Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

86. Upper Respiratory Tract Infections

Christopher Frei and Bradi Frei


KEY CONCEPTS

 Images Most upper respiratory tract infections have a viral etiology and tend to resolve spontaneously without pharmacologic therapy.

 Images The most common bacterial causes are Streptococcus pneumoniae (acute otitis media and acute rhinosinusitis) and group A β-hemolytic Streptococcus (acute pharyngitis).

 Images Vaccination against influenza and pneumococcus may decrease the risk of acute otitis media.

 Images Because upper respiratory tract infections are so common, antibiotics used to treat them serve as catalysts for the emergence and spread of antibiotic resistance, thereby making prudent antibiotic use critically important.

 Images When antibiotics are prescribed, the empirical medications of choice are amoxicillin for acute otitis media, amoxicillin–clavulanate for acute rhinosinusitis, and amoxicillin and penicillin for acute pharyngitis.

 Images For otitis media, high-dose amoxicillin (80–90 mg/kg/day) is recommended if the patient is at high risk for a penicillin-resistant pneumococcal infection.


More patients present to physicians’ offices and emergency departments for upper respiratory tract infections than any other infectious disease.1,2 Otitis media, rhinosinusitis, and pharyngitis are the three most common upper respiratory tract infections. Because they are so common, community and emergency health care workers must be familiar with the diagnosis, assessment, and management of patients with these infections. Furthermore, antibiotics used for the treatment of upper respiratory tract infections serve as catalysts for the emergence and spread of antibiotic resistance, thereby making prudent antibiotic use critically important.

ACUTE OTITIS MEDIA

The term otitis media comes from the Latin oto- for “ear,” itis for “inflammation,” and medi- for “middle”; otitis media, then, is an inflammation of the middle ear. There are three subtypes of otitis media: acute otitis media, otitis media with effusion, and chronic otitis media. The three are differentiated by (a) acute signs of infection, (b) evidence of middle ear inflammation, and (c) presence of fluid in the middle ear.3 Acute otitis media is the subtype with the greatest role for antibiotics and will be discussed in detail.

Epidemiology

Otitis media is one of the leading reasons for physicians’ office visits and emergency department visits in the United States, accounting for more than 16 million clinic and emergency department visits annually.1,2 There are more than 709 million cases of otitis media worldwide each year; half of these cases occur in children under 5 years of age.4 Many patients with acute otitis media will receive a prescription, and the costs associated with managing otitis media are almost $3 billion annually in the United States.5

Etiology

Images Approximately 40% to 75% of acute otitis media cases are caused by viral pathogens.6 Images Common bacterial pathogens include Streptococcus pneumoniae (35% to 40%), nontypeable Haemophilus influenzae (30% to 35%), and Moraxella catarrhalis (15% to 18%).7 The microbial etiology has changed as a result of the introduction and widespread use of the seven-valent pneumococcal conjugate vaccine (PCV7). Specifically, the proportion of S. pneumoniae cases has declined, and the proportion of H. influenzae cases has risen.3 A new S. pneumoniae serotype (19A) has begun to emerge.8

S. pneumoniaeH. influenzae, and M. catarrhalis can all possess resistance to β-lactams. S. pneumoniae develops resistance through alteration of penicillin-binding proteins, whereas H. influenzae and M. catarrhalis produce β-lactamases. Up to 40% of S. pneumoniae isolates in the United States are penicillin nonsusceptible, and up to half of these have high-level penicillin resistance.9 Approximately 30% to 40% of H. influenzae and greater than 90% of M. catarrhalis isolates from the upper respiratory tract produce β-lactamases.1012 Risk factors have been identified for amoxicillin-resistant bacteria. These include attendance at child care centers, recent receipt of antibiotic treatment (within the past 30 days), and age younger than 2 years.6

Pathophysiology

Acute otitis media usually follows a viral upper respiratory tract infection that impairs the mucociliary apparatus and causes Eustachian tube dysfunction in the middle ear.7,13 The middle ear is the space behind the tympanic membrane, or eardrum. A noninfected ear has a thin, clear tympanic membrane. In otitis media, this space becomes blocked with fluid, resulting in a bulging and erythematous tympanic membrane. Bacteria that colonize the nasopharynx enter the middle ear and are not cleared properly by the mucociliary system. The bacteria proliferate and cause infection. Children tend to be more susceptible to otitis media than adults because the anatomy of their Eustachian tube is shorter and more horizontal, facilitating bacterial entry into the middle ear.

Clinical Presentation

Patients or caregivers frequently characterize acute otitis media as having an acute onset of otalgia (ear pain). For parents of young children, irritability and tugging on the ear are often the first clues that a child has acute otitis media.


CLINICAL PRESENTATION   Acute Otitis Media

General

    • Cases of acute otitis media often follow viral upper respiratory tract infections. A diagnosis of acute otitis media requires the following three criteria: (a) acute signs of infection, (b) evidence of middle ear inflammation, and (c) presence of fluid in the middle ear. The latter two criteria must be determined by otoscopic exam. The signs of infection must be acute and may be nonspecific, including fever (<25% of patients) and otalgia (>75% of patients). Younger children may be irritable, tug on the involved ear, and have difficulty sleeping.

Signs and Symptoms of Middle Ear Inflammation

    • Erythema of the tympanic membrane

    • Otalgia

Signs and Symptoms of Middle Ear Effusion

    • Fullness or bulging of the tympanic membrane (most important sign)

    • Limited or absent mobility of the tympanic membrane

    • Otorrhea

_______________

Compiled from references 6, 7, and 13.

The diagnoses of acute otitis media and otitis media with effusion are easily confused, and careful attention to history, signs, and symptoms is important. Otitis media with effusion is characterized by fluid in the middle ear without signs and symptoms of acute ear infection, such as pain and a bulging eardrum.3,7 A diagnosis of acute otitis media requires that three criteria be satisfied: (a) acute signs of infection, (b) evidence of middle ear inflammation, and (c) presence of fluid in the middle ear.3 Middle ear effusion is indicated by any of the following: bulging of the tympanic membrane, limited or absent mobility of the tympanic membrane, or otorrhea.6 Signs and symptoms of middle ear inflammation include either distinct erythema of the tympanic membrane or distinct otalgia.6 A diagnosis is considered to be “uncertain” if the patient does not have all three of these diagnostic criteria.

