to the high failure rate of b-lactam antimicrobials. The microbiology of infected cholesteatomas is similar to the one of chronic otitis media (COM) involving P aeruginosa, S aureus, AGNB, Fusobacterium, and Peptostreptococcus spp [28,29]. Because cholesteatoma associated with COM media harbors organisms similar to those isolated from chronically infected ears, the cholesteatoma may serve as a nidus of the chronic infection. Antimicrobial management. Treatment choices include clindamycin, cefoxitin, a combination of metronidazole plus a macrolide or amoxicillin, a penicillin (ie, amoxicillin or ticarcillin) plus a b-lactamase inhibitor (ie, clavulanic acid or sulbactam) [30]. In instances where P aeruginosa is considered to be a true pathogen, parenteral therapy with an aminoglycoside, cefepime, ceftazidime or ciprofloxacin (only in postpubertal patients) should be added. Parenteral therapy with a carbapenem (ie, imipenem, meropenem) provides adequate coverage for all potential pathogens, anaerobic and aerobic bacteria. Mastoiditis Acute mastoiditis Microbiology. S pneumoniae, GABHS, S aureus, and H influenzae are the most common organisms recovered [31]. Rare organisms are P aeruginosa and other aerobic gram-negative bacilli, anaerobes, and Mycobacterium tuberculosis. Antimicrobial management. Treatment is guided by cultures and includes parenteral antimicrobials and myrinyotomy with tympanostomy tube. Cefuroxime, ceftriaxone, or a combination of a penicillin plus a b-lactamase inhibitor (ie, ticarcillin plus clavulamate) is appropriate. With proper therapy, improvement occurs within 48 hours. In this event, treatment should be continued for 7 to 10 days. If the toxicity increases or the disease progresses or does not improve within 48 hours, surgical intervention and drainage may be necessary. Chronic mastoiditis Microbiology. Most infections are polymicrobial and the predominant anaerobic organisms are AGNB (including pigmented Prevotella and Porphyromonas spp and B fragilis group), F nucleatum, gram-positive cocci (Peptostreptococcus spp and microaerophilic streptococci), Actinomyces spp, P acnes, and Clostridium spp. The main aerobes are S aureus (including methicillin resistant S aureus [MRSA]), P aeruginosa, E coli, and K pneumoniae [32]. S pneumoniae and H influenzae rarely are recovered. Antimicrobial management. Antimicrobials should be directed at the eradication of aerobic and anaerobic bacteria. Some of the anaerobes, such as B fragilis group,

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and many pigmented Prevotella and Porphyromonas and Fusobacterium spp are resistant to b-lactam antibiotics. Clindamycin, metronidazole, chloramphenicol, cefoxitin, or the combination of a penicillin and a b-lactamase inhibitor cover anaerobic bacteria. Therapy also includes antimicrobials effective against S aureus (oxacillin, vancomycin, or linezolid) and gram-negative aerobic bacilli, including P aeruginosa (an aminoglycoside, ceftazidime, cefipime, or ciprofloxacin). Carbapenems provide therapy for all potential pathogens. Surgical drainage is indicated in many cases. Sinusitis Acute sinusitis Microbiology. The bacteria recovered from pediatric and adult patients who have community-acquired acute purulent sinusitis are the common respiratory pathogens (S pneumoniae, H influenzae, M catarrhalis, and GABHS) and S aureus (see Table 1) [33,34]. After the introduction of vaccination of children who have the 7-valent pneumococcal vaccine on 2000 in the United States, the rate of recovery of S pneumoniae from patients who had acute sinusitis declined and the rate of H influenzae increased [35]. S aureus is a common pathogen in sphenoid sinusitis [36]. The infection is polymicrobial in approximately a third of the cases. Enteric bacteria rarely are recovered in community-acquired infection. When appropriate methods for their recovery are used, anaerobes account for approximately 8% of isolates and are commonly in acute sinusitis associated with an odontogenic origin, mostly as an extension of the infection from the roots of the premolar or molar teeth [37]. P aeruginosa and other gram-negative rods are common in sinusitis of nosocomial origin (especially in patients who have nasal tubes or catheters), patients who are immunocompromised, HIV infection, and cystic fibrosis [38]. Anaerobic bacteria also can be recovered in these patients. Antimicrobial management. The choice of therapy is similar to the one of AOM. The recommendations of the Sinus and Allergy Health Partnership guidelines for the optimal treatment of acute bacterial sinusitis in adults and children are based on calculations of the expected clinical efficacy of the different antimicrobials [30,39,40]. The calculated expected efficacy in descending order is the ‘‘respiratory’’ fluroquinolones (ie, levofloxacin, gatifloxacin, and moxifloxacin) and amoxicillin/clavulanate (>90% efficacy); high-dose of amoxicillin, cefpodoxime proxetil, cefuroxime axetil, and TMP/SMX (80% to 90%); clindamycin, doxycycline, cefprozil, azithromycin, clarithromycin, and erythromycin (70% to 80%); and cefaclor and loracarbef (50% to 60%). Fluroquinolones are not advocated in children. Azithromycin, clarithromycin, erythromycin, or TMX/SMT are recommended in patients who have hypersensitivity to the b—lactam antimicrobials. The recommended length of therapy is 10 to 14 days, which is based on results of clinical trials that performed pre- and posttreatment sinus aspirates [33]. Antimicrobials facilitate recovery and prevent septic complications.

