Most cases of acute pharyngotonsillitis are viral. Currently known respiratory viruses include rhinovirus, adenovirus, influenza virus, parainfluenza virus, coxsackievirus, coronavirus, echovirus, respiratory syncytial virus, and metapneumovirus. These conditions should be differentiated from infectious mononucleosis, which is caused by Epstein–Barr virus (EBV) generally among young adults, acute human immunodeficiency virus (HIV) infection, cytomegalovirus infection, and herpes simplex virus infection [91011]. Universal use of antibiotics for patients with sore throat is beneficial in terms of shortening the length of acute pharyngotonsillitis symptoms and reducing the frequency of bacterial complications; however, such use may heighten the prevalence of side effects and facilitate the spread of antimicrobial-resistant bacteria, thereby increasing medical costs [10]. Therefore, antibiotic prescription should be avoided for acute viral pharyngotonsillitis and appropriate antimicrobial therapy should be administered for acute bacterial pharyngotonsillitis based on aggressive differentiation of the causative pathogen in the clinical setting [1112].

The most common cause of acute bacterial pharyngotonsillitis is S. pyogenes, which accounts for 5–15% of all cases of acute bacterial pharyngotonsillitis in adults [5613]. S. pyogenes-induced acute pharyngotonsillitis may lead to acute suppurative complications, such as otitis media and peritonsillar abscess, as well as non-suppurative complications, such as rheumatic fever and acute glomerulonephritis; therefore, prompt diagnosis and appropriate antimicrobial therapy are necessary [514]. Although acute rheumatic fever is considerably less prevalent today, its clinical significance is substantial. Group C or G beta-hemolytic streptococci, C. pneumoniae, M. pneumoniae, Arcanobacterium haemolyticum, Corynebacterium diphtheriae, Fusobacterium necrophorum, Neisseria gonorrheae, Treponema pallidum, and Francisella tularensis are also rare pathogens of acute pharyngotonsillitis.

History-taking and physical examination, throat swab culture, and rapid antigen tests are helpful in differentiation of the causative pathogen for acute pharyngotonsillitis. Symptoms such as nasal drainage, nasal congestion, cough, conjunctivitis, hoarseness, diarrhea, oral ulcer, or bullous oral lesions are more suggestive of viral than bacterial acute pharyngotonsillitis [15]. On the other hand, symptoms such as swallowing difficulty (dysphagia), sore throat, fever, headache, abdominal pain, nausea, vomiting or petechial hemorrhage of the soft palate, enlarged lymph nodes in the neck, and scarlet fever rash suggest acute bacterial pharyngotonsillitis, especially caused by S. pyogenes infection [15]. Although differentiation of the pathogen based on clinical symptoms and signs produces high concordance among physicians [1617], the sensitivity and specificity of predicting positivity in a throat swab culture test ranges from 55–74% and 58–76%, respectively, even among highly experienced physicians [61819].

A variety of clinical prediction tools have been proposed, although these have been associated with limited diagnostic accuracy [6]. In practice, the most commonly used clinical instrument is the Centor criteria [56]. It was first suggested for use in adults in 1981 to score symptoms and signs, and a modified Centor criteria (Mclsaac criteria) with the addition of age criteria was proposed in 1998 (Fig. 1) [20]. The modified Centor criteria (McIsaac criteria) is the clinical prediction model to classify the likelihood of S. pyogenes infection (Table 2) [21]. Although it varies in relation to the prevalence of S. pyogenes infection, a Centor score of 3 or higher showed a positivity predictive value of 40-60% and a negativity predictive value of 80% on the diagnosis of S. pyogenes infection using a throat swab culture, with 75% sensitivity and specificity [6212223]. The 2008 National Institute of Health and Care Excellence (NICE) guideline recommends antibiotic prescription for three or more Centor criteria [24]. Prior studies have reported that antibiotic therapy that depends on the presence of three or four Centor criteria was conducive to improving symptoms and preventing complications as well as to reducing inappropriate use of antibiotics [222325]. The present guideline recommends that clinicians use the modified Centor criteria.

According to the 2012 guideline published by the Infectious Diseases Society of America (IDSA), it is difficult to differentiate between S. pyogenes-induced pharyngotonsillitis and viral pharyngotonsillitis merely based on clinical manifestations. The guideline recommends a rapid antigen diagnostic test (RADT) or bacterial culture for cases suggestive of S. pyogenes-induced pharyngotonsillitis, except for cases in which a viral disease is highly suspected [11]. Pharyngotonsillitis caused by S. pyogenes is diagnosed when S. pyogenes is identified using an RADT or culture test with a throat swab [11]. A throat swab follows the steps in the Figure 2 [26].

