Acute Bacterial Rhinosinusitis

Acute bacterial rhinosinusitis (ABRS) occurs in approximately 0.5% to 2% of all cases of viral upper respiratory tract infections (URI). ¹ It is estimated that 20 million people acquire ABRS each year in the United States. ² Sinusitis is the 5th most common diagnosis for which an antibiotic is prescribed in the United States. ³ In fact, 9% and 21% of all antibiotic prescriptions in 2002 were written for pediatric and adult patients, respectively, with a diagnosis of sinusitis. ⁴ Antibiotic prescriptions for acute sinusitis accounted for approximately $400 million to $600 million in health care expenditures in 2002. ⁴ The estimated total expenditures associated with sinusitis were $3.5 billion in 1996. ⁵

Pathogenesis

rhinosinusitis

The 4 pairs of sinuses include the maxillary, ethmoid, frontal, and sphenoid sinuses. Most cases of sinusitis involve the maxillary and/or ethmoid sinuses. Far less common is an isolated infection of the frontal or sphenoid sinus. Sinusitis is more properly termed because it is an inflammatory process that involves the mucous membranes of the nose and paranasal sinuses. Rhinosinusitis is classified as acute (sudden onset of symptoms with duration of < 4 weeks), subacute (duration 4 to 12 weeks), or chronic (duration > 12 consecutive weeks).

Viruses are responsible for the majority of acute rhinosinusitis. ⁶ The human rhinovirus accounts for almost 50% of all viral URIs. Other viruses that can cause acute rhinosinusitis include influenza A and B viruses, parainfluenza virus, respiratory syncytial virus, adenovirus, and enterovirus. Most cases of acute viral rhinosinusitis are self-limiting and resolve within 7 to 10 days. Viruses inhibit macrophage and lymphocyte function, increasing susceptibility to secondary bacterial infection. In addition, viruses cause inflammatory changes which can block the sinus ostia, impair mucous drainage, and cause poor aeration, which creates an environment conducive for developing a bacterial infection. ⁷ Therefore, ABRS is generally considered as a superinfection that can occur any time during a viral URI. Although infrequent, ABRS may complicate 0.5% to 2% of viral URIs. ¹ The incidence of ABRS parallels the pattern of viral URIs and increases during early fall to early spring. Fungi, on rare occasions, can cause rhinosinusitis. Nasal allergy, trauma, swimming, local irritants, and nasal obstruction from polyps or foreign bodies may also precipitate ABRS.

Streptococcus pneumoniae, Haemophilus influenzae

Moraxella catarrhalis

S pneumoniae

H influenzae

M catarrhalis

Staphylococcus aureus

Streptococcus pyogenes

Chlamydia pneumoniae

Mycoplasma pneumoniae

ABRS occurs when bacteria that colonize the nasopharynx invade the normally sterile paranasal sinuses. By early childhood, most children are colonized by at least 1 of 3 respiratory tract pathogens, including , and . ^8-10 Colonization may persist for up to 12 months and increases during the winter season when the incidence of viral URI rises. ⁸ and are the most common bacteria isolated from adult patients with community-acquired ABRS (Table 1). ^6,11-13 , anaerobic bacteria, , and can also cause ABRS. The distribution of bacterial pathogens in adults is similar in children, except M catarrhalis is more prevalent in children than adults. ^11,12 Rhinosinusitis caused by anaerobic bacteria usually occurs after a dental root infection. ¹² The clinical significance of atypical pathogens, including and , in the pathogenesis of community-acquired ABRS remains unclear.

Table 1

S aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae

Candida

Candida albicans

Nosocomial ABRS may occur during hospitalization, especially in patients with nasal colonization by enteric gram-negative bacilli, patients being fed by nasogastric tubes, patients undergoing sedation, and those scoring 7 on the Glasgow coma score. ¹⁴ The common pathogens associated with nosocomial rhinosinusitis in adults and children include , and other Enterobacteriaceae organisms. ^15,16 Anaerobic bacteria, species (especially ), and fungi may also cause nosocomial ABRS. Polymicrobial infection may occur in the hospital setting. ^15,16