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Patients who fail to show significant improvement within 48 hours or show signs of deterioration require antral puncture with lavage or surgical drainage. Culture of the aspirate should be obtained during these proceedures [24,30]. Chronic sinusitis Microbiology. Although the etiology of the inflammation associated with chronic sinusitis is uncertain, bacteria can be isolated in the sinus cavity in these patients [36]. Bacteria are believed to play a major role in the etiology and pathogenesis of most cases of chronic sinusitis, and antimicrobials often are prescribed for the treatment of this infection. Many studies have examined the bacterial pathogens associated with chronic sinusitis. Most, however, did not use methods that are adequate for the recovery of anaerobic bacteria. These organisms were recovered, however, from more than half of the patients in studies where methods adequate for their recovery were used [36]. The pathogenicity of some of the low virulence organisms, such as Staphylococcus epidermidis, a colonizer of the nasal cavity is questionable [41]. Gram-negative enteric rods also were reported, especially in nosocomial sinusitis and sinusitis in intubated patients [42]. These included P aeruginosa, K pneumoniae, Proteus mirabilis, Enterobacter spp, and E coli. Recent data illustrates the growing importance of S aureus (including MRSA) [43]. Anaerobic organisms are isolated from up to 67% of patients who have chronic maxillary [36], ethmoid [44], and frontal [45] sinusitis and acute exacerbation of chronic sinusitis [46]. An average of three anaerobes and two aerobes per sinus was recovered in patients who had these infections [36,44–46]. Anaerobes predominate in chronic maxillary sinusitis associated with odontogenic infection [37]. Persistent sinusitis that fails to respond to antimicrobials can become a chronic infection that is associated with emergence of resistant anaerobic and aerobic bacteria. The gradual appearance of such bacterial flora was demonstrated in a series of five patients who had repeated endoscopic aspirations of the maxillary sinus over a period of 34 to 50 days [47]. The usual pathogens in acute sinusitis (eg, S pneumoniae, H influenzae, and M catarrhalis) are found with lower frequency [36,44–46]. Polymicrobial infection is common in chronic sinusitis, which is synergistic and may be more difficult to eradicate with narrow-spectrum antimicrobial agents. Chronic sinusitis caused by anaerobes is a particular concern because many of the complications (eg, mucocele formation, osteomyelitis, and intracranial abscess) are associated with recovery of these organisms [3,4]. Antimicrobial management. Antimicrobials used for chronic sinusitis therapy should be effective against aerobic and anaerobic BLPB; these include clindamycin, the combination of metronidazole and a penicillin or a macrolide, the combination of penicillin (eg, amoxicillin) and a b-lactamase inhibitor (eg, clavulanate), or a ‘‘respiratory’’ quinolone with antianaerobic coverage (eg, moxifloxacin). All of these agents (or similar ones) are available in oral and parenteral forms.

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Other effective agents are available only in parenteral form (eg, cefoxitin and carbapenems). If gram-negative organisms, such as P aeruginosa, may be involved, parenteral therapy with aminoglycosides, a fourth-generation cephalosporin (cefepime or ceftazidime), or oral or parenteral treatment with a fluoroquinolone (only in postpubertal patients) is added. The length of therapy is at least 21 days and may be extended up to 3 months. Fungal sinusitis can be treated with surgical de´bridement and antifungal therapy. In contrast to acute sinusitis, which generally is treated vigorously with antibiotics, many physicians believe that surgical drainage, not antibiotics, is the mainstay of therapy in chronic sinusitis. PHARYNGOTONSILLITIS Microbiology The pathogens implicated in pharyngotonsillitis (PT) are groups A, B, C, and G streptococci, Neisseria gonorrhoeae, N meningitides, Corynebacerium diphtheriae, C hemolyticum, and Arcanobacterium hemolyticum. Indirect evidence supports the involvement of anaerobes in acute and chronic tonsillitis [48]. The anaerobes associated with the infection are Fusobacterium spp, AGNB, and Peptostreptococcus spp. The pathogenic role of anaerobes in the acute and chronic inflammatory process of the tonsils is supported by several clinical observations: their major role in complications of tonsillitis, such as thrombophlebitis of the internal jugular veins, which often causes postanginal sepsis [3,4]; their isolation from 25% of suppurative cervical lymph nodes associated with the presence of dental or tonsillar infections [49]; their recovery in a polymicrobial infection from tonsillar, peritonsillar, or retropharyngeal abscesses in many cases without any aerobic bacteria [50]; the isolation of anaerobes from tonsils in Vincent’s angina [3,4]; the recovery of encapsulated pigmented Prevotella and Porphyromonas spp in acutely inflamed tonsils; the isolation of anaerobes from the core of recurrently inflamed non-GABHS tonsils [51]; and the response to antimicrobials in patients who have non-GABHS tonsillitis [52–54]. Furthermore, immune response against P intermedia can be detected in patients who have non-GABHS tonsillitis [55], and an immune response also can be detected against P intermedia and F nucleatum in patients who recovered from peritonsillar cellulitis or abscesses [56] and infectious mononucleosis [57]. Antimicrobial management The growing inability of penicillin to eradicate GABHS, which leads to clinical and bacteriologic failures, is an important clinical problem. Recent studies showed that penicillin failed to eradicate GABHS in acute-onset pharyngitis in 35% of patients treated with oral penicillin V and 37% who received intramuscular penicillin [58]. Various theories have been offered to explain this penicillin failure that may lead to recurrent tonsillitis (Box 1) [6,59–61]. Some postulate that bacterial interactions between GABHS and members of the PT bacterial flora can