The RADT is a convenient test that can be performed and provides results at the point of care. Its sensitivity and specificity vary depending on the patient and test method, ranging from 65–91% and 62–97%, respectively, compared with a culture test [2728293031]. A throat swab culture can be performed if the RADT is negative, but performing both tests is generally not recommended in adults [11]. If the RADT is positive, the patient can be diagnosed with pharyngotonsillitis caused by S. pyogenes without a bacterial culture [11]. Data on the RADT in Korea generally involve children and most studies have reported that the test is useful [32333435]. It is necessary that its use be more activated for proper use of antibiotics [12].

Antistreptolysin O (ASO) titer may be useful in the diagnosis of non-suppurative complications, such as acute rheumatic fever and acute glomerulonephritis [36]. However, as the titer does not reach peak levels until 3–8 weeks of onset and continues to rise for several months, the ASO is not useful for the diagnosis of acute pharyngotonsillitis [3738]. In general, patients with acute pharyngotonsillitis have elevated C-reactive protein, total white blood cell count, and neutrophilic granulocyte count. The ASO test has low sensitivity (66–90%) and specificity (45–75%) for diagnosing acute bacterial pharyngotonsillitis in adults [39]. Procalcitonin and erythrocyte sedimentation rate are also not very useful for differentiating acute bacterial pharyngotonsillitis [40]. One report suggested that using both C-reactive protein level (35 mg/L, or 3.5 mg/dL) and the clinical score may be helpful for diagnosing acute bacterial pharyngotonsillitis [41]; however, blood tests are not generally recommended for patients with suspected acute pharyngotonsillitis.

The 2008 NICE guideline suggests antibiotic prescription for S. pyogenes infection depending on the patient's state when the patient has three or more Centor criteria [2442]. On the other hand, IDSA recommends that clinicians prescribe antibiotics only after accurate bacteriological diagnosis [11]. The present guideline recommends that antibiotics be prescribed for acute pharyngotonsillitis patients with complications, patients with a modified Centor score (McIsaac score) of more than 3, and patients with a positive RADT. If an RADT cannot be performed, antimicrobial therapy may be considered depending on the modified Centor score (McIsaac score) (Fig. 1).

A recent large-scale cohort study reported that delayed antibiotic therapy led to reductions of suppurative complications similar to those produced by immediate antibiotics therapy [14] .

Acute bacterial pharyngotonsillitis may also be caused by diverse types of bacteria other than S. pyogenes. Therefore, the appropriate antibiotics should be chosen in consideration of the type of pathogen to be treated, antibiotic susceptibility, spectrum of antibiotics, side effects, patient's underlying diseases, drug interactions, and cost. US and European clinical care guidelines for pharyngotonsillitis recommend penicillin V as the first-line antibiotic therapy [1142]. To date, penicillin resistance has not been found in clinical isolates of S. pyogenes from acute pharyngotonsillitis specimens in Korea and globally [434445464748495051]. Beta-lactam resistance in S. pyogenes has rarely been reported, unlike increased antimicrobial resistance among other bacteria [434445464748495051]. Penicillin is the most useful antibiotics available for first-line therapy for bacterial pharyngotonsillitis as it is a cost-effective, narrow-spectrum antibiotics whose efficacy has been proven through long-accumulated data [4344454647].

However, oral penicillin V is not produced or distributed in Korea; amoxicillin can be used as a first-line antibiotics instead (Table 3) [11]. A multicenter study conducted in France reported that 6-day amoxicillin therapy and 10-day penicillin V therapy did not differ significantly in therapeutic efficacy and safety among patients with acute pharyngotonsillitis [5253]. A prospective observational study conducted in the US also reported that amoxicillin is superior to penicillin in microbial responses and clinical efficacy [54]. Amoxicillin is particularly beneficial over penicillin in that despite its wider microbiologic spectrum, it has higher oral bioavailability even when taken together with food, and once-daily administration helps to improve patient compliance [5556575859]. However, amoxicillin must not be used in cases involving infectious mononucleosis caused by EBV because it induces drug rash in 70–100% of cases [1142]. Second-line antibiotics may be considered in such cases.

Since the 1950s, benzathine penicillin G injections, along with penicillin V, have been used as first-line therapy for acute bacterial pharyngotonsillitis. The American Heart Association and IDSA also recommend IM injection of benzathine penicillin G in addition to penicillin V [1112]. Compared with injectable antibiotics, oral antibiotics are associated with fewer complications, less severe hypersensitivity reactions, and no pain at the injection site; however, drug compliance may be a problem [1260]. Therefore, IM benzathine penicillin G may be used for patients deemed to have difficulty complying with a 10-day oral antibiotic regimen [126061]. Studies have found no significant differences in the clinical efficacy of 10-day amoxicillin oral antibiotic therapy and single IM injection of benzathine penicillin G [6162].