TREATMENT

Desired Outcome

Images Treatment goals include pain management and prudent antibiotic use. These will be discussed in detail, but, first, it is important to consider primary prevention of acute otitis media through the use of bacterial and viral vaccines.

Images A systematic review demonstrated that the PCV7 reduced the occurrence of acute otitis media episodes by 6% to 7% when the vaccine was administered during infancy.14 Children with a history of acute otitis media did not benefit when the PCV7 was administered at an older age.14 In June 2012, a new 13-valent pneumococcal conjugate vaccine was approved for use in adults 19 years of age or older.

The H. influenzae type b (Hib) vaccine has been available for two decades and is thought to be responsible for a significant reduction in invasive Hib disease; now it is the nontypeable H. influenzae that is of greatest concern in acute otitis media.15 Other vaccines, including nontypeable H. influenzae and M. catarrhalis vaccines, are in development.

Finally, because acute otitis media cases often follow influenza cases, influenza vaccination should be considered as a possible means to prevent acute otitis media. Refer to the U.S. Centers for Disease Control and Prevention website (www.cdc.gov) and statements from the Advisory Committee on Immunization Practices for the most up-to-date information regarding recommended immunization practices.

General Approach to Treatment

The first step is to differentiate acute otitis media from otitis media with effusion or chronic otitis media, as the latter two types do not benefit substantially from antibiotic therapy. If the patient has acute otitis media, then consider if the disease severity warrants antibiotic therapy. Recognize that amoxicillin is the mainstay of therapy and that penicillin resistance can be overcome, in many cases, with higher doses of amoxicillin. Address the patient’s pain as described below. The therapeutic strategy should be changed if complications develop or if symptoms fail to resolve within 3 days.

Nonpharmacologic Therapy

Regardless of the decision to administer antibiotics, acetaminophen or a nonsteroidal antiinflammatory drug, such as ibuprofen, should be offered early to relieve pain in acute otitis media.6 In addition, eardrops with a local anesthetic, such as amethocaine, benzocaine, or lidocaine, provide pain relief when administered with oral pain medication to children aged 3 to 18 years.16 Because of minimal benefit and increased side effects, neither decongestants nor antihistamines should be routinely recommended in cases of acute otitis media or otitis media with effusion.6,17,18

Pharmacologic Therapy

National clinical practice guidelines for appropriate diagnosis and treatment of acute otitis media were first published in 2004 by the American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP).6 These guidelines are focused on children 2 months to 12 years of age with uncomplicated cases. These guidelines do not pertain to children with systemic illness or with underlying conditions that may alter the course of acute otitis media (e.g., anatomic abnormalities, genetic conditions such as Down’s syndrome, immunodeficiencies, and cochlear implants).

Systematic reviews and randomized controlled trials have more closely examined the value of antibiotics for acute otitis media.3,1922 Taken together, these studies suggest a moderate benefit of antibiotics for the treatment of acute otitis media, particularly in patients with severe symptoms.

Images Antibiotic therapy for upper respiratory diseases must be balanced with possible increases in adverse drug events and increased antibiotic pressure. One strategy to reduce antibiotic use in this setting is “delayed therapy.”23Delayed therapy most often means that a healthcare worker provides the patient with a prescription, but encourages the patient to wait to use the medication for 48 to 72 hours to see if the symptoms will resolve on their own. Candidates for delayed therapy include (a) children 6 months to 2 years of age without severe symptoms plus uncertain diagnosis, (b) children 2 years and older without severe symptoms, and (c) children 2 years and older with an uncertain diagnosis.6 Delayed therapy decreases antibiotic use but also decreases patient satisfaction and may harm patients.3 A Cochrane review concluded that this strategy is no better than avoiding antibiotics altogether.23

Images If antibiotics are to be administered, then amoxicillin should be given to most children (80 to 90 mg/kg/day in two divided doses).6 S. pneumoniae resistance to penicillin can be overcome with this amoxicillin dose. If pathogens that produce β-lactamase are known or suspected, then amoxicillin should be given in combination with a β-lactamase inhibitor: amoxicillin–clavulanate (90 mg/kg/day of amoxicillin with 6.4 mg/kg/day of clavulanate in two divided doses).6 In patients with moderate to severe illness (temperature greater than 39°C [102°F] and/or severe otalgia), amoxicillin–clavulanate is recommended. Table 86–1 lists antibiotic recommendations for acute otitis media.

TABLE 86-1 Antibiotics and Doses for Acute Otitis Media

Images

Clinical trials have not provided a clear answer as to which antibiotics are most efficacious3; therefore, the choice of amoxicillin is largely based on microbiology and pharmacokinetic–pharmacodynamic studies. Amoxicillin has the best phar-macodynamic profile against drug-resistant S. pneumoniae of all available oral antibiotics. In addition, amoxicillin has a long record of safety, possesses a narrow spectrum of activity, and is inexpensive. Higher middle ear fluid concentrations of amoxicillin as a result of higher dosing overcome most drug-resistant S. pneumoniae even with its increased minimum inhibitory concentration (MIC).6 Its excellent efficacy against S. pneumoniaeoutweighs the issue of β-lactamase-producing H. influenzae and M. catarrhalis, against which amoxicillin may not be effective. This is because both H. influenzae and M. catarrhalis are more likely than S. pneumoniae to lead to a spontaneous resolution of the infection.