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Box 1: Possible causes for antibiotic failure or relapse in therapy of group A b-hemolytic streptococci tonsillitis Bacterial interactions The presence of BLPB that ‘‘protect’’ GABHS from penicillins Co-aggregation between GABHS and M catarrhalis Absence of members of the oral bacterial flora capable of interfering with the growth of GABHS (through production of bacteriocins or competition on nutrients) Internalization of GABHS (survives within epithelial cells, escaping eradication by penicillins) Poor penetration of penicillin into the tonsillar tissues when the inflammation subsides Resistance (ie, erythromycin) or tolerance (ie, penicillin) to the antibiotic used Inappropriate dose, duration of therapy, or choice of antibiotic Poor compliance Reacquisition of GABHS from a contact or an object (ie, toothbrush or dental braces) Carrier state, not disease

explain these failures. These explanations include the ‘‘shielding’’ of GABHS from penicillins by BLPB that colonize the pharynx and tonsils [6,59], the absence of normal flora organisms that interfere with the growth of GABHS [60], and the co-aggregation between M catarrhalis and GABHS [61]. Antimicrobial management Acute pharyngotonsillitis. Even though antibiotics other than penicillin are more effective in the bacteriologic and clinical cure of GABHS PT, penicillin still is recommended in some guidelines as the antibiotic of choice. The antibiotics found more effective included cephalosporins, lincomycin, clindamycin, macrolides, and amoxicillin clavulanate [36,59]. Some of these agents were more effective than penicillin in acute (cephalosporins and macrolides) and others in recurrent (lincomycin, clindamycin, and amoxicillin-clavulanate) GABHS PT. There are patients where more effective antimicrobials that are less likely to fail to eradicate GABHS should be considered. Individual medical, economic, and social issues should be considered before selecting an antimicrobial for the treatment of GABHS PT (Box 2) [62]. These include the existence of a high probability for the presence in the PT area of BLPB and the absence of interfering organisms, the recent failure of penicillin therapy, or a history of recurrent GABHS PT [62]. The macrolides also are an alternative choice in therapy for PT. Compliance with the newer macrolides (clarithromycin and azithromycin) is better compared with erythromycin, because of their longer half-life and reduced adverse

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Box 2: Indications for the use of antimicrobial other than a penicillin (ie, cehalosporins and clindamycin) for group A b-hemolytic streptococci tonsillitis Presence of BLPB (recent antibiotic exposure, increase in winter, regional prevalence) Absence of ‘‘interfering flora‘‘ (recent antibiotic therapy) Recurrent GABHS tonsillitis Past failures to eradicate GABHS High failures of penicillins in the community Comorbidities When failure is a medical, economical, or social hardship Penicillin allergy (non–type I)

gastrointestinal side effects. The increased use of macrolides, however, for the treatment of various respiratory and other infections is associated with increased GABHS resistance to these agents [63,64]. Resistance of GABHS to macrolides reached up to 70% in Finland, Italy, Japan, and Turkey [63]. Of concern is the recent significant increase of such resistance in the United States that reached 48% at specific populations [64]. The current resistance of GABHS to macrolides in the United States is 5% to 16% [64]. It is advisable, therefore, to avoid the routine use of macrolides for GABHS PT and save them for those who have type I penicillin allergy. The success rate of treatment of acute GABHS tonsillitis was found consistently higher with cephalosporins than with penicillin [65]. The cephalosporins’ increased efficacy may be the result of their activity against aerobic BLPB, such as S aureus, Haemophilus spp, and M cattarrhalis. Another possible reason is that the nonpathogenic interfering aerobic and anaerobic bacteria, which compete with GABHS [60], hamper their ability to colonize and help to eliminate them, are less susceptible to cephalosporins than to penicillin [62]. These organisms, therefore, are more likely to survive cephalosporin therapy. Shorter course of therapy with several antimicrobials (ie, cefdinir and azythromycin) were found equal or superior to 10 days of penicillin [66]. Early initiation of antimicrobial therapy results in faster resolution of signs and symptoms. Prevention of recurrent tonsillitis due to GABHS by prophylactic administration of daily oral or monthly benzathine penicillin should be attempted in patients who suffered from rheumatic fever. If any family members are carrying GABHS, the organisms should be eradicated and the carrier state monitored. When C diphtheriae infection is suspected, erythromycin is the drug of choice, and penicillin or rifampin is an alternative. Recurrent and chronic pharyngotonsillitis. Penicillin failure in treatment of recurrent and chronic tonsillitis is even higher than the failure of therapy for acute infection. Several clinical studies demonstrated the superiority of lincomycin,

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clindamycin, and amoxicillin-clavulanic acid or a macrolide (eg, erythromycin) plus metronidazole over penicillin. These antimicrobial agents are effective against aerobic and anaerobic BLPB and GABHS in eradicating recurrent tonsillar infection. Referral of a patient for tonsillectomy because of recurrent GABHS PT should be considered only if these medical therapeutic modalities have failed. CERVICAL LYMPHADENITIS Microbiology The cervical lymphatic system is a first line of defense against URTI and dental or soft tissues infections of the face and scalp. Viruses are the most common cause of bilateral cervical lymphadenitis (CL) in children [67]. The most common viruses are Epstein-Barr, cytomegalovirus, herpes simplex, adenovirus, enterovirus, roseola, rubella, and HIV. Other pathogens of CL include Mycoplasma pneumoniae and C diphtheriae. The most common bacterial organisms causing acute unilateral infection associated with facial trauma or impetigo are S aureus and GABHS [49,68,69]. Other causes include Bartonella henselae, H influenzae, Francisella tularensis, Pasteurella multocida, Yersinia pestis, Y entercolitica, Listeria monocytogenes, A actinomycetemcomitans, Burkholderia gladioli, Spirillum minor, Nocardia brasiliensis, M tuberculosis, and nontuberculous mycobacteria [70]. Other rare aerobic pathogens are S pneumoniae and gram-negative rods. Adenitis in newborns often is associated with group B streptococci. The most common fungi involved in CL are Histoplasma capsulatum, Coccidioides immitis, and Paracoccidioides spp. Studies that used methodologies that were adequate for the recovery of anaerobes demonstrated their importance in CL mostly in association with dental or periodontal disease [49,68]. The predominate anaerobes are AGNB, Fusobacterium spp, and Peptostreptococcus spp. Antimicrobial management The majority of patients who have CL do not require specific therapy as they are a result of viral pharyngitis or stomatitis. Empiric antimicrobial therapy should provide adequate coverage for S aureus and GABHS. Oral antimicrobials should include penicillinase-resistant penicillins, such as cloxacillinor dicloxacillin, or the combination of a penicillin (ie, amoxicillin) and a b-lactamase inhibitor (ie, clavulanic acid). Parenteral therapy may be required in toxic patients. Patients allergic to penicillin can be treated with a macrolide or clindamycin. Treatment should be administered for at least 14 days. Antimicrobial therapy effective against anaerobic and aerobic BLPB includes either clindamycin, the combination of a penicillin and a b-lactamase inhibitor, and the combination of penicillin or macrolide and metronidazole. If no improvement occurs after 36 to 48 hours of therapy, a reassessment is required. Early institution of antibiotics prevents most cases of pyogenic adenitis from progressing to suppuration. Once fluctuation occurs, however, antibiotics alone generally are not sufficient and the abscess should be incised and drained.