Clinical Presentation and Diagnosis

No single sign or symptom clinically distinguishes a viral rhinosinusitis ("common cold") from ABRS, presenting a challenge to primary care physicians. Most patients with ABRS initially report symptoms of the common cold, including sneezing, rhinorrhea, nasal congestion, postnasal drip, sore throat, cough, fever, and myalgia. ABRS is a secondary infection that occurs after the onset of a viral URI, especially if symptoms persist after 7 to 10 days or symptoms worsen after 5 to 7 days of illness. ^6,13 Double sickening, which occurs when a patient clinically worsens after initial improvement, is also suggestive of ABRS. In patients with rhinorrhea, nose blowing may create enough pressure to introduce bacteria from the middle meatus to the sinus cavity and thereby cause infection. 17 Inflammation of the nose and paranasal sinuses may persist for 2 months.

Predictors for ABRS consist of maxillary dental pain, facial erythema/ swelling/pain (especially when unilateral), purulent (thick, colored, and opaque) nasal secretions, history of colored nasal discharge, poor response to decongestants, and fever. ^6,13,18 It is important to note that purulent nasal secretions and a change in the color of nasal discharge are not specific indicators of bacterial infection. Purulent discharge can also occur in patients with viral rhinosinusitis. Localization of facial pain or tenderness may assist in determining the affected sinus (ie, cheek or upper teeth pain for maxillary infection, forehead pain for frontal, tenderness over the medial canthal region for ethmoid, or retro-orbital pain for sphenoid). Symptoms of ABRS may persist for 4 weeks.

Community-acquired ABRS should be highly considered in patients with persistent symptoms of the common cold-lasting more than 7 to 10 days- or in patients with worsening symptoms after 5 to 7 days. Persistent or worsening symptoms are highly indicative of a secondary bacterial infection, especially in the presence of facial erythema/swelling/pain, fever, and poor response to decongestants. Some patients may present without initial symptoms of viral URI. In these patients, tooth pain or other signs of a dental infection, a history of allergy, swimming, and/or persistent nasal obstruction are usually present. Nosocomial ABRS should be considered in patients with nasal intubation or impaired sinus drainage.

Complications of acute rhinosinusitis that involve the central nervous system, orbit of the eye, and periorbital tissues rarely occur. ^6,11 In the presence of these complications, immediate medical attention is necessary. Abnormal vision, altered mental status, and periorbital edema may signify the presence of complications. Patients presenting with these symptoms should be closely monitored.

The gold standard for diagnosing ABRS is sinus puncture with subsequent aspirate culture. ^6,12 Sinus puncture is rarely performed in the ambulatory setting for immunocompetent patients, however, because it is an invasive and painful procedure. As a result, the diagnosis of ABRS is almost always a clinical diagnosis. Although no single sign or symptom is highly sensitive or specific, the presumptive diagnosis of ABRS based on the overall constellation of clinical findings is generally sufficient for treatment. The use of imaging studies (radiography, computerized tomography [CT], or magnetic resonance imaging) is not necessary to confirm diagnosis because abnormal findings indicate presence of inflammation without providing the cause (ie, virus, bacteria, or allergy). Imaging studies should, however, be considered in patients with suspected acute complications (eg, orbital cellulitis) or in those individuals with persistent or recurrent infection who are unresponsive to therapy. ¹¹ CT scanning is the imaging study of choice because it is more sensitive and specific than plain radiographs.

Treatment

Symptomatic relief is the primary goal in the treatment of viral rhinosinusitis. Initial therapy with decongestants, humidifiers, nonsteroidal antiinflammatory drugs (NSAIDs including ibuprofen and naproxen), acetaminophen, and/or possibly mucolytics may help suppress symptoms in patients with viral rhinosinusitis. In the presence of cough, a cough suppressant (dextromethorphan) may be added. Although commonly used, there is lack of evidence supporting the benefits of first-generation antihistamines (eg, chlorpheniramine, brompheniramine, and clemastine), mucolytic agents, and topical intranasal steroids for symptomatic treatment. ^1,11 Saline nasal drops or spray, however, may be beneficial by serving as a mild vasoconstrictor, dissolving secretions, and preventing crust formation. ¹¹ Treatment should continue for several days. If symptoms persist after 7 to 10 days or worsen after 5 to 7 days, initiation of antibiotic therapy to treat a potential secondary bacterial infection should be considered.