For patients with type 4 penicillin hypersensitivity (e.g., rash), 10-day first-generation cephalosporin (cephalexin, cefadroxil) therapy, 10-day clindamycin or clarithromycin therapy, 5-day azithromycin therapy, or 5-day cefdinir or cefpodoxime therapy may be used (Table 3) [11]. All types of beta-lactam antibiotics (e.g., cephalosporin) should not be used for patients with type 1 hypersensitivity (e.g., anaphylaxis) (Table 3). Some studies have found that 5-day broad-spectrum cephalosporin therapy had slightly better efficacy than 10-day penicillin V treatment. However, 5-day therapies using cefdinir or cefpodoxime are not generally considered for use as first-line therapy owing to their relatively higher costs and wider antibiotic spectrum (Table 3) [112442].

In general, first-line therapy for bacterial pharyngotonsillitis (penicillin V or amoxicillin) includes antibiotics against S. pyogenes [63], with treatment responses within 48–72 hours of administration and improvement of clinical symptoms within 4–5 days [864]. If there are no treatment responses within 48–72 hours of administration, first-line treatment should be deemed a failure and the following should be reviewed [6465]. First, check drug compliance. Second, although penicillin-resistance is very rare in S. pyogenes, ampicillin/sulbactam, amoxicillin/clavulanate, narrow-spectrum cephalosporin, and clindamycin may be considered as second-line antibiotics, after reviewing the patient's recent history of antibiotic therapy (Table 3) [64]. Ten-day cephalexin therapy and 10-day amoxicillin (once daily) therapy have not led to significantly different treatment outcomes [66], and data on the therapeutic outcomes of ampicillin/sulbactam and amoxicillin/clavulanate are very limited [126768]. Penicillin are popular as first-line antibiotic therapy owing to their proven clinical efficacy, safety, and low cost. However, the growing popularity of macrolides (such as erythromycin) and clindamycin, in response to concerns about hypersensitivity to penicillin have led to increased resistance to these antimicrobials among S. pyogenes strains. Macrolides resistance among S. pyogenes strains isolated from patients with acute pharyngitis living in Jinju, Korea reached 51% in 2002 [48]. Erythromycin resistance in Seoul and Masan was 28.5% and 20.5%, respectively, in 1998–2003 [4950]. During 2009–2011, resistance to erythromycin, azithromycin, and clindamycin increased to 42.9%, 42.9%, and 30.6%, respectively [51]. Therefore, macrolides and clindamycin are not recommended as first-line antibiotics, and treatment failure should be assessed if they are used.

Third, in addition to S. pyogenes, acute pharyngotonsillitis may be caused by a variety of other pathogens, including EBV, adenovirus, mycoplasma, Fusobacterium spp., Corynebacterium diphtheriae, Acanobacterium haemolyticum, and N. gonorrhoeae [69]. Rash that develops after amoxicillin administration may suggest EBV infection [42]. Fusobacterium infection should be treated with ampicillin/sulbactam or ampicillin/metronidazole. Penicillin-resistant Fusobacterium spp. have been reported in rare cases [70]. Penicillin and erythromycin are the recommended antibiotic therapy for C. diphtheriae infection. For acute tonsillitis caused by N. gonorrhoeae, follow-up bacterial culture is recommended after treatment completion owing to the difficulty in complete removal of the microorganisms, and the infection is treated with ceftriaxone (single dose, 250 mg IM) [71].

Second-line antimicrobial therapy may be considered if S. pyogenes is repeatedly detected in cultures or the infection recurs. Additional details are delineated below the key question 4.

Suppurative complications of acute pharyngotonsillitis include peritonsillar abscess, parapharyngeal abscess, lymphnoditis, sinusitis, otitis media, mastoiditis, necrotizing fasciitis, and toxic shock syndrome [53839]. Deep abscesses in the head and neck can be treated with a combination of second- or third-generation cephalosporin (e.g., ceftriaxone, cefuroxime) and clindamycin or ampicillin/sulbactam. Needle aspiration or incision and drainage should be actively considered for treatment and pathogen identification purposes. In rare cases, Fusobacterium spp. may also induce Lemierre syndrome caused by septic thrombophlebitis of the internal jugular vein [29]. Non-suppurative complications of S. pyogenes infection include rheumatic fever and acute glomerulonephritis [11].

Acute bacterial pharyngotonsillitis may recur despite antibiotic therapy owing to inappropriate use of antibiotics, insufficient antibiotic dosage or treatment duration, low patient compliance, re-infection, and though rare, penicillin resistance [7273]. Further, it may be considered for cases in which S. pyogenes colonization continues after acute upper respiratory infection due to viral pathogen.