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When mycobacterial or cat-scratch disease is suspected, incision and drainage should be avoided as chronically draining cutaneous fistulae often develops. A large needle (18- or 19-gauge needle) is preferred to avoid formation of a fistula. Therapy with rifampin, TMP/SMX, or gentamicin should be considered in cat-scratch disease directed at B henselae. Total surgical removal is most effective therapy for nontuberculous mycobacterial CL. Therapy with antimycobacterial therapy generally is initiated until the organisms are identified as atypical mycobacteria. This includes the administration of rifampin and isoniazid. When atypical mycobacteria are recovered, these drugs generally are stopped; however, therapy is continued for 9 to 12 months if M tuberculosis is identified. SUPPURATIVE THYROIDITIS Microbiology S aureus, GABHS, S epidermidis, and S pneumoniae are the predominant aerobic isolates. The most common anaerobic bacteria are AGNB, Peptostreptococcus spp, and Actinomyces spp [71–73]. Klebsiella spp, H influenzae, S viridans, Salmonella spp, Enterobacteriaceae, M tuberculosis, atypical mycobacteria, Aspergillus spp, C immitis, Candida spp, Treponema pallidum, and Echinococcus spp rarely are recovered. Viruses associated with subacute thyroiditis are measles, mumps, influenza, enterovirus, Epstein-Barr, adenovirus, echovirus, and St. Louis encephalitis. Antimicrobial management A broad coverage by antimicrobials is indicated, at least until culture results are available. Empiric therapy should be effective against S aureus and GABHS. Oral antimicrobials should include penicillinase-resistant penicillins (ie, dicloxacillin) or the combination of a penicillin (ie, amoxicillin) and a b-lactamase inhibitor (ie, clavulamate). Parenteral therapy may be required in patients who show toxicity. Patients allergic to penicillin can be treated with a macrolide or clindamycin. Treatment should be administered for at least 14 days. Early institution of treatment with antibiotics can prevent most cases of suppurative thyroiditis from progressing to suppuration. Once fluctuation occurs, however, antibiotic therapy alone generally is not sufficient. Surgical drainage is indicated when antibiotic therapy fails to control the infection. If extensive necrosis or persistence of infection is demonstrated despite antibiotics, lobectomy may be required [71]. PERITONSILLAR, RETROPHARYNGEAL, AND PARAPHARYNGEAL ABSCESSES Microbiology The microbiology of all deep neck abscesses is similar because the causative bacteria reflect the host’s oropharyngeal flora. Predominant anaerobic organisms isolated in peritonsillar, lateral pharyngeal, and retropharyngeal abscesses are Prevotella, Porphyromonas, Fusobacterium, and Peptostreptococcus

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spp; aerobic organisms are GABHS, S aureus, and H influenzae. Anaerobes are isolated from most abscesses whenever appropriate techniques for their cultivation have been used whereas GABHS is isolated in only approximately one third of cases [50]. Elevated antibody levels against F nucleatum and Prevotella intermedia, known oral pathogens, was found in children who had peritonsillar abscess or cellulitis, supporting their pathogenic role [74]. More than two thirds of deep neck abscesses contain BLPB [50,60]. Retropharyngeal cellulitis and abscess in young children is more likely to have pathogenic aerobic isolates (Streptococcus spp and S aureus), alone or mixed [75]. F necrophorum is associated especially with deep neck infections that cause septic thrombophlebitis of great vessels and metastatic abscesses (Lemierre’s disease) [76]. M tuberculosis, atypical mycobacteria, or C immiti rarely are recovered. Antimicrobial management Surgical drainage of an abscess is the therapy of choice. Administration of antimicrobial agents also is required, however. Because of their similar microbiology, the antimicrobial management of these abscesses is not different. Early initiation of antimicrobials at the stage of cellulites can prevent abscess formation. When an abscess is diagnosed, antimicrobial therapy should be given and the abscess drained. Because of the risk for recurrence, tonsillectomy is performed 6 to 8 weeks later. This not always is needed, however, in children where recurrence rate is 7%, compared with 16% in adults. Controversy exists regarding management of peritonsillar abscess on an outpatient basis, after needle aspiration of the abscess [77]. The isolation of aerobic and anaerobic BLPB from most abscesses mandates the use of antimicrobials effective against these organisms. Efficacy antimicrobial agents include cefoxitin, a carbapenem (ie, imipenem or meropenem), the combination of a penicillin (ie, ticarcillin) and a b-lactamase inhibitor (ie, clavulanate), or clindamycin.