S pneumoniae

H influenzae

M catarrhalis

Because the clinical features of viral rhinosinusitis and ABRS are similar, it is not surprising to observe excessive use of antibiotics. Overuse of antibiotics has contributed to emergence and increasing prevalence of resistance in the United States, particularly to penicillin, trimethoprim/ sulfamethoxazole (TMP/SMX), macrolides, doxycycline, and ofloxacin. ¹⁹ In addition, and produce ß-lactamases, which render resistance to all ß-lactam antibiotics except ß-lactamase inhibitor combinations and cephalosporins. ^19-21

S pneumoniae, H influenzae

M catarrhalis

ABRS may spontaneously resolve without antibiotic treatment in both adults and children. ^6,22 In fact, the results of 2 meta-analyses indicate that the benefit of using antibiotics in patients with ABRS is minimal and that 69% of patients receiving placebo improve by 14 days. ^23,24 If initiated, antibiotic treatment of ABRS should target the common pathogens, particularly , and . Although ABRS is usually a self-limited infection, eradication of bacterial pathogens may lead to decreased duration of illness and prevent complications associated with ABRS. Bacterial resistance is an important concern when considering therapeutic options. The risk of acquiring infection caused by resistant pathogens increases with recent antibiotic use. ²⁵

M catarrhalis

M catarrhalis

Treatment recommended by the Sinus and Allergy Health Partnership for adult patients with mild community- acquired ABRS and no recent antibiotic exposure are listed in Table 2. ¹³ The recommended first-line agents are amoxicillin (± clavulanate) and second- and third-generation cephalosporins (specifically, cefuroxime, cefpodoxime, and cefdinir). High-dose amoxicillin (± clavulanate) should be used in patients with suspected drugresistant pneumococci (eg, recent antibiotic use, immunodeficiency, and contact with children attending day care). When is highly suspected, the use of amoxicillin alone is ineffective because most isolates produce ß-lactamases. Treatment options for include amoxicillin with clavulanate and cephalosporins. Because failure rates can reach 25%, TMP/SMX, doxycycline, macrolides, and telithromycin should be reserved for patients with true allergy or intolerance to ß-lactam antibiotics. Patients generally respond to appropriate treatment within 48 to 72 hours. Recommendation for initial antibiotic treatment provided by the Centers for Disease Control and Prevention and the Infectious Diseases Society of America is similar to the Sinus and Allergy Health Partnership. Initial therapy should include narrow-spectrum agents including amoxicillin, doxycycline, and TMP/SMX. ⁶

Patients with mild disease who are unresponsive after 72 hours of antibiotic therapy, patients with mild ABRS and recent exposure to antibiotics (within the previous 4 to 6 months), and patients with moderate disease should be treated with respiratory fluoroquinolones (levofloxacin, gatifloxacin, and moxifloxacin), highdose amoxicillin/clavulanate (4 g/ 250 mg per day), or ceftriaxone. ¹³ Clinical response is predicted in 90% to 92% of patients receiving respiratory fluoroquinolones, ceftriaxone, or amoxicillin/clavulanate, and 83% to 88% with amoxicillin, cefpodoxime, cefixime, cefuroxime, and cefdinir. The recommended duration of therapy for all patients with ABRS is 10 to 14 days, although a 7-day course of amoxicillin (± clavulanate) has been evaluated. ¹³ Studies indicate that 5 days of ceftriaxone or telithromycin and 3 days of azithromycin are also effective. ^13,26,27

Treatment options for ABRS in children (Table 2) are similar to adults, except doxycycline is contraindicated in children less than or equal to 8 years of age because of the risk for permanent teeth discoloration. ^11,13 In addition, telithromycin has not been approved by the FDA for pediatric use. ²⁶ Because of its safety, palatability, and low cost, the American Academy of Pediatrics recommends amoxicillin as first-line therapy in children with mild to moderate symptoms. High-dose amoxicillin should be used in patients with suspected drug-resistant pneumococci. High-dose amoxicillin with clavulanate is recommended for children with moderate to severe symptoms (fever greater than or equal to 39°C with concurrent purulent nasal discharge for at least 3 to 4 consecutive days or persistent symptoms exceeding 10 days), recent antibiotic exposure, or in those who attend day care. ¹¹ When using high-dose amoxicillin with clavulanate, the recommended dose of clavulanate is 6.4 mg/kg/day to limit the incidence of diarrhea. Other therapeutic options include cefpodoxime, cefuroxime, cefdinir, and ceftriaxone. Except for a history of immediate Type I hypersensitivity reaction to ß-lactams, children with other types of reactions to one specific ß-lactam antibiotic may tolerate another ß-lactam. Therapy should continue for 10 to 14 days, or 7 days after the beginning of clinical improvement.