Bacterial culture should be performed after completion of antibiotic therapy for S. pyogenes infection if symptoms persist, recurrence is suspected, or the patient has a history of rheumatic fever or acute glomerulonephritis. Culture should generally be performed within 2–7 days of treatment completion. Because treatment failure and chronic carriers must be distinguished [65], antibiotics should not be administered again if the symptoms have improved, even if a bacterial strain is isolated in the follow-up test. However, patients with a history or family history of rheumatic fever are subject to retreatment even if they are asymptomatic. If symptoms persist, first-line antibiotics may be used more than once, and benzathine penicillin G may be considered for patients with low compliance; however, established data is lacking. After treatment failure with penicillin, second-line therapy may involve narrow-spectrum cephalosporins (cephradine, cefadroxil), clindamycin, amoxicillin/clavulanate, or a combination of penicillin and rifampin [1265]. Broad-spectrum cephalosporins (e.g., cefprozil, cefuroxime axetil, cefdinir, cefditoren, cefpodoxime, cefaclor) are not generally recommended owing to their high costs and wide microbiologic spectrum [6074]. One study reported that 10-day cefaclor therapy had similar clinical effects as those of a 10-day amoxicillin/clavulanate for acute bacterial pharyngotonsillitis, and the incidence of some digestive tract side effects was lower in the former treatment group [75]. Moreover, 5-day cefaclor therapy and 10-day amoxicillin therapy had similar treatment effects [76]. On the other hand, the treatment responses of 10-day cefaclor therapy were superior to those of 10-day erythromycin treatment, which has been reported to be attributable to macrolides-resistant S. pyogenes strains [77]. In addition, the treatment responses of 5-day cefditoren pivoxil therapy and 10-day amoxicillin therapy were not significantly different [78].

Previous RCTs have investigated whether antibiotic therapy for patients with acute pharyngotonsillitis reduces the incidence of future episodes of pharyngotonsillitis and whether prophylactic antibiotic therapy reduces recurrent episodes of pharyngotonsillitis [737980]. In one study, prophylactic use of benzathine penicillin G in children led to a lower incidence of S. pyogenes-induced pharyngitis during a 4-month period after administration compared with the incidence during a 4-month period before administration; however, the study is flawed in that it did not administer a placebo to the control group [79]. Prolonged azithromycin therapy as an alternative to tonsillectomy was ineffective in treating frequent recurrent tonsillitis [73]. In another study, prophylactic use of cefpodoxime proxetil in children reduced the incidence of acute pharyngotonsillitis by 10% after 12 months compared with the group that did not receive prophylactic treatment; however, the study was limited to children, and it only showed the risk of antimicrobial resistance and short-term treatment progress, necessitating a more long-term study [80]. In summary, one of three previous studies have suggested that prophylactic antibiotic therapy is ineffective, and the remaining two studies have showed that it has small but statistically significant effects. However, it is difficult to generalize these findings due to their methodological limitations. These studies also reported that the use of cephalosporin for treatment and prevention purposes lowered the incidence of sore throat but that macrolide, such as azithromycin, did not produce similar effects [7980].

Peritonsillar abscess is the most common deep neck infection. Other deep neck infections include parapharyngeal abscess and retropharyngeal abscess, and infection of the parapharyngeal space may occur as a complication of pharyngitis [81828384]. Furthermore, these diseases must be differentiated from pharyngotonsillitis from the beginning. Peritonsillar cellulitis or phlegmon is a term used for cases in which the peritonsillar space is infected without the formation of an abscess. Peritonsillar abscess accounts for about 50% of all deep neck infections; it is common among adults and adolescents and possible in children [285]. The most important management strategy for deep neck infection is airway assessment and management [26]. For patients who are restless, have swallowing difficulty, and are drooling, the airway should be closely observed to ensure patency. Further, patients should be assessed to determine whether they need procedures such as intubation and if so, proper procedures should be performed before referring them to a specialist [86]. Serious clinical symptoms and signs are listed in Table 4. Ultrasound or computed tomography (CT) may be required. Ultrasound should be performed by a skilled expert. Although CT is associated with the potential adverse effects of radiation exposure and use of contrasting agents, it can be performed quickly (if the facility is equipped with a CT scan) and it provides objective images. CT is commonly performed for diagnosis and differential diagnosis from other diseases [8384]. Magnetic resonance imaging (MRI) may also be used [83]. Abscess in the neck is associated with the teeth in many adults; it is more common as a complication of tonsillitis among children, adolescents, and young adults [2681828384].

Immunocompromised individuals may have non-responsive tonsillitis caused by various unusual pathogens, so it is important to refer them to a specialist for a broader approach to identifying the cause and for effective treatment [8788].