PAROTITIS AND SIALADENITIS Microbiology The parotid gland is the salivary gland affected most commonly by inflammation. The most common pathogens associated with acute bacterial parotitis and sialadenitis are S aureus and anaerobic bacteria. The predominant anaerobes include AGNB, Fusobacterium spp, and Peptostreptococcus spp. Streptococcus spp (including S pneumoniae) and gram-negative bacilli (including E coli) also are reported [78,79]. Gram-negative organisms often are seen in hospitalized patients. Organisms found less frequently are Arachnia spp, H influenzae, K pneumoniae, Salmonella spp, P aeruginosa, Treponema pallidum, cat-scratch bacillus, and Eikenella corrodens. M tuberculosis and atypical mycobacteria are rare causes of parotitis.

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Antimicrobial management Therapy includes maintenance of hydration and administration of parenteral antimicrobial therapy. Once an abscess has formed, surgical drainage is required. The choice of antimicrobials depends on the etiologic agent. Prolonged high-dose antimicrobial therapy is important in insuring cure and preventing local and systemic extension of these infections. Antimicrobials should be directed at the eradication of the predominant organisms causing these infections. To assure that therapy is individualized, appropriate specimens should be collected from the infected site and processed for aerobic and anaerobic bacteria. The choice of the proper antibiotics depends on an organism’s susceptibility. Most patients respond adequately to proper antimicrobial therapy; however, once an abscess has formed, surgical drainage is required. Ultrasonography or CT scan can be used to detect suppuration. Progressive induration, edema, and toxicity also are indications for drainage. Broad antimicrobial therapy is indicated to cover all possible aerobic and anaerobic pathogens, including adequate coverage for S aureus, hemolytic streptococci, and b-lactamase producing AGNB [74]. Clindamycin, cefoxitin, chloramphenicol, imipenem, meropenem, the combination of a penicillin (ie, amoxicillin) and b-lactamase inhibitor (ie, clavulanate), or metronidazole plus a macrolide provides adequate coverage for anaerobic and aerobic bacteria. A penicillinase-resistant penicillin (ie, nafcillin) or first-generation cephalosporin generally is adequate when the infection occurs is caused only by staphyloccoci. The presence of MRSA may mandate the use of vancomycin or linezolid. DEEP NECK INFECTIONS Microbiology These infections generally follow oral, dental, and pharyngeal infections and generally are polymicrobial, involving the aerobic and anaerobic bacteria that caused the primary infections. They occur in the deep posterior neck (retropharyngeal, prevertebral, and visceral vascular), suprahyoid (pharygomaxillary, submandibullar, mandibular, masticator, temporal, parotid, and peritonsillar), and infrahyoid spaces. The predominant organisms recovered from deep facial infections are S aureus, GABHS, and anaerobic bacteria of oral origin. These include pigmented Prevotella, Porphyromonas, and Fusobacterium spp [3]. These organisms are recovered mostly in polymicrobial infections, mixed with aerobic bacteria. The classic Ludwig’s angina involves a bilateral infection of the submandibular and sublingual spaces [3]. A variety of microorganisms have been isolated from cases of Ludwig’s angina. In recent years, anaerobic bacteria have predominated, including Fusobacterium spp, AGNB, and Peptostreptococcus spp. Often, one or more of the following also have been found: staphylococci, streptococci, S pneumoniae, E coli, spirochetes, H influenzae, and Candida albicans. Cysts (thyroglossal duct, cystic hygromas, branchial cleft, laryngoceles, and dermoid cysts) can become inflamed and secondarily infected. The organisms

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causing these infections can originate from the skin or the oropharynx and include oral anaerobes [80]. Antimicrobial management See the earlier discussion of parotitis and sialadenitis. LEMIERRE’S SYNDROME Microbiology This syndrome is a rare but severe life-threatening complication of oral infections, particularly those resulting in lateral pharyngeal space infection. It is characterized as thrombosis and suppurative thrombophlebitis of the internal jugular vein that is associated with spread of septic emboli to the lungs and other sites. Before the availability of antimicrobial agents, death was a common result, unless patients were treated with surgical ligation of the vein [76,81]. Fusobacterium is the predominate genus and F necrophorum is the most prevalent species. Other fusobacteria include F nucleatum, F gonidiaforum, and F varium. Other isolates recovered alone or in combination include pigmented Prevotella, Bacteroides spp, and Peptostreptococcus spp [81]. Antimicrobial management See the later discussion of parotitis and sialadenitis. WOUND INFECTION AFTER HEAD AND NECK SURGERY Microbiology These infections are the result of the exposure of the surgical site to the oropharyngeal flora. They generally are infected by polymicrobial aerobic and anaerobic flora and the number of isolates varies from one to nine (average six) [82]. The isolates most frequently recovered are S aureus, enteric gram-negative rods, Peptostreptococcus spp, Fusobacterium spp, and AGNB. Antimicrobial management Cefoxitin, carbapenems, and the combinations of clindamycin or metronidazole and gentamicin and ampicillin and sulbactam were found effective in treatment of these infections [83]. Antimicrobial prophylaxis prior to surgery with cefoxitin or clindamycin is effective in preventing wound infections and should be administered for only 24 hours. GENERAL CONSIDERATIONS FOR USE OF ANTIMICROBIALS FOR THE TREATMENT OF POLYMICROBIAL AEROBIC-ANAEROBIC INFECTIONS Environmental control is achieved by de´bridement of necrotic tissues, drainage of the pus, improving circulation, alleviating obstructions, and increasing the tissue oxygenation. Hyperbaric oxygen also may be useful [84]. Surgical therapy is important and sometimes the only form of treatment required in many cases, whereas in others, it is an essential adjunct to the medical approach. It is used to drain abscesses; de´bride necrotic tissues; decompress