Table 2

S aureus

The bacterial pathogens associated with nosocomial rhinosinusitis differ from those in community-acquired rhinosinusitis. Empiric antimicrobial therapy for nosocomial rhinosinusitis should provide adequate coverage for and gram-negative bacteria. If sinus aspirate culture and sensitivity information are available, treatment should be tailored toward the specific pathogen. Polymicrobial infection may occur in patients with nosocomial bacterial rhinosinusitis.

Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) is a commonly diagnosed illness that affected almost 30 million people in the United States in 2002. ²⁸ The socioeconomic impact of CRS is significant. CRS results in an estimated 18 million to 22 million physician office visits annually and $200 million in expenditures on medications. ^29,30 Furthermore, this chronic disease may lead to functional and emotional impairments that affect quality of life. ³¹

Pathogenesis

The pathogenesis of CRS is an ongoing area of research. The cause of CRS is believed to be multifactorial. Potential causes or predisposing factors include microorganisms (bacteria, fungi), inflammatory agents (eg, allergens, pollutants, smoke), asthma, cystic fibrosis, immunodeficiency, nasal polyposis, and autoimmune diseases (eg, systemic lupus erythematosus, Wegener's granulomatosis). ³⁰ These factors may appear concurrently to cause persistent inflammation of the nose and paranasal sinuses.

S aureus

Streptococcus

Staphylococcus

The microbiology and role of bacteria in the pathogenesis of CRS are not as well established as for ABRS. The presence of bacteria may provide a direct insult to the nose and paranasal sinuses to cause CRS. Alternatively, the bacteria can indirectly cause CRS by aggravating a noninfectious inflammatory process. The predominant bacteria associated with CRS are coagulase-negative staphylococci (24% to 36%), (22% to 25%), species (20% to 27%), and anaerobes (6% to 10%). ^32-34 The clinical significance of coagulase-negative is uncertain. Some studies report a high incidence (19% to 48%) of anaerobic bacteria isolated in patients with CRS. ^35,36 The most common anaerobes are Prevotella species, anaerobic streptococci, and Fusobacterium species. Polymicrobial infections occur more often in CRS than ABRS. ³⁷

The clinical significance of fungi remains controversial. Some studies demonstrate a role of fungi in the pathogenesis of CRS. ³⁰ Disease occurs either by formation of fungal balls or inflammatory response to the presence of the fungus. A clinically distinct form of CRS is allergic fungal rhinosinusitis. Patients with allergic fungal rhinosinusitis present with nasal polyposis, allergy, production of eosinophilic mucin, and unilateral predominance. ³⁸

Clinical Presentation and Diagnosis

The clinical features of CRS are comparable to acute sinusitis, making diagnosis of CRS very difficult. The main distinction between chronic and acute disease is duration of symptoms. Patients with CRS present with persistent inflammation of the mucosa of the nose and paranasal sinuses lasting > 12 weeks. ³⁰ The most common and problematic symptoms experienced by patients with chronic infection include nasal obstruction or congestion, headache, and fatigue. ³⁹ The presence of nasal polyps, crusts, and turbinate edema or hypertrophy are also common findings in patients with CRS. In contrast to ABRS, purulent nasal discharge is highly suggestive of a bacterial etiology in patients with CRS. A diagnosis of CRS should be confirmed by physical evidence of mucosal inflammation. ³⁰

Patients with CRS who are unresponsive to treatment are candidates for sinus cultures and/or imaging studies. A standard sinus CT scan is the preferred method to locate, confirm, and determine severity of disease. ^40,41 It should be used to evaluate patients before undergoing sinus surgery.