If treatment failure occurs with amoxicillin, an antibiotic should be chosen with activity against β-lactamase-producing H. influenzae and M. catarrhalis, as well as drug-resistant S. pneumoniae.6 Amoxicillin–clavulanate is recommended. Other choices are cefuroxime, cefdinir, cefpodoxime, and intramuscular ceftriaxone.6 Second-generation cephalosporins, though β-lactamase stable, are expensive, have an increased incidence of side effects, and may increase selective pressure for resistant bacteria. Furthermore, most cephalosporins do not achieve adequate middle ear fluid concentrations against drug-resistant S. pneumoniae for the desired duration of the dosing interval. Use of trimethoprim–sulfamethoxazole and erythromycin–sulfisoxazole is discouraged because of high rates of resistance.6 Intramuscular ceftriaxone is the only antibiotic other than amoxicillin that achieves middle ear fluid concentrations above the MIC for greater than 40% of the dosing interval.6 Although single doses of ceftriaxone have been used, daily doses for 3 days are recommended to optimize clinical outcomes.6 Ceftriaxone should be reserved for severe and unresponsive infections or for patients for whom oral medication is inappropriate because of vomiting, diarrhea, or possible nonadherence. It is an expensive antibiotic, and the intramuscular injections are painful. The drug can be given IV, but the risk-to-benefit ratio of starting an IV line must also be examined. Tympanocentesis can also be considered for treatment failure or persistent acute otitis media. It has a therapeutic effect of relieving pain and pressure and can be used to collect fluid to identify the causative agent. Clindamycin may also be considered at this point for coverage of documented penicillin-resistant S. pneumoniae.6 Patients with a penicillin allergy can be treated with several alternative antibiotics. If the reaction is not type I hypersensitivity, cefdinir, cefpodoxime, or cefuroxime can be used. If the reaction is type I, a macrolide such as azithromycin or clarithromycin may be used. If S. pneumoniae is documented, clindamycin is an alternative. However, the incidence of resistance is much higher with these antibiotics, and of these antibiotics, only clindamycin is recommended by the AAP/AAFP guidelines.6

There is ongoing debate regarding the optimal duration of therapy for acute otitis media. Traditional recommendations call for 10 days of antibiotic therapy; however, some experts have speculated that patients can be treated for as little as 3 to 5 days. Unfortunately, the data to support this theory are inconclusive, with some studies demonstrating similar outcomes and others demonstrating worse outcomes with short-course therapy.3 The advantages of short-course therapy are an increased likelihood that the patient will adhere to the full course of treatment, decreased side effects and cost, and decreased bacterial-selective pressure for both the individual and the community. Short-course treatment is not recommended in children younger than 2 years of age. In children at least 6 years old who have mild to moderate acute otitis media, a 5- to 7-day course may be used.


Clinical Controversy…

The 2004 AAP/AAFP guidelines for acute otitis media recommended a “wait and see” approach prior to administering antibiotics.6 This is because many cases of acute otitis media will resolve without antibiotics and the guideline authors believed that a “delayed therapy” approach might serve as a mechanism to reduce antibiotic overuse. A systematic review examined studies that have investigated this practice.3 The review found two studies that reported similar outcomes in patients who received immediate antibiotic therapy as compared with those who received delayed antibiotic therapy; however, two other studies found it detrimental to delay antibiotic therapy. Regardless of the evidence, it appears that prescribers are reluctant to withhold antibiotic therapy and the rate of immediate antibiotic prescribing for acute otitis media has been found to be similar before and after publication of the 2004 AAP/AAFP guidelines (89% vs. 84%, P = 0.103).24

Recurrent acute otitis media is defined as at least three episodes in 6 months or at least four episodes in 12 months. Recurrent infections are of concern because patients younger than 3 years are at high risk for hearing loss and language and learning disabilities. Clinical studies generally do not favor prophylaxis. Treatment can be delayed until the onset of symptoms of an upper respiratory tract infection or antibiotic prophylaxis can be limited to 6 months’ duration during the winter months. Surgical insertion of tympanostomy tubes (T tubes) is an effective method for the prevention of recurrent otitis media. These small tubes are placed through the inferior portion of the tympanic membrane under general anesthesia and aerate the middle ear. Children with recurrent acute otitis media should be considered for T-tube placement.

Personalized Pharmacotherapy

One of the most exciting developments in the world of infectious diseases has to do with clinical biomarkers. Procalcitonin increases in response to bacterial infection and declines as the infection resolves. Clinicians are starting to use procalcitonin blood levels to decide when to initiate and discontinue antibiotics in patients with acute upper respiratory infections (URIs).25 A Cochrane systematic review of 14 trials with 4,221 participants found that procalcitonin protocols significantly reduced antibiotic consumption without negatively impacting patient survival or treatment failure.26 The finding was driven by lower prescription rates in primary care and shorter durations of antibiotic therapy in emergency departments and intensive care units.26 Despite the enthusiasm for this approach, there are still several aspects of procalcitonin monitoring that need to be resolved, including the timing of levels, the procalcitonin cutoff values for different clinical decision points, and the cost-effectiveness of this technology.27

Evaluation of Therapeutic Outcomes

Patients with acute otitis media should be reassessed after 3 days. By this time, there should be clinical improvement in the signs and symptoms of infection, including pain, fever, and erythema/bulging of the tympanic membrane. If the patient has not responded and antibiotics were withheld initially, they should be instituted now. If the patient initially received an antibiotic, then the antibiotic should be changed (Table 86–1). Most children will become asymptomatic at 7 days.

Early reevaluation of the eardrum when signs and symptoms are improving can be misleading because effusions persist. Over a period of 1 week, changes in the eardrum normalize, and the pus becomes serous fluid. Air–fluid levels are apparent behind the eardrum, at which point the stage is now referred to as otitis media with effusion. This does not represent ongoing infection, nor are additional antibiotics required. Two weeks after an acute otitis media episode, 60% to 70% of children still have a middle ear effusion—40% at 1 month and 10% to 25% at 3 months.6 Younger children and those with a history of recurrent infections have a further delay in resolution.