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closed space infections, such as sinuses; relieve obstructions; and correct underlying pathology. When not performed, the infection may persist, and serious complications may arise. Adequate management of mixed aerobic and anaerobic infections necessitates the administration of agents effective against both types of organisms. Several factors should be considered when choosing appropriate antimicrobial agents. They should be effective against all target organisms, induce little or no resistance, achieve sufficient concentration in the infected site, have a safety record and appropriate dosage schedules, cause minimal toxicity, and have maximum stability. Antimicrobials may fail to cure the infection. Among the reasons for this are the development of bacterial resistance, achievement of insufficient tissue concentration, incompatible drug interactions, and the formation of an abscess. The abscess environment is detrimental to many antimicrobials. The abscess capsule can interfere with the penetration of antimicrobials, and the intraabscess low pH and high content of binding proteins or inactivating enzymes (ie, b-lactamase) may impair their activity [59]. The low pH and the anaerobic environment are especially unfavorable for the aminoglycosides and fluroquinolones [85]. An anaerobic environment, an acidic pH, and high osmolarity also can develop in an infection site in the absence of an abscess. The selection of antimicrobials should be guided by their aerobic and anaerobic antibacterial spectrum and their availability in oral or parenteral form. Some antimicrobials have a narrow spectrum of activity. For example, metronidazole is effective only against most anaerobes and, therefore, cannot be administered as a single-agent therapy for mixed infections. Others (ie, carbapenems) possess a wide spectrum of activity that also includes Enterobacteriaceae. The selection of antimicrobials is simplified when reliable culture results are available. This not always is possible, however, because of the problems in obtaining appropriate specimens. Many patients, therefore, are treated empirically on the basis of suspected, rather than known, pathogens. Fortunately, the types of anaerobes involved in most anaerobic infections and their antimicrobial susceptibility patterns tend to be predictable, although they may vary in particular settings. Some anaerobes, however, have become resistant to selected antimicrobial agents or may become so while a patient is receiving therapy [86]. Controversies exist regarding the need to provide coverage against all resistant isolates as some studies of the treatment of acute maxillary sinusitis suggested that use of narrow-spectrum antimicrobials are as effective as wide-spectrum ones [87]. Other studies, however, demonstrated the superiority of more effective agents in attaining clinical and bacteriologic success [88]. The choice of antimicrobial therapy also is influenced by factors other than susceptibility patterns. These include pharmacokinetic and pharmacodynamic characteristics of the various drugs, their toxicity, their effect on the normal flora, and bactericidal activity. The clinical setting and gram-stain preparation of the specimen may suggest what types of anaerobes are present and the nature of the infectious process.

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The duration of therapy for anaerobic infections, which often are chronic, usually is longer than for infections because of aerobic and facultative anaerobes. Duration of treatment also must be individualized, depending on the response. Oral therapy often is substituted for parenteral therapy after an initial period. The number of antimicrobials available for oral therapy is limited and includes amoxicillin plus clavulanic acid, clindamycin, chloramphenicol, and metronidazole. References [1] Niederman MS. Principles of appropriate antibiotic use. Int J Antimicrob Agents 2005;26: S170–5. [2] Brook I. Antibiotic resistance of oral anaerobic bacteria and their effect on the management of upper respiratory tract and head and neck infections. Semin Respir Infect 2002;17: 195–203. [3] Gibbons RJ. Aspects of the pathogenicity and ecology of the indigenous oral flora of man. In: Ballow A, Dehaan RM, Dowell VR, et al, editors. Anaerobic bacteria: role in disease. Springfield (Il): Charles C. Thomas Publisher; 1974. p. 267–85. [4] Finegold SM. Anaerobic infections in humans: an overview. Anaerobe 1995;1:3–9. [5] Brook I. Pediatric anaerobic infection: diagnosis and management. 2nd edition. St. Louis (MO): Mosby; 1989. [6] Summanen P, Baron EJ, Citron DM, et al. Wadsworth anaerobic bacteriology manual. 5th edition. Belmont (CA): Star Publishing; 1995. [7] Brook I. The role of beta-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Rev Infect Dis 1984;6:601–7. [8] LoeschE WJ, SyeD SA, Laughon BE, et al. The bacteriology of acute necrotizing ulcerative gingivitis. J Periodontol 1982;53:223–30. [9] Socransky SS, Haffajee AD. Evidence of bacterial etiology: a historical perspective. Periodontol 2000 1994;5:7–25. [10] Brook I, Douma M. Antimicrobials therapy guide for the dentist. Newtown, Pennsylvania: Handbooks in Health Care Co; 2004. [11] Darby I, Curtis M. Microbiology of periodontal disease in children and young adults. Periodontol 2000 2001;26:33–53. [12] Loesche WJ. Rationale for the use of antimicrobial agents in periodontal disease. Int J Technol Assess Health Care 1990;6:403–17. [13] Heimdahl A, Von-Konow L, Nord CE. Isolation of beta-lactamase producing Bacteroides strains associated with clinical failures with penicillin treatment of human orofacial infections. Arch Oral Biol 1980;25:689–92. [14] Loesche WJ, Giordano JR. Treatment paradigms in periodontal disease. Compend Contin Educ Dent 1997;18:221–32. [15] Pichichero ME, Pichichero CL. Persistent otitis media: causative pathogen. Pediatr Infect Dis J 1995;14:178–83. [16] Leibovitz E, Raiz S, Piglansky L, et al. Resistance pattern of middle ear fluid isolates in acute otitis media recently treated with antibiotics. Pediatr Infect Dis J 1998;17:463–9. [17] Brook I, Gober AE. Microbiologic characteristics of persistent otitis media. Arch Otolaryngol Head Neck Surg 1998;124:1350–2. [18] Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995–2003. Pediatr Infect Dis J 2004;23:824–8. [19] Schwartz RH, Brook I. Gram-negative rod bacteria as a cause of acute otitis media in children. Ear Nose Throat J 1981;60:9–12. [20] Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999;340:260–4.