Table 5 shows a comparison of this guideline with Korean Guidelines for the Antibiotic Use in Children with Acute Upper Respiratory Tract Infection (2016) and other major guidelines for acute pharyngotonsillitis caused by S. pyogenes, as suggested by IDSA (2012), the American College of Physicians (2001), American Academy of Pediatrics (2003), and NICE (2008) [118990919293].

Sinusitis is an inflammation of the nasal passage and mucosa lining the sinuses resulting from infection, allergy, and autoimmunity. Because it is usually accompanied by inflammation of the nasal cavity and paranasal sinuses, sinusitis is also commonly referred to as rhinosinusitis [94]. Sinusitis may be classified according to the main site of infection such as maxillary, frontal, ethmoid, and sphenoid sinusitis; it is also classified according to the stage of infection, such as acute (less than 4 weeks), subacute (4 weeks–3 months), and chronic (more than 3 months) [95]. Moreover, sinusitis can be classified into community-acquired, healthcare-associated, and nosocomial infection depending on the location of pathogen exposure. More detailed definitions of acute sinusitis are given in Table 6 [94959697]. In addition to identifying the infectious causes of sinusitis, differentiating the noninfectious causes is important, such as in vasomotor and atrophic sinusitis as well as the recently increasing allergic sinusitis [98].

Infectious causes of sinusitis encompass a variety of microorganisms, including viruses, bacteria, or fungal organisms. Bacterial causes only account for 2–10%, with viral infections accounting for the remaining 90–98% of cases [99]. About 0.5–2% of acute viral sinusitis cases may progress to acute bacterial sinusitis [100101]. Bacterial pathogens that have been identified with needle biopsies of maxillary sinus specimens in patients with acute sinusitis include S. pneumoniae, H. influenzae, anaerobic bacteria, streptococcal species, M. catarrhalis, and Staphylococcus aureus. Other known viral pathogens include rhinovirus, parainfluenza virus, and influenza virus; though rare, fungal pathogens, such as Aspergillus, zygomycetes, Phaeohyphomycis, Pseudallescheria, and Hyalohyphomycis have also been identified [102103].

About 85% of acute sinusitis in adults, including acute community-acquired bacterial sinusitis, shows improvement of symptoms within 7–15 days without antibiotic therapy [104]. However, bacterial sinusitis generally requires antibiotic therapy because the sinuses are normally a sterile environment. In addition, certain types of acute bacterial sinusitis may lead to severe complications, such as bacterial encephalomeningitis, brain abscess, and periocular tissue infection. Further, the possibility of chronic sinus disease cannot be completely eliminated [105106]. In fact, proper antibiotic therapy for acute community-acquired bacterial sinusitis leads to a more than 90% eradication rate in the sinuses, which is superior to that in the inappropriate antibiotic therapy group [106]. However, inappropriate antibiotic therapy increases antimicrobial resistance and drug side effects, thereby elevating medical costs. This situation calls for efforts to differentiate acute viral and bacterial sinusitis in the clinical setting [106].

Unfortunately, it is very difficult to differentiate acute viral sinusitis from acute bacterial sinusitis in the clinical setting owing to the low agreement among examination, imaging, and laboratory findings that are used for diagnosis in addition to the clinical symptoms of acute sinusitis, such as nasal congestion, nasal drainage, sneezing, and nose itching [105107]. Nevertheless, clinicians must try to differentiate viral and bacterial sinusitis based on the symptoms and signs as well as the typical manifestations and chronological changes of symptoms [108].

Although needle aspiration cultures of sinus specimens may be performed to diagnose acute bacterial sinusitis, clinicians generally make clinical diagnoses because this method is an invasive technique that cannot be performed in the clinical setting. Clinical diagnosis of acute bacterial sinusitis generally requires progress observation for 7 days, and radiologic testing may aid in clinical diagnosis if symptoms (such as purulent nasal drainage, unilateral maxillary toothache, facial pain, and unilateral tenderness of the maxillary sinus) improve initially but worsen over time [4108]. According to the IDSA guideline, the clinical symptoms and signs of acute bacterial sinusitis persist for more than 10 days without any improvement, and severe symptoms and signs such as high fever of 39°C or more that lasts 3–4 days, purulent nasal drainage, and facial tenderness, develop after onset. According to guideline recommendations, when double sickening, such as new fever, headache, and increased nasal drainage, begins after acute viral upper respiratory infection symptoms had begun to improve 5–6 days after symptom onset, acute bacterial sinusitis should be suspected and antibiotic therapy initiated [108]. In addition, foul smelling discharge is suggestive of anaerobic bacterial infection, and clinicians should assess the possibility of tooth infections and begin antibiotic therapy.