Immediate reevaluation is appropriate if hearing loss results from persistent middle ear effusions following infection. Complications of otitis media are infrequent but include mastoiditis, bacteremia, meningitis, and auditory sequelae with the potential for speech and language impairment.6

ACUTE BACTERIAL RHINOSINUSITIS

Sinusitis is an inflammation and/or infection of the paranasal sinuses, or membrane-lined air spaces, around the nose.28 The term rhinosinusitis is now preferred because sinusitis typically also involves the nasal mucosa.28 Even though the majority of rhinosinusitis infections are viral in origin, antibiotics are frequently prescribed. It is thus important to differentiate between viral and bacterial rhinosinusitis to avoid antibiotic overuse.

A new set of clinical practice guidelines for acute bacterial rhinosinusitis was published in 2012.28 These guidelines provide “a systematic weighting of the strength of recommendation (e.g., ‘high, moderate, low, very low’) and quality of evidence (e.g., ‘strong, weak’)” using a well-known rating system.29 Several of the recommendations in these new guidelines differ substantially from prior guidelines.

Epidemiology

Images Nearly 30 million cases of rhinosinusitis are diagnosed annually in the United States.30 Acute bacterial rhinosinusitis is overdiagnosed; thus, antibiotics are overprescribed. Most rhinosinusitis infections have a viral etiology; nevertheless, one in five antibiotics prescribed for adults in the United States is for rhinosinusitis.31,32 Adults with rhinosinusitis miss an average of 6 workdays/y with these infections.33Patients with rhinosinusitis are significantly more likely to use the emergency room, spend more than $500/y on medical care, and see a medical specialist.33

Etiology

Images Acute bacterial rhinosinusitis is caused, most often, by the same bacteria implicated in acute otitis media: S. pneumoniae and H. influenzae. These organisms are responsible for ~50% to 70% of bacterial causes of acute bacterial rhinosinusitis in both adults and children.28 M. catarrhalis is also frequently implicated in adults and children (~8% to 16%).28 Streptococcus pyogenesStaphylococcus aureus, gram-negative bacilli, and anaerobes are associated less frequently with acute bacterial rhinosinusitis.28 Issues of bacterial resistance are similar to those found with acute otitis media.


CLINICAL PRESENTATION AND DIAGNOSIS   Acute Bacterial Rhinosinusitis

General

    • There are three clinical presentations that are most consistent with acute bacterial versus viral rhinosinusitis:

      • Onset with persistent signs or symptoms compatible with acute rhinosinusitis, lasting for ≥10 days without any evidence of clinical improvement (strong, low–moderate)

      • Onset with severe signs or symptoms of high fever (≥39°C [102°F]) and purulent nasal discharge or facial pain lasting for at least 3 to 4 consecutive days at the beginning of illness (strong, low–moderate)

      • Onset with worsening signs or symptoms characterized by new-onset fever, headache, or increase in nasal discharge following a typical viral URI that lasted 5 to 6 days and were initially improving (“double sickening”) (strong, low–moderate)

Signs and Symptoms

    • Purulent anterior nasal discharge, purulent or discolored posterior nasal discharge, nasal congestion or obstruction, facial congestion or fullness, facial pain or pressure, fever, headache, ear pain/pressure/fullness, halitosis, dental pain, cough, and fatigue

Pathophysiology

Similar to acute otitis media, acute bacterial rhinosinusitis is often preceded by a viral respiratory tract infection that causes mucosal inflammation.34 This can lead to obstruction of the sinus ostia—the pathways that drain the sinuses.7 Mucosal secretions become trapped, local defenses are impaired, and bacteria from adjacent surfaces begin to proliferate. The maxillary and ethmoid sinuses are the ones most frequently involved.7 The pathogenesis of chronic rhinosinusitis has not been well studied. Whether it is caused by more persistent pathogens or a subtle defect in the host’s immune function, some patients develop chronic symptoms after their acute infection.

Clinical Presentation

The greatest barrier to efficient use of antibiotics in acute bacterial rhinosinusitis is the lack of a simple and accurate diagnostic test. The gold standard for diagnosis is sinus puncture with recovery of bacteria in high density (104colony-forming units/mL [107 CFU/L] or greater)28; however, sinus puncture is invasive and costly, and can be painful, so it is not routinely done. Sinus radiography can help, but it is not routinely recommended. Because there is no simple and accurate office-based test for acute bacterial rhinosinusitis, clinicians rely on clinical findings to make the diagnosis.

TREATMENT

Desired Outcome

The goals of treatment for acute bacterial rhinosinusitis are to reduce signs and symptoms, achieve and maintain patency of the ostia, limit antibiotic treatment to those who may benefit, eradicate the bacterial infection with appropriate antibiotic therapy, minimize the duration of illness, prevent complications, and prevent progression from acute disease to chronic disease.

General Approach to Treatment

Images The first step is to delineate viral and bacterial rhinosinusitis. This is based on disease duration, initial severity of illness, and worsening symptomatology. Viral rhinosinusitis typically improves in 7 to 10 days; therefore, a diagnosis of acute bacterial rhinosinusitis requires persistent symptoms (10 days or greater) or a worsening of symptoms after 5 to 6 days. Acute bacterial rhinosinusitis may also be suspected if the patient has severe symptoms at the beginning of his or her illness. Amoxicillin–clavulanate is now recommended as the first-line antibiotic therapy for patients with acute bacterial rhinosinusitis.28Adjuvant, non-antibiotic therapies have a limited role.

The next step is to decide if the patient needs to be referred to a specialist. Potential reasons for referral include mental status changes, visual disturbances, immunosuppressive illness, nosocomial infections, anatomic defects causing obstruction and possibly requiring surgery, unusually severe symptoms, multiple recurrent episodes (3 to 4/y), unilateral findings, significant coexisting illnesses, risk factors for unusual or resistant pathogens, and history of antibiotic failure. The specialist may perform computed tomography to assess the severity and extent of disease and identify the underlying causes.

Nonpharmacologic Therapy

Several nonprescription therapies are used in the management of nonbacterial rhinosinusitis for symptomatic relief. These include nasal decongestant sprays that reduce inflammation by vasoconstriction, such as phenylephrine and oxymetazoline. Use should be limited to no more than 3 days to prevent the development of tolerance and/or rebound congestion. Oral decongestants also may aid in nasal/sinus patency. Irrigation of the nasal cavity with saline and steam inhalation may be used to increase mucosal moisture, and mucolytics (e.g., guaifenesin) may be used to decrease the viscosity of nasal secretions.