Treatment

Because the pathogenesis may involve multiple factors, which currently remain largely unknown, the optimal treatment of CRS is uncertain. In fact, there are currently no antimicrobials approved by the FDA for treatment of CRS. Antibiotics that have been studied in patients with bacterial CRS or acute exacerbation of CRS are amoxicillin/clavulanate and cefuroxime. ⁴² The use of clarithromycin, clindamycin, or a respiratory fluoroquinolone can be considered in patients with allergy to pencillin. ⁴³ The recommended duration of therapy is 3 to 6 weeks; however a 14-day course has been shown to produce a 90% clinical response. ⁴²

Other treatment modalities that show benefit in providing symptomatic relief are nasal lavage and topical steroids. Nasal irrigation with a warm saline solution (isotonic or hypertonic) twice daily has been shown to reduce nasal congestion. ^44,45 In patients with allergic disease, steroidal intranasal sprays (fluticasone) may help reduce mucosal inflammation and swelling. ⁴⁶ Nebulized antibiotics, decongestants, mucolytic agents, and antihistamines may serve as adjunctive therapies; the evidence for their value in treatment of CRS, however, is either inconclusive or deficient. Sinus surgery may be considered in patients who fail aggressive pharmacologic therapy.

Challenges of Bacterial Resistance

Over the past few decades, antibiotic resistance has increased dramatically. To address resistance, the most recent guidelines for treatment of acute rhinosinusitis focus on judicious use of antibiotics. ^6,11,13,47 Improper diagnosis of ABRS leading to overuse of antibiotics may have contributed to the increasing trend of resistance among respiratory bacterial pathogens. Multidrug resistant pneumococci, defined as strains resistant to at least 3 classes of antibiotics, were recovered in 26% of all isolates. ¹⁹

S pneumoniae, H influenzae

M catarrhalis

S pneumoniae

S pneumoniae

S pneumoniae

S pneumoniae

The most common bacterial pathogens associated with ABRS are , and . Alteration of the penicillin-binding proteins, a resistance mechanism acquired by pneumococci, renders the organism resistant to penicillins, cephalosporins, and other ß-lactam antibiotics. In the United States, the prevalence of penicillin-nonsusceptible (include resistant and intermediately susceptible) strains of reached a peak of 36% in 2001. ⁴⁸ In addition, penicillin-nonsusceptible strains of are associated with cross-resistance to other classes of antibiotics; thus these isolates are termed drug-resistant (DRSP). Resistance of DRSP to other antibiotics includes TMP/SMX (37%), macrolides (29%), doxycycline (21%), clindamycin (10%), and ofloxacin (7%). ¹⁹ Most isolates of remain susceptible to respiratory fluoroquinolones (including gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin). However, concern for development of resistance is arising from extensive use of fluoroquinolones in the treatment of community-acquired respiratory tract infections, however. ⁴⁹

S pneumoniae

erm

S pneumoniae

mef

Cross-resistance between erythromycin and clindamycin occurred in approximately 32% of isolates in the United States. ¹⁹ Resistance to both erythromycin and clindamycin is mediated by the B ribosomal methylation mechanism (MLSBphenotype), which inhibits binding of the antibiotic to the target site. ^50,51 Most erythromycin-resistant strains (68%) remain susceptible to clindamycin, however. ⁵² In these isolates, resistance occurs by the A efflux pump (M-phenotype), which decreases antibiotic accumulation in the bacteria. ^50,53

H influenzae

M catarrhalis

H influenzae

M catarrhalis

H influenzae

(30%) and (92%) confer resistance to penicillins by producing ß-lactamases. ¹⁹ ß-lactamase- inhibitor combinations (eg, amoxicillin with clavulanate) and cephalosporins (specifically, ceftriaxone, cefixime, and cefdinir) retain excellent activity against these pathogens. Both and are highly susceptible to the fluoroquinolones. Resistance of to TMP/SMX (22%) has been observed. ¹⁹

Recently Available Agents

H influenzae

M catarrhalis

Newer antibiotics and dosage formulations provide treatment options for infections caused by resistant respiratory pathogens. High-dose amoxicillin with clavulanate is now available in formulations intended to enhance compliance and effectiveness against DRSP (1000 mg amoxicillin and 62.5 mg clavulanate per extended-release tablet; 14:1 ratio of amoxicillin to clavulanate in powder for oral suspension). Amoxicillin (± clavulanate), which exerts its bactericidal activity by inhibiting cell-wall synthesis, remains a first-line agent in the treatment of ABRS. In addition, the clavulanate component provides activity against ß-lactamase producers, and .