Previous RCTs have shown that antibiotic therapy groups (7–10 days) had a higher rate of improvement (91%) than placebo groups (86%). And the duration of pain or morbidity were not correlated with initial treatment for acute bacterial sinusitis [9496]. Therefore, antibiotics may be prescribed during primary care for patients with acute bacterial sinusitis without complications; however, clinicians may also delay initial antibiotic therapy and opt for a watchful waiting approach depending on the case at hand. However, early antibiotic therapy should only be delayed in cases where the clinician is confident that the patient will attend follow-up appointments [94]. Empirical antibiotic therapy should be initiated in cases where the patient shows no improvement of symptoms or when symptoms worsen within 7 days of proper non-antibiotic, symptomatic treatment after the diagnosis of acute bacterial sinusitis [109110]. Further, empirical antibiotic therapy should also be initiated in cases involving symptoms or findings suggestive of severe acute bacterial sinusitis, such as fever of 39°C or higher, facial pain lasting more than 3–4 days, and purulent nasal drainage (Figure 3) [108111112113114].

To choose the appropriate antibiotics for acute bacterial sinusitis, the main causative pathogen and its antibiotic susceptibility must be considered. Although there are no Korean epidemiological data on the causative pathogens of acute bacterial sinusitis, data from other countries show that S. pneumoniae, H. influenzae, M. catarrhalis, and S. aureus are the most common, and S. pneumoniae and H. influenzae account for about 75% of all isolated strains [102103]. However, epidemiological changes are anticipated in Korea in response to the progressive rise in the pneumococcal vaccination rate [115]. Among clinical isolates taken from patients who visited primary care clinics for sinusitis between 1999 and 2000 in the United States, the sensitivity of S. pneumoniae to penicillin, azithromycin, and levofloxacin was 65%, 64.7%, and 99.8%, respectively, whereas the sensitivity of H. influenzae to azithromycin and levofloxacin was 99.4% and 100% [103].

There are two RCTs and one systematic literature review pertaining to the possible first-line empirical antibiotics for acute sinusitis. According to these reports, there are no differences in the clinical treatment outcomes for several antibiotics, including amoxicillin, cefuroxime axetil, amoxicillin/clavulanate, levofloxacin, moxifloxacin, and clarithromycin, in patients radiologically or bacteriologically diagnosed with acute sinusitis [116117118]. In particular, considering the safety, efficacy, price, and narrow-spectrum of the amoxicillin or amoxicillin/clavulanate [108111119], amoxicillin or amoxicillin/clavulanate (amoxicillin 500 mg/clavulanate 125 mg three times a day or amoxicillin 875 mg/clavulanate 125 mg twice a day) should be preferentially considered as first-line empirical antibiotics for acute sinusitis (Table 7) [108111]. Further, amoxicillin/clavulanate may be preferred over amoxicillin in cases suspected to involve antimirobial-resistant bacteria, such as beta-lactamase-producing H. influenzae [120], for patients showing moderate to severe infection, for older patients, and for patients with chronic diseases or immune-related diseases [121]. Although adults are at lower risk of acute bacterial sinusitis caused by M. catarrhalis than are children, M. catarrhalis is resistant to amoxicillin but susceptible to amoxicillin/clavulanate.

A high dose of amoxicillin (90 mg/kg/day) or amoxicillin/clavulanate (amoxicillin 2 g or 90 mg/kg/day, twice a day) should be considered in the following cases: 1) patients live in areas with high prevalence of penicillin-resistant S. pneumoniae (endemic rate >10%), 2) patients display severe symptoms, such as high fever of 39°C or greater or possibility of suppurative complications, 3) patients older than 65 years, 4) patients with a recent history of hospitalization, 5) patients with a history of antibiotic therapy within the past month, and 6) patients with compromised immunity [94108122123124125].

For patients with type 4 penicillin allergy (e.g., rash), doxycycline or fluoroquinolones, third-generation cephalosporins, or clindamycin may be considered. For patients with type 1 allergy (e.g., anaphylaxis), all beta-lactams (e.g., cephalosporins) are prohibited [94]. Only non-beta-lactams should be used (e.g., doxycycline, clindamycin, fluoroquinolone) [94]. According to a meta-analysis, the treatment success rate with use of fluoroquinolones in patients without penicillin allergy (87%) was not significantly different from that with use of beta-lactams (86%), but the former is associated with a higher incidence of adverse effects [126]. Foreign data reveal that the main pathogens of acute sinusitis, namely S. pneumoniae and H. influenzae, are highly resistant to macrolides and trimethoprim/sulfamethoxazole [102103121127].