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[21] Brook I, Anthony BV, Finegold SM. Aerobic and anaerobic bacteriology of acute otitis media in children. J Pediatr 1978;92:13–5. [22] Brook I, Yocum P, Shah K, et al. The aerobic and anaerobic bacteriology of serous otitis media. Am J Otol 1983;4:389–92. [23] Wientzen RL Jr, Barbey-Morel C. Current concepts of therapy for otitis media. Curr Infect Dis Rep 1999;1:22–6. [24] American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics 2004;113:1451–65. [25] Brook I. Use of oral cephalosporins in the treatment of acute otitis media in children. Int J Antimicrob Agents 2004;24:18–23. [26] Brook I. Prevalence of beta-lactamase-producing bacteria in chronic suppurative otitis media. Am J Dis Child 1985;139:280–4. [27] Sweeney G, Picozzi GI, Browning GG. A quantitative study of aerobic and anaerobic bacteria in chronic suppurative otitis media. J Infect 1982;5:47–55. [28] Brook I. Aerobic and anaerobic bacteriology of cholesteatoma. Laryngoscope 1981;91: 250–5. [29] Lino Y, Hoshimi E, Tomioko S, et al. Organic acids and anaerobic microorganisms in the contents of the cholesteatoma sac. Ann Otol Rhinol Laryngol 1983;92:91–4. [30] American Academy of Pediatrics, Subcommittee on management of sinusitis and committee on quality control. Clinical Practice Guidelines: management of sinusitis. Pediatrics 2001;108:798–807. [31] Niv A, Nash M, Peiser J, et al. Outpatient management of acute mastoiditis with periosteitis in children. Int J Pediatr Otorhinolaryngol 1998;46:9–13. [32] Brook I. Aerobic and anaerobic bacteriology of chronic mastoiditis in children. Am J Dis Child 1981;135:478–9. [33] Gwaltney JM Jr, Scheld WM, Sande MA, et al. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992;90:457–62. [34] Wald ER, Milmore GJ, Bowen AD, et al. Acute maxillary sinusitis in children. N Engl J Med 1981;304:749–54. [35] Brook I, Foote PA, Hausfeld JN. Frequency of recovery of pathogens causing acute maxillary sinusitis in adults before and after introduction of vaccination of children with the 7-valent pneumococcal vaccine. J Med Microbiol 2006;55:943–6. [36] Nord CE. The role of anaerobic bacteria in recurrent episodes of sinusitis and tonsillitis. Clin Infect Dis 1995;20:1512–24. [37] Brook I. Microbiology of acute and chronic maxillary sinusitis associated with an odontogenic origin. Laryngoscope 2005;115:823–5. [38] Decker CF. Sinusitis in the immunocompromised host. Curr Infect Dis Rep 1999;1:27–32. [39] Brook I. Management of chronic suppurative otitis media: superiority of therapy effective against anaerobic bacteria. Pediatr Infect Dis J 1994;13:188–93. [40] Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004;130(Suppl 1):1S–45S. [41] Gordts F, Halewyck S, Pierard D, et al. Microbiology of the middle meatus: a comparison between normal adults and children. J Laryngol Otol 2000;14:184–8. [42] Bolger WE. Gram negative sinusitis: emerging clinical entity. Am J Rhinol 1994;8:279–83. [43] Brook I, Foote PA, Hausfeld JN. Increase in the frequency of recovery of meticillinresistant Staphylococcus aureus in acute and chronic maxillary sinusitis. J Med Microbiol 2008;57(Pt 8):1015–7. [44] Brook I. Bacteriology of acute and chronic ethmoid sinusitis. J Clin Microbiol 2005;43: 3479–80. [45] Brook I. Bacteriology of acute and chronic frontal sinusitis. Arch Otolaryngol Head Neck Surg 2002;128:583–5.