In contrast, if a patient is suspected of having acute bacterial rhinosinusitis, then decongestants and antihistamines are not recommended (strong, low–moderate).28 These can dry mucosa and disturb clearance of mucosal secretions. Other therapies are recommended to be used as adjuncts to antibiotics for patients with acute bacterial rhinosinusitis. Intranasal saline irrigation with either physiologic or hypertonic saline is recommended for adults (weak, low–-moderate),28 but the evidence from a Cochrane review is unimpressive.35 Intranasal corticosteroids are now recommended for patients with a history of allergic rhinitis (weak, moderate) based on good data from a randomized controlled trial and a Cochrane review.36,37

Pharmacologic Therapy

Several prestigious groups have published statements and clinical practice guidelines for the management of patients with acute bacterial rhinosinusitis, including the Academy of Pediatrics, the Sinus and Allergy Health Partnership, the American Academy of Otolaryngology–Head and Neck Surgery, the Agency for Healthcare Research and Quality, and the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma, and Immunology, the American College of Allergy, Asthma, and Immunology, and the Joint Council of Allergy, Asthma, and Immunology. The most recent set of clinical practice guidelines was published by the Infectious Diseases Society of America (IDSA) in 201228; these guidelines are the primary source for many of the statements in this chapter.

Images Amoxicillin–clavulanate is now the first-line treatment for acute bacterial rhinosinusitis in children (strong, moderate) and adults (weak, low) (Tables 86–2 and 86-3).28 In contrast, prior guidelines, including the ones published by the Canadian government in 2011,38 list amoxicillin as the first-line treatment option due to its safety, narrow spectrum of activity, good tolerability, and favorable cost. Other randomized controlled trials have even questioned the value of amoxicillin in nonsevere cases of acute bacterial rhinosinusitis.3942 Nevertheless, the IDSA guidelines support the choice of amoxicillin–clavulanate based on (a) the emergence of H. influenzae as a more common cause of upper respiratory tract infections in children than in the past3,43 and (b) the high prevalence of β-lactam-producing respiratory pathogens in acute bacterial rhinosinusitis (particularly H. influenzae and M. catarrhalis).44 Recall that approximately 30% to 40% of H. influenzae and greater than 90% of M. catarrhalis isolates from the upper respiratory tract produce β-lactamases.1012 The advantage of amoxicillin–clavulanate, as compared with amoxicillin, is a greater spectrum of coverage. The disadvantage is increased cost, greater risk of adverse effects including diarrhea, and an added risk of hypersensitivity to the clavulanate component.28 No other antibiotics are recommended as first-line for initial empirical therapy.

TABLE 86-2 Antibiotics and Doses for Acute Bacterial Rhinosinusitis in Children

Images

TABLE 86-3 Antibiotics and Doses for Acute Bacterial Rhinosinusitis in Adults

Images

High-dose amoxicillin–clavulanate is recommended as second-line for initial empirical therapy in children and adults (weak, moderate); doxycycline is also second-line for adults (weak, low) but should be avoided in children.28High-dose amoxicillin–clavulanate is preferred in the following situations: (a) geographic regions with high endemic rates (10% or greater) of invasive penicillin-nonsusceptible S. pneumoniae, (b) severe infection, (c) attendance at daycare, (d) age less than 2 or greater than 65 years, (e) recent hospitalization, (f) antibiotic use within the last month, and (g) immunocompromised persons (weak, moderate).28 Severe infections are those with “evidence of systemic toxicity with fever of 39°C (102°F) or higher, and threat of suppurative complications.”28


Clinical Controversy…

The new IDSA guidelines support the use of intranasal corticosteroids for patients with acute bacterial rhinosinusitis, especially those who also have a history of allergic rhinitis; however, the guidelines are silent regarding the use of oral corticosteroids.28 A Cochrane systematic review addressed this question.45 The authors of the review identified four randomized controlled trials with a total of 1,008 adult participants with acute bacterial rhinosinusitis. All participants received oral antibiotics and either oral corticosteroids (prednisone 24 to 80 mg daily or betamethasone 1 mg daily) or a control treatment (placebo in three trials, nonsteroidal antiinflammatory drugs in one trial). All four trials observed faster resolution or improvement in symptoms among the patients who received oral corticosteroids. These studies did not report any information regarding the long-term effects of oral corticosteroids, such as relapse and recurrence of acute bacterial rhinosinusitis. This systematic review supports the use of oral corticosteroids as adjuvant therapy to antibiotics for the treatment of acute bacterial rhinosinusitis.

If a child has a β-lactam allergy, he or she may receive levofloxacin monotherapy (weak, low) or clindamycin plus cefixime or cefpodoxime combination therapy (weak, low).28 Adults may receive doxycycline, levofloxacin, or moxifloxacin monotherapy (weak, low).28 The guidelines also provide several options for patients at risk for antibiotic resistance, who failed initial therapy, or who have a severe infection requiring hospitalization (Tables 86–2 and 86-3).28 Notably, cephalosporins are no longer recommended as monotherapy due to variable rates of resistance against S. pneumoniae (weak, moderate).28Macrolides are no longer recommended because of high rates of S. pneumoniae resistance (strong, moderate).28 Trimethoprim–sulfamethoxazole has not been recommended for some time due to resistance among S. pneumoniae and H. influenzae (strong, moderate).28

The duration of therapy for the treatment of acute bacterial rhinosinusitis is not well established. Most trials have used 10- to 14-day antibiotic courses for uncomplicated rhinosinusitis,42 and the guidelines support this treatment duration in children (weak, low–moderate).28 For adults, the recommended duration is only 5 to 7 days (weak, low–moderate).28

Personalized Pharmacotherapy

Scientists are investigating a link between human genetics and the predisposition for chronic rhinosinusitis. There is limited evidence to suggest that people with certain genetic polymorphisms may be at greater risk for chronic rhinosinusitis46; however, no such link has been identified for acute bacterial rhinosinusitis. Furthermore, patient genetics are not currently used to guide selection of antibiotic therapy for this condition. It is important to consider patient weight and renal function when selecting antibiotic therapy for acute bacterial rhinosinusitis. Notice that all of the antibiotics recommended for children are dosed according to patient weight. Furthermore, most of the recommended antibiotics are excreted through the kidneys and should be adjusted for renal function as described in the package labeling.