In general, the recommended duration of first-line empirical antibiotics for adults with acute bacterial sinusitis without complications is 5–10 days or 4–7 days after improvement of symptoms/signs [94108128]. According to a review of 12 RCTs that investigated the duration of antibiotic therapy for patients radiologically diagnosed with acute sinusitis, there were no significant differences in the treatment success rate between the short-duration antibiotic therapy group (3–7 days) and long-duration antibiotic therapy group (6–10 days) [122]. The antibiotics group showed about 10–12% greater incidence of adverse drug response than the non-antibiotics group. Moreover, the long-duration antibiotic therapy group (more than 10 days) had higher incidences of adverse drug responses than other groups [116123]. As stated in the treatment guideline for children, additional antibiotics may be administered for 4–7 days even after the symptoms have improved after antibiotic therapy in patients with delayed drug response [129]. Thus, first-line empirical antibiotics are recommended to be used in short durations, within 5–10 days or 4–7 days after improvement of symptoms/signs, with the exception of cases of severe acute sinusitis involving high fever (>39°C) or potential suppurative complications [94108128].

If symptoms worsen within 72 hours of beginning the initial treatment or the symptoms do not show improvement even after 3–5 days of beginning treatment, the patient should be reassessed in terms of 1) the accuracy of diagnosis, 2) non-infectious cause, 3) antimicrobial-resistant bacteria, and 4) presence of structural problems. Imaging techniques, such as paranasal sinus plain radiography and CT/MRI, as well as microbial cultures and antimicrobial resistance testing can be performed in the reassessment. It is best to perform cultures with fine needle aspiration of the sinus, but cultures can be performed using samples taken from the middle nasal meatus via nasal endoscopy [94108]. Cultures using nasopharyngeal swabs are not recommended [94108].

If the patient is indeed diagnosed with acute bacterial rhinosinusitis after reassessment, initiate antibiotic therapy for patients who initially had been placed on watchful waiting, and change antibiotics for patients who had been on antibiotic therapy [94108]. Although it is best to choose antibiotics according to the results of bacterial cultures and susceptibility tests, in cases where empirical antibiotics are warranted, use 1) high-dose amoxicillin/clavulanate, 2) doxycycline, or 3) clindamycin/third-generation cephalosporins, which can treat multidrug-resistant S. pneumoniae or beta-lactamase-producing H. influenzae and M. catarrhalis [108116].

The following must be considered if a second-line regimen must be chosen due to failure of the initial empirical antibiotic therapy. However, if low-dose amoxicillin/clavulanate was chosen as the initial treatment, high-dose amoxicillin/clavulanate therapy may be used [108116]. Cefaclor and cefprozil, a second-generation cephalosporin, are not recommended because the most common pathogens of acute bacterial rhinosinusitis, namely, S. pneumoniae, H. influenzae, and M. catarrhalis have low susceptibility to these antibiotics [108130131132133]. Oral cefditoren and cefcapene and cefpodoxime have been reported to be efficacious for treating acute bacterial rhinosinusitis caused by penicillin-resistant S. pneumoniae and that by H. influenzae and M. catarrhalis, respectively [116132133134135]. Oral cefuroxime and cefdinir are known to be effective for acute bacterial rhinosinusitis caused by moderately penicillin-resistant S. pneumoniae, H. influenzae, and M. catarrhalis, but its therapeutic efficacy in Korea is uncertain owing to the high proportion of penicillin-resistant S. pneumoniae in the country [136137]. To widen the microbiologic spectrum to cover anaerobes, additional use of metronidazole or clindamycin is recommended with cephalosporin [108].

The fluoroquinolones such as levofloxacin, and moxifloxacin may be effective, but the possibility of resistance to these antibiotics among Myocobacterium tuberculosis and S. pneumoniae should be noted. It should further be noted that the FDA recommended in 2016 that fluoroquinolones be used for sinusitis, bronchitis, and urinary tract infection without complications only when there are no other treatment alternatives [16138].

Canadian and British studies have reported that the susceptibility rates of S. pneumoniae, H. influenzae, and M. catarrhalis to doxycycline exceeds 90% [139140141]. Doxycycline may be used as the second-line antibiotic therapy for adults with acute bacterial rhinosinusitis as an alternative to fluoroquinolones when the patient has difficulty receiving or has not responded to the initial empirical antibiotic therapy [108]. This choice is supported by the pharmacokinetic superiority of doxycycline and the finding that doxycycline and levofloxacin have no differences in clinical outcomes but that doxycycline is associated with lower medical costs in patients admitted to community hospitals with pneumonia [142143].

Some have raised concerns about the uncertain therapeutic efficacy of the macrolides such as erythromycin, roxythromycin, azithromycin, and clarithromycin in Korea due to the high proportion (80-90%) of macrolides-resistant S. pneumoniae in the country. Although telithromycin, a ketolide, is known to have antibacterial activity against macrolide-resistant S. pneumoniae, it is not yet a viable option in Korea [108136137144].