Pharmacokinetic and pharmacodynamic studies demonstrate that highdose amoxicillin (± clavulanate), defined as 4 g/day in adults and 80 mg/kg/day to 90 mg/kg/day in children, provides enhanced activity against DRSP. ^54,55 The most common adverse effects are gastrointestinalrelated, including nausea and diarrhea. The incidence of adverse effects associated with high-dose amoxicillin is comparable to standard-dose amoxicillin. ^55,56 Compared with twice daily dosing, however, 3-times-daily dosing of high-dose amoxicillin was associated with significantly higher incidence of diarrhea. ⁵⁴

S pneumoniae, H influenzae, M catarrhalis

S aureus

H influenzae

M catarrhalis

Fluoroquinolones bind to DNA gyrase and topoisomerase IV to inhibit bacterial DNA synthesis. The respiratory fluoroquinolones provide excellent coverage against respiratory pathogens, including atypical bacteria. The role of atypical bacteria in rhinosinusitis is uncertain, however. Levofloxacin, gatifloxacin, and moxifloxacin, which have been available for a number of years, provide excellent activity against , and ⁵⁷ and are FDA-approved for treatment of ABRS. A newer agent, gemifloxacin, also provides excellent activity against respiratory pathogens, but this agent has yet to gain FDA approval for use in ABRS. Ciprofloxacin, while active against and , has limited activity against pneumococci. The primary concern with the use of fluoroquinolones is the recent emergence of pneumococci with reduced susceptibility to fluoroquinolones. ^47,49,58

S pneumoniae, H influenzae, M catarrhalis

The more recent macrolides, including clarithromycin and azithromycin, also possess excellent activity against , and atypical respiratory pathogens. By binding to the 50S ribosomal subunit, macrolides inhibit protein synthesis to exert their bacteriostatic activity. FDA recently approved the extended-release formulation of clarithromycin for once-daily dosing to enhance compliance. Fluoroquinolones and macrolides are therapeutic options in patients with true hypersensitivity to penicillin. They have been associated with emerging resistance, however, particularly among penicillin-nonsusceptible pneumococcal isolates in the United States. ^19,47,59

erm

erm

mef

S pneumoniae, H influenzae, M catarrhalis

S aureus

A new class of antibiotics called the ketolides was developed to address macrolide-resistant bacteria. ⁶⁰ In the presence of the B gene (and in the case of telithromycin, B and A genes), ketolides remain active against macrolide-resistant pathogens. ⁶¹ Although similar to the macrolides, ketolides bind more tightly to the 50S ribosomal subunit to enhance activity against respiratory pathogens. ⁶² Telithromycin, the first ketolide, recently received FDA approval for the treatment of acute bacterial rhinosinusitis. The spectrum of activity of telithromycin in acute bacterial sinusitis includes , and . ⁶³ Telithromycin 800 mg once daily for 5 days provided a clinical cure rate of 75% to 91%. ^26,64,65 The most common adverse effects reported were gastrointestinalrelated, including nausea and diarrhea.

Conclusion

To optimize treatment of acute and chronic rhinosinusitis, the clinician must understand the pathogenesis and distinct clinical features of these infections. Viruses are responsible for most cases of acute rhinosinusitis. The cause of chronic rhinosinusitis is multifactorial, and the role of bacteria in its pathogenesis is not well established. The use of antibiotics in viral acute rhinosinusitis is inappropriate and contributes to the increasing prevalence of bacterial resistance. Antibiotic resistance is a limitation in the management of ABRS, thereby necessitating appropriate use of antibiotics. To encourage judicious use of antibiotics, the clinician must determine when bacterial infection is highly probable and subsequently consider guidelines when selecting the optimal therapy.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com .

Jennifer Le is Assistant Professor of Pharmacy Practice, College of Pharmacy, Western University of Health Sciences

Martin S. Lipsky is Dean and Professor of Family Medicine, University of Illinois, College of Medicine, Rockford

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