Evaluation of Therapeutic Outcomes

If symptoms persist or worsen after 48 to 72 hours of appropriate antibiotic therapy, then the patient should be reevaluated and alternative antibiotics should be considered (strong, moderate).28 Patients who do not respond to first- or second-line therapies should be referred to a specialist and worked up more aggressively, potentially with direct sinus aspiration (strong, moderate) or contrast-enhanced computed tomography (weak, low).28

ACUTE PHARYNGITIS

Images Images Pharyngitis is an acute infection of the oropharynx or nasopharynx.47 It is responsible for 1% to 2% of all outpatient visits.48 Although viral causes are most common, group A β-hemolytic streptococci (GABHS; also known as S. pyogenes), is the primary bacterial cause47; pharyngitis due to GABHS is commonly known as “strep throat.”

A new set of clinical practice guidelines for GABHS was published in 2012.47 These guidelines provide “a systematic weighting of the strength of recommendation (e.g., ‘high, moderate, low, very low’) and quality of evidence (e.g., ‘strong, weak’)” using a well-known rating system.29 Several of the recommendations in these new guidelines differ substantially from prior guidelines.

Epidemiology

Acute pharyngitis accounts for ~2 million emergency department and outpatient department visits per year,2 at a cost of approximately $1.2 billion total and up to $539 million for children alone.49 Although viral causes are most common, GABHS is the primary bacterial cause and is associated with rare but severe sequelae if not treated appropriately.47,50 Nonsuppurative complications include acute rheumatic fever, acute glomerulonephritis, reactive arthritis, peritonsillar abscess, retropharyngeal abscess, cervical lymphadenitis, mastoiditis, otitis media, rhinosinusitis, and necrotizing fasciitis.

Although all age groups are susceptible, epidemiologic data demonstrate certain groups are at higher risk. Children 5 to 15 years of age are most susceptible; parents of school-age children and those who work with children are also at increased risk. Pharyngitis in a child younger than 3 years of age is rarely caused by GABHS.47

Seasonal outbreaks occur, and the incidence of GABHS is highest in winter and early spring.47 The incubation period is 2 to 5 days, and the illness often occurs in clusters.51 Spread occurs via direct contact (usually from hands) with droplets of saliva or nasal secretions, and transmission is thus worse in institutions, schools, families, and crowded areas.51 Untreated, patients with streptococcal pharyngitis are infectious during the acute illness and for another week thereafter. Effective antibiotic therapy reduces the infectious period to about 24 hours.

Acute rheumatic fever is rarely seen in developed countries. In the United States, acute rheumatic fever secondary to GABHS infection was a cause of concern in the 1950s and was the major reason for penicillin therapy, but the annual incidence of this disease today is extremely rare (≤1 case per 1 million population); however, some risk does remain. Outbreaks have been reported in the United States as recently as the late 1980s and early 1990s. Furthermore, acute rheumatic fever is widespread in developing countries.

Etiology

Images Viruses cause the majority of acute pharyngitis cases. Specific etiologies include rhinovirus (20%), coronavirus (5%), adenovirus (5%), herpes simplex virus (4%), influenza virus (2%), parainfluenza virus (2%), and Epstein-Barr virus (1%).47,52

Images A bacterial etiology is far less likely. Of all the bacterial causes, GABHS is the most common (10% to 30% of persons of all ages with pharyngitis) and is the only commonly occurring form of acute pharyngitis for which antibiotic therapy is indicated.47 In the pediatric population, GABHS causes 15% to 30% of pharyngitis cases. In adults, GABHS is responsible for 5% to 15% of all symptomatic episodes of pharyngitis.47

Other, less common causes of acute pharyngitis are groups C and G StreptococcusCorynebacterium diphtheriaeNeisseria gonorrhoeaeMycoplasma pneumoniaeArcanobacterium haemolyticumYersinia enterocolitica, and Chlamydia pneumoniae.47 Treatment options for these organisms are not addressed in this chapter.

Pathophysiology

The mechanism by which GABHS causes pharyngitis is not well defined. Asymptomatic pharyngeal carriers of the organism may have an alteration in host immunity (e.g., a breach in the pharyngeal mucosa) and the bacteria of the oropharynx may migrate to cause an infection. Pathogenic factors associated with the organism itself may also play a role. These include pyrogenic toxins, hemolysins, streptokinase, and proteinase.

Clinical Presentation

Sore throat is the most common symptom of pharyngitis. Accurate differentiation of GABHS from pharyngitis caused by other agents is important for treatment decisions; however, this can be difficult even for experienced clinicians. Therefore, microbiologic testing is recommended for symptomatic patients unless they have symptoms suggestive of viral etiology or are younger than 3 years of age (strong, high).47

In previous national guidelines, clinical scoring systems such as the Centor criteria or modifications of the Centor criteria have been advocated for clinical diagnosis in adults as a way to overcome the lack of sensitivity and specificity of clinician judgment and to avoid laboratory testing of all patients; however, recent guidelines from Infectious Disease Society of America and the American Heart Association suggest testing be done in all patients with signs and symptoms of streptococcal pharyngitis (strong, high).47 Only those with a positive test for GABHS require antibiotic treatment.47,53 Laboratory tests should not be performed unless the patient has symptoms consistent with GABHS pharyngitis. This is because a positive test does not necessarily indicate disease. A positive test may simply indicate that the patient is a carrier for GABHS and is not actively infected.