For severe cases of acute sinusitis that require hospitalization, the following antibiotics may be used: ampicillin/sulbactam (1.5–3 g, injection every 6 hours), ceftriaxone (1–2 g, injection 1–2 times), cefotaxime (1–2 g, injection every 6–8 hours), levofloxacin (500–750 mg, oral/injection), and moxifloxacin (400 mg, oral). IV ceftriaxone and cefotaxime have been found to act on all strains of S. pneumoniae, including penicillin-resistant S. pneumoniae [124]. Furthermore, if the prevalent S. pneumoniae 19A strains continue to exhibit about 30% rates of clindamycin minimum inhibitory concentrations (MICs) >0.5 mg/L, levofloxacin or moxifloxacin may be recommended as empirical therapy for patients with severe conditions that require hospitalization, rather than clindamycin plus ceftriaxone [127].

Additional tests and surgical treatment may be considered when symptoms worsen without improvement within 48–72 hours after proper antibiotic therapy or when ocular or central nervous system complications are suspected [145]. Treatment duration is generally 4–7 additional days after the improvement of clinical symptoms, and total treatment duration generally ranges 10–14 days.

Regarding the treatment of acute bacterial rhinosinusitis, the Health Insurance Review and Assessment Service (HIRA) suggests in their General Principles of Antibiotics Use (Announcement No. 2013-127): 1) Choosing antibiotics is based on drug susceptibility tests rather than by indication, so antibiotics should be phased in within the permitted range, with reference to the patient's history. 2) In cases of severe infection where oral administration alone cannot produce an adequate treatment outcome, parenteral injections may be additionally used.

In cases where the patient fails to show improvement despite appropriate first- and second-line antibiotic therapy, including antibiotic therapy, and cases defined as recurrent acute sinusitis (more than four episodes of sinusitis per year with symptom-free intervals) [146], differential diagnosis in consideration of allergic rhinitis, immune abnormalities, and tooth infections, is recommended. Surgical treatment may be considered for continual episodes of acute sinusitis [147].

According to a systematic literature review, allergy tests may be run for recurrent acute sinusitis or chronic sinusitis [148]. Allergic patients characteristically have obstructions of the natural ostium caused by the edema of the nasal cavity and sinus mucosa. Particularly, the ethmoid sinus with several natural ostia is susceptible to allergic sinusitis or nasal polyp. If a patient is indeed positive for allergy, environmental therapy, immune therapy, or drug therapy may be considered depending on the patient. However, there is limited evidence supporting that environmental therapy and immune therapy are effective in improving the clinical outcome of recurrent acute sinusitis or chronic sinusitis [149150].

Asthma is closely related to recurrent acute sinusitis or chronic sinusitis and is the cause of frequent recurrent episodes of sinusitis [151]. For patients diagnosed with immunodeficiency, such as antibody deficiency, prophylactic antibiotic therapy, pneumococcal vaccination, or regular IV IgG may be considered [151]. In addition, sinusitis may be induced by dental caries or extraction of maxillary molars and premolars, trauma, malnutrition, prolonged steroid therapy, general weakness as a result of diabetes, and tumor in the nasal cavity or sinus; therefore, the corresponding examinations should be performed when such conditions are suspected.

A lack of improvement or worsening of symptoms even after 3–5 days of antibiotic therapy for acute rhinosinusitis is considered a treatment failure. The exact cause should be identified when the patient is nonresponsive even to the second-line antibiotic regimen as well as in cases of recurrent rhinosinusitis, defined as more than four episodes of acute rhinosinusitis per year with symptom-free intervals [108].

Potential causes include chronic rhinosinusitis, allergic rhinitis, abnormal anatomical structure within the nasal cavity, reduced immunity, fungal infection, granuloma, and tumor. For accurate differentiation of the cause and administration of appropriate treatment, the patient must be referred to a specialist who can perform nasal endoscopy and, when necessary, imaging tests such as CT and MRI [152].

Paranasal sinuses are in close proximity to the orbits laterally and to the base of the skull superiorly. Therefore, an infection in the sinuses may spread to the orbits and cranium, causing fatal diseases such as cellulitis, cerebromeningitis, and abscess [153]. A lack of proper antibiotic therapy and surgical drainage may lead to blindness, brain injury, and in severe cases, to death [154155].

Severe ocular pain, periocular edema, oculomotor disability, exophthalmos, purulent conjunctivitis, and reduced visual acuity in patients with acute rhinosinusitis are suggestive of ocular complications whereas high fever, severe headache, meningeal irritation sign, and insanity are suggestive of intracranial complications. Patients with such conditions must be referred to a specialist immediately [128].

Table 8 shows a comparison of the recommendations pertaining to acute sinusitis of the present guideline, IDSA (2012), American Academy of Otolaryngology-Head and Neck Surgery (2015), American Academy of Pediatrics (2013), and Korean Guideline for Antibiotics Usage in Children with Acute Upper Respiratory Infections (2016) [8994108156].