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[46] Brook I, Foote PA, Frazier EH. Microbiology of acute exacerbation of chronic sinusitis. Ann Otol Rhinol Laryngol 2005;114:573–6. [47] Brook I, Frazier EH, Foote PA. Microbiology of the transition from acute to chronic maxillary sinusitis. J Med Microbiol 1996;45:372–5. [48] Brook I. The role of anaerobic bacteria in tonsillitis. Int J Pediatr Otorhinolaryngol 2005;69: 9–19. [49] Brook I. Aerobic and anaerobic bacteriology of cervical adenitis in children. Clin Pediatr 1980;19:693–6. [50] Brook I. Aerobic and anaerobic microbiology of peritonsillar abscess in children. Acta Paediatr Scand 1981;70:831–5. [51] Brook I, Yocum P. Comparison of the microbiology of group A streptococcal and non-group A streptococcal tonsillitis. Ann Otol Rhinol Laryngol 1988;97:243–6. [52] Brook I, Gober AE. Treatment of non-streptococcal tonsillitis with metronidazole. Int J Pediatr Otorhinolaryngol 2005;69:65–8. [53] Helstrom SA, Mandi PA, Ripa T. Treatment of infectious mononucleosis with metronidazole. Scand J Infect Dis 1978;10:7–9. [54] Puto A. Febrile exudative tonsillitis: viral or streptococcal. Pediatrics 1987;80:6–12. [55] Brook I, Foote PA Jr, Slots J, et al. Immune response to Prevotella intermedia in patients with recurrent non-streptococcal tonsillitis. Ann Otol Rhinol Laryngol 1993;102: 113–6. [56] Brook I, Foote PA, Slots J. Immune response to Fusobacterium nucleatum and Prevotella intermedia in patients with peritonsillar cellulitis and abscess. Clin infect Dis 1995;20: S220–1. [57] Brook I, de Leyva F. immune response to Fusobacterium nucleatum and Prevotella intermedia in patients with infectious mononucleosis. J Med Microbiol 1996;44:131–4. [58] Kaplan EL, Johnson DR. Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and of oral penicillin V in eradication of group A streptococci from children with acute pharyngitis. Pediatrics 2001;108:1180–6. [59] Brook I. The role of beta-lactamase producing bacteria and bacterial interference in streptococcal tonsillitis. Int J Antimicrob Agents 2001;17:439–42. [60] Brook I. The role of bacterial interference in otitis, sinusitis and tonsillitis. Otolaryngol Head Neck Surg 2005;133:139–46. [61] Brook I, Gober AE. Increased recovery of Moraxella catarrhalis and Haemophilus influenzae in association with group A beta-haemolytic streptococci in healthy children and those with pharyngo-tonsillitis. J Med Microbiol 2006;55:989–92. [62] Brook I. Penicillin failure in treatment of acute and recurrent tonsillopharyngitis is associated with copathogens and alteration of microbial balance—a role for cephalosporins. Clin Pediatr 2007;46:175–245. [63] Colakoglu S, Alacam R, Hascelik G. Prevalence and mechanisms of macrolide resistance in Streptococcus pyogenes in Ankara, Turkey. Scand J Infect Dis 2006;38:456–9. [64] Richter SS, Heilmann KP, Beekmann SE, et al. Macrolide-resistant Streptococcus pyogenes in the United States, 2002-2003. Clin Infect Dis 2005;41:599–608. [65] Casey JR, Pichichero ME. Meta-analysis of cephalosporins versus penicillin for treatment of group A strepharyngo-tonsillitisococcal tonsillopharyngitis in adults. Clin Infect Dis 2004;38:1526–34. [66] Brook I. Antibacterial therapy for acute group a streptococcal pharyngotonsillitis: shortcourse versus traditional 10-day oral regimens. Paediatr Drugs 2002;4:747–54. [67] Peters TR, Edwards KM. Cervical lymphadenopathy and adenitis. Pediatr Rev 2000;21: 399–405. [68] Brook I, Frazier EH. Microbiology of cervical lymphadenitis in adults. Acta Otolaryngol 1998;118:443–6. [69] Graves M, Robin T, Chipman AM, et al. Four additional cases of Burkholderia gladioli infection with microbiological correlates and review. Clin Infect Dis 1997;25:838–42.

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[70] Hazra R, Robson CD, Perez-Atayde AR, et al. Lymphadenitis due to nontuberculous mycobacteria in children: presentation and response to therapy. Clin Infect Dis 1999;28: 123–9. [71] Shah SS, Baum SB. Infectious thyroiditis: diagnosis and management. Curr Infect Dis Rep 2000;2:147–53. [72] Jeng LB, Lin JD, Chen MF. Acute suppurative thyroiditis: a ten year review in a Taiwanese hospital. Scand J Infect Dis 1994;26:297–300. [73] Yu EH, Ko WC, Chuang YC, et al. Suppurative Acinetobacter baumanii thyroiditis with bacteremic pneumonia: case-report and review. Clin Infect Dis 1998;27:1286–90. [74] Brook I. Microbiology of abscesses of the head and neck in children. Ann Otol Rhinol Laryngol 1987;96:429–33. [75] Asmar BI. Bacteriology of retropharyngeal abscess in children. Pediatr Infect Dis J 1990;9: 595–6. [76] Hughes CE, Spear RK, Shinabarger CE, et al. Septic pulmonary emboli complicating mastoiditis: Lemierre’s syndrome. Clin Infect Dis 1994;18:633–5. [77] Khayr W, Taepke J. Management of peritonsillar abscess: needle aspiration versus incision and drainage versus tonsillectomy. Am J Ther 2005;12:344–50. [78] Brook I. Aerobic and anaerobic microbiology of suppurative sialadenitis. J Med Microbiol 2002;51:526–9. [79] Brook I. Acute bacterial suppurative parotitis: microbiology and management. J Craniofac Surg 2003;14:37–40. [80] Brook I. Microbiology of infected epidermal cysts. Arch Dermatol 1989;125:1658–61. [81] Lemierre A. On certain septicemias due to anaerobic organisms. Lancet 1936;2:701–3. [82] Brook I, Hirokawa R. Post surgical wound infection after head and neck cancer surgery. Ann Otol Rhinol Laryngol 1989;98:322–5. [83] Fraioli R, Johnson JT. Prevention and treatment of postsurgical head and neck infections. Curr Infect Dis Rep 2004;6:172–80. [84] Kindwall EP. Uses of hyperbaric oxygen therapy in the 1990s. Cleve Clin J Med 1992;59: 517–28. [85] Verklin RM, Mandell GL. Alteration of antibiotics by anaerobiosis. J Lab Clin Med 1977;89: 65–72. [86] Hecht DW. Antibiotic resistance, clinical significance, and the role of susceptibility testing. Anaerobe 2006;12:115–21. [87] Lindbaek M. Acute sinusitis: guide to selection of antibacterial therapy. Drugs 2004;64: 805–19. [88] Brook I, Foote PA, Hausfeld JN. Eradication of pathogens from the nasopharynx after therapy of acute maxillary sinusitis with low- or high-dose amoxicillin/clavulanic acid. Int J Antimicrob Agents 2005;26:416–9.