Approximately 20% of children are carriers; the prevalence is lower among adults.47 Table 86–4 lists the evidence-based principles for diagnosis of GABHS. There are several options to test for GABHS. A throat swab can be sent for culture or used for the rapid antigen-detection test (RADT). Cultures are the gold standard, but they require 24 to 48 hours for results. The RADT is more practical in that it provides results quickly, it can be performed at the bedside, and it is less expensive than culture. If RADT is positive, it does not require a follow-up throat culture (strong, high).47 If RADT yields negative test results, it is generally recommended to follow up with a throat culture to confirm the results for children and adolescents but not necessary in adults (strong, moderate).47 Delaying therapy while awaiting culture results does not affect the risk of complications (although some argue that symptomatic benefit is postponed, and contagion remains), and patients must be educated as to the value of waiting, given the low false-negative rate of RADT.53

TABLE 86-4 Evidence-Based Principles for Diagnosis of Group A Streptococcus

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CLINICAL PRESENTATION AND DIAGNOSIS   Group A Streptococcal Pharyngitis

General

    • A sore throat of sudden onset that is mostly self-limited

    • Fever and constitutional symptoms resolving in about 3 to 5 days

    • Clinical signs and symptoms are similar for viral causes and nonstreptococcal bacterial causes

Signs and Symptoms of GABHS Pharyngitis

    • Sore throat

    • Pain on swallowing

    • Fever

    • Headache, nausea, vomiting, and abdominal pain (especially in children)

    • Erythema/inflammation of the tonsils and pharynx with or without patchy exudates

    • Enlarged, tender lymph nodes

    • Red swollen uvula, petechiae on the soft palate, and a scarlatiniform rash

Signs Suggestive of Viral Origin for Pharyngitis

    • Conjunctivitis

    • Coryza

    • Cough

Laboratory Tests

    • Throat swab and culture

    • RADT

_______________

From reference 47.

TREATMENT

Desired Outcome

The goals of treatment for pharyngitis are to improve clinical signs and symptoms, minimize adverse drug reactions, prevent transmission to close contacts, and prevent acute rheumatic fever and suppurative complications, such as peritonsillar abscess, cervical lymphadenitis, and mastoiditis.47

General Approach to Treatment

Once the diagnosis of GABHS pharyngitis has been made, the clinician must decide appropriate supportive care, when to initiate antibiotic therapy, the appropriate antibiotic, and the duration of therapy. The selection of appropriate antibiotic therapy will involve careful consideration of cost, safety, efficacy, potential for regimen adherence, and bacterial resistance rates. Clinicians should be aware of the local resistance patterns, which may differ from the national patterns.

Images Antibiotic overuse has been well documented.47,52 Antibiotics are prescribed for 73% of patients who visit their provider with a complaint of “sore throat.”54 This rate is well above the incidence of GABHS pharyngitis. Antibiotic therapy should be reserved for those patients with clinical and epidemiologic features of GABHS pharyngitis, preferably with a positive laboratory test (strong, high). Empirical therapy is not recommended unless there is a high index of suspicion based on clinical or epidemiologic data and laboratory results are pending. However, it is important to discontinue empirical antibiotics if laboratory results are negative.

Nonpharmacologic Therapy

Supportive care should be offered to all patients with acute pharyngitis. Little evidence is available for nonpharmacologic therapy for pharyngitis. However, pharmacologic supportive care interventions include antipyretic medications, analgesics, and nonprescription lozenges and sprays containing menthol and topical anesthetics for temporary relief of pain (strong, high).47 There are limited data for use of corticosteroids to reduce the symptoms of GABHS pharyngitis and given the risk of adverse effects its use is not recommended (weak, moderate).47 Because pain is often the primary reason for visiting a physician, emphasis on analgesics such as acetaminophen and nonsteroidal antiinflammatory drugs to aid in pain relief is strongly recommended.

Pharmacologic Therapy

The most recent set of clinical practice guidelines was published by the IDSA in 201247; these guidelines are the primary source for many of the statements in this chapter. Tables 86–5 and 86-6 outline dosing for acute GABHS pharyngitis and chronic carriers of GABHS.

TABLE 86-5 Antibiotics and Doses for Group A β-Hemolytic Streptococcal Pharyngitis

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TABLE 86-6 Antibiotics and Doses for Eradication of Group A β-Hemolytic Streptococcal Pharyngitis in Chronic Carriers

Images

Images For over 30 years, GABHS isolated in the United States have been susceptible to penicillin, with no reported cases of GABHS resistance to penicillin.47 Because penicillin and amoxicillin have narrow spectrums of activity and are readily available, safe, and inexpensive, they are considered to be the treatments of choice (strong, high).47,53 The only controlled studies that have demonstrated that antibiotic therapy prevents rheumatic fever following GABHS pharyngitis were done with procaine penicillin, which was later replaced with benzathine penicillin.53 Penicillin given by other routes is assumed to be equally efficacious. The ability of other antibiotics to eradicate GABHS has led to extrapolation that these antibiotics will also prevent rheumatic fever.53

Amoxicillin may be preferable for children with GABHS pharyngitis because the suspension is more palatable than penicillin.47 GI adverse effects and rash are more common with amoxicillin. A once-daily, extended-release formulation of amoxicillin has been approved for treatment of GABHS pharyngitis in adults and children aged 12 years and older; however, use of once-daily dosing in GABHS pharyngitis is not recommended by current guidelines.47

If patients are unable to take oral medications, intramuscular benzathine penicillin can be given, although it is painful.47 In penicillin-allergic patients, azithromycin, clarithromycin, clindamycin, or a first-generation cephalosporin such as cephalexin can be used if the reaction is non–IgE-mediated (strong, moderate).47,53 Newer macrolides such as azithromycin and clarithromycin are equally effective as erythromycin and cause fewer GI adverse effects; therefore, these newer macrolides are preferred to erythromycin. GABHS resistance to macrolides is low (5% to 8%) in the United States, but is higher in some other areas of the world.47

In previous pharyngitis guidelines, clindamycin was only an alternative to erythromycin-resistant strains; however, it is now considered an acceptable alternative for penicillin-allergic patients due to the low GABHS resistance rate of 1%.47,53 Tonsillectomy is not recommended because a Cochrane review found that its impact on “sore throat” due to pharyngitis is unpredictable (strong, high).55

GABHS resistance rates to tetracyclines are high. Sulfonamides and trimethoprim–sulfamethoxazole have poor eradication rates for GABHS; therefore, use of these antibiotics is no longer recommended.47Fluoroquinolones are not recommended due to poor activity of the older agents. The newer fluoroquinolones have activity against GABHS but are expensive and have a broad spectrum of activity.47,53

The ideal time to start antibiotics has not been established. The immediate start of antibiotics does not affect the risk of developing rheumatic fever, and no evidence suggests it reduces recurrent infection.53Clinical guidelines recommend withholding antibiotics unless the patient has a positive laboratory result.47,53 Nevertheless, a survey of clinicians treating children and adolescents with acute pharyngitis revealed that 42% of clinicians would start antibiotics before diagnostic results were received and many would continue antibiotics despite a negative test result.56 A retrospective analysis of visits to a primary care clinic for acute pharyngitis demonstrated that 66% of providers did not adhere to any of the recommended pharyngitis guidelines.54

The impact of appropriate antibiotic therapy is limited to decreasing the duration of signs and symptoms by 1 or 2 days.48 It can decrease the severity of pharyngitis symptoms when initiated within 2 or 3 days of onset in patients with proven GABHS. Microbiologic eradication will occur in 48 to 72 hours, which aids in decreasing transmission.48 The duration of therapy for GABHS pharyngitis is 10 days, except for benzathine penicillin and azithromycin, to maximize bacterial eradication (strong, moderate).47 Although some clinicians have proposed shorter courses of treatment for pharyngitis, confounding factors from these studies, such as the lack of strict entry criteria or differentiation between new and failed infections, limit the widespread application of short antibiotic courses at this time.47

Approximately 25% of household contacts of a person with acute GABHS pharyngitis harbor GABHS in their upper respiratory tracts.47 Routine testing and/or treating of asymptomatic household contacts of an index patient is not recommended (strong, moderate).47 GABHS carriers do not need antimicrobial therapy due to very low risk of spreading GABHS pharyngitis or developing suppurative or nonsuppurative complications.49 If tested, it is not necessary to treat these asymptomatic carriers. It is difficult to ascertain the cause of symptomatic pharyngitis in carriers of GABHS if they do develop symptoms. Providers should pay close attention to the symptoms to help differentiate viral versus bacteriologic cause of pharyngitis because laboratory tests will be positive in these patients (strong, moderate).47


Clinical Controversy…

A study explored the value of pharmacist-provided care for patients with GABHS pharyngitis. The study measured treatment costs and health outcomes in patients diagnosed and managed by a community pharmacist or usual care.57Groups were compared in terms of treatment costs (excluding diagnostic costs) and quality-adjusted life days. The two models scored similarly in terms of quality-adjusted life days; however, the community pharmacist provided care at a lower treatment cost. The feasibility of pharmacist-directed care for patients with GABHS pharyngitis needs to be determined in additional studies involving larger populations.

When acute GABHS pharyngitis occurs in a carrier, a treatment course of appropriate antibiotics is recommended.47,53 In the treatment of recurring episodes of culture-positive GABHS pharyngitis, there are limited data to support a particular antibiotic regimen. Several alternative antibiotics are preferred over penicillin or amoxicillin with GABHS carriers and recurrent pharyngitis. Amoxicillin–clavulanate, clindamycin, penicillin/rifampin combination, and benzathine penicillin G/rifampin combination may be considered for recurrent episodes of pharyngitis to maximize bacterial eradication in potential carriers and to counter copathogens that produce β-lactamases.47Table 86–6 outlines dosing for eradication of GABHS in chronic carriers and those who experience symptomatic episodes.

Patients with documented histories of rheumatic fever (including cases manifested solely by Sydenham’s chorea) and those with definite evidence of rheumatic heart disease should receive continuous prophylaxis initiated as soon as the patient is diagnosed and the initial infection has been treated. The duration of secondary prophylaxis is individualized based on patient risk of recurrence of rheumatic fever and/or rheumatic heart disease. Intramuscular benzathine penicillin G every 4 weeks is the recommended regimen for secondary prevention in the United States in most circumstances.53 Additional options for secondary prophylaxis include oral penicillin V and sulfadiazine. Medication adherence is critical for successful secondary prevention with oral antibiotics. Sulfadiazine is an effective antibiotic for the prevention of infection and is appropriate if the patient is penicillin-allergic. Sulfonamides are not appropriate for treatment of GABHS pharyngitis because they are not effective for eradication of GABHS. If individuals are allergic to penicillin and sulfadiazine, a macrolide or azalide is recommended; however, this recommendation is based on expert opinion rather than clinical trial data.53

Personalized Pharmacotherapy

Currently, there are no pharmacogenetic or genomic factors involved in the diagnosis or treatment of GABHS pharyngitis. Factors that should be considered when personalizing therapy for a patient include allergy status, prior antibiotic use, and adherence. Those with a history of antibiotic use for acne may be at higher risk for resistant strains of GABHS. Short-course antibiotics or penicillin G benzathine may be considered in patients with a history of nonadherence.

Evaluation of Therapeutic Outcomes

Most pharyngitis cases are self-limited; however, antibiotics hasten resolution when given early for proven cases of GABHS pharyngitis.47 Generally, fever and other symptoms resolve within 3 or 4 days of onset without antibiotics; however, symptoms will improve 0.5 to 2.5 days earlier with antibiotic therapy.47 Follow-up testing is generally not necessary for index cases or in asymptomatic contacts of the index patient47,50; however, throat cultures 2 to 7 days after completion of antibiotics are warranted for patients who remain symptomatic or when symptoms recur despite completion of treatment.53

ABBREVIATIONS

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