Management of Group A [beta]-hemolytic streptococcal pharyngotonsillitis in children.
Diagnosis of GABHS Pharyngotonsillitis
The presence of GABHS pharyngotonsillitis may be suspected on the basis of clinical findings, and the diagnosis should be confirmed by laboratory testing (FIGURE 1). (3,6) GABHS infections usually occur in children aged 5 to 15 years during the winter and early spring in temperate climates. Symptoms frequently include acute throat pain, severe pain on swallowing, and fever, but headache, nausea, vomiting, and abdominal pain may also be present, especially in younger children. Clinical examination shows tonsillopharyngeal erythema, sometimes with exudate, and tender, enlarged anterior cervical lymph nodes (lymphadenitis). Other findings may also be present, including a scarlatiniform rash and palatal petechiae. Unfortunately, these signs and symptoms are not specific for GABHS pharyngotonsillitis and consequently are not sufficient for making an accurate diagnosis. On the other hand, a viral rather than a bacterial etiology is strongly suggested by the absence of fever or by the presence of certain clinical features, such as conjunctivitis, cough, hoarseness, coryza, anterior stomatitis, discrete ulcerative lesions, viral exanthem, and diarrhea.
[FIGURE 1 OMITTED]
When GABHS pharyngotonsillitis is suspected, a laboratory test--either throat culture or rapid antigen detection test (RADT)--should be conducted to document the presence of GABHS in the pharynx and confirm the diagnosis. (3,6) The culture of a throat swab on a sheep blood agar plate remains the gold standard and, when properly performed, has a sensitivity of 90% to 95% for detecting GABHS in the pharynx. Because culture results are not available for at least 1 day, RADTs were developed to permit the more timely identification of GABHS on a throat swab. The RADTs detect a carbohydrate antigen unique to GABHS by enzyme, optical immunoassay techniques, or the presence of unique gene sequences by chemiluminescent DNA probes. Compared to throat culture, most available RADTs have a specificity of [greater than or equal to] 95%, making false-positive results unlikely. (3) Therapeutic decisions, therefore, can be made reliably from a positive RADT result. Rapid identification of GABHS permits earlier antibiotic therapy, thus reducing the risk of transmission and allowing children to return sooner to school. (2) However, the sensitivity of RADTs is in the range of 80% to 90%, which raises the possibility of false-negative results. Therefore, the Infectious Diseases Society of America (IDSA) recommends that negative RADT results in children and adolescents be confirmed with a throat culture, unless the physician has documented in his or her practice that the RADT that is being used provides results comparable to those provided by throat culture. (3)
Accurately diagnosing GABHS pharyngotonsillitis and treating with appropriate antibiotic therapy provides positive benefits, including prevention of complications such as acute rheumatic fever and tonsillar abscess, shortened clinical course, and decreased contagiousness. Conversely, improper diagnosis may result in negative consequences, including unnecessary antibiotic prescriptions that confer increased health care costs and contribute to the development of bacterial resistance, as well as adding the risk of adverse side effects, including allergic reactions from the antibiotic itself. (7)
Goals of GABHS Pharyngotonsillitis Therapy
Primary goals of therapy for acute GABHS pharyngotonsillitis include preventing acute rheumatic fever and suppurative complications (eg, peritonsillar abscess). Other goals of antimicrobial therapy include improving clinical symptoms, reducing transmission, and achieving bacteriologic eradication. (3) Following an appropriate diagnosis, patients with GABHS pharyngotonsillitis should be treated with an antibiotic in an adequate dosage for sufficient duration to eradicate the infecting organism from the pharynx.
According to IDSA clinical practice guidelines, antibiotic therapy is indicated for patients with acute pharyngotonsillitis if the presence of GABHS has been confirmed by RADT or throat culture. (3) In order to be considered for first-line treatment of GABHS pharyngotonsillitis, the US Food and Drug Administration (FDA) requires that an antibiotic achieve an eradication rate of at least 85% in a statistically adequate and well-controlled multicenter trial, in which bacteriologic eradication correlates with clinical cure. (8)
In selecting antibiotic therapy, it is important to consider the efficacy, safety, antimicrobial spectrum, dosing schedule, likely compliance with therapy, and cost. Several classes of antibiotics have been evaluated in clinical studies of the treatment of GABHS pharyngotonsillitis, including the penicillins, cephalosporins, macrolides, ketolides, and clindamycin. (3) Both the American Academy of Pediatrics (AAP) and IDSA guidelines list penicillin as the agent of choice for first-line treatment of GABHS pharyngotonsillitis due to its proven efficacy, safety, narrow spectrum, and low cost. (3,9) For young children, amoxicillin may be preferred to penicillin, since the suspension is more palatable. For patients unlikely to complete the full 10-day course of oral antibiotic therapy, an intramuscular injection of benzathine penicillin G is preferred. According to the recent IDSA guidelines, erythromycin is identified as a suitable alternative for patients allergic to penicillin; first-generation cephalosporins are also recommended, providing the patient does not have immediate-type hypersensitivity to [beta]-lactam antibiotics. (3) Cephalosporins and macrolides have demonstrated greater bacteriologic eradication and clinical resolution of infection compared with penicillins. (10-13)
The 2006-2007 Nelson's Pocket Book of Pediatric Antimicrobial Therapy recommends cephalosporins as first-line treatment, representing what may be a justified challenge to AAP and IDSA guidelines that recommend penicillin as the preferred first-line therapy, with other antibiotics reserved for recurrences or treatment failures. (14)
As outlined and discussed in the first case (CASE 1), accurate diagnosis and appropriate treatment of GABHS pharyngotonsillitis become essential to treatment success as the incidence of treatment failure with first-line penicillins increases.
Case 1 demonstrates the utility of following a negative RADT result with culture, a practice recommended by IDSA guidelines. As will be discussed in more detail, penicillin and amoxicillin kill both GABHS and [alpha]-hemolytic streptococci (AHS), while cefdinir only attacks GABHS. There is evidence that the presence of AHS prevents GABHS from attaching to the mucous membrane of the pharynx and thereby provides a protective barrier. Considering the higher eradication rates of GABHS with cephalosporins compared with those of penicillin/amoxicillin and the ability of cephalosporins to spare protective organisms, choosing a third-generation cephalosporin after amoxicillin failure was an appropriate and effective treatment decision.
Clinical cure with penicillin/amoxicillin should not be equated with eradication of pharyngeal GABHS--a common but potentially detrimental assumption sometimes made by clinicians. Lack of bacteriologic eradication can lead to lost school days for the child, lost workdays for parents, and transmission of infection to siblings and playmates, as well as increased treatment failure and recurrence. Indeed, treatment failure rates with penicillin have increased since the early 1970s, when the bacteriologic failure rate after 10 days of penicillin therapy was approximately 2% to 10%. (5) Several recent studies suggest that treatment failure after penicillin therapy may now approach 25% to 35% in the United States. Two multicenter, randomized, single-blind studies conducted in 1994 and 1995 reported that 35% of children aged 2 to 12 years treated with oral penicillin V and 37% treated with intramuscular benzathine penicillin G had a positive throat culture result for a concordant serotype of GABHS when tested either 10 to 14 days or 1 month after starting treatment (FIGURE 2). (15) All of these children were microbiological failures only; however, approximately half were also clinically symptomatic, and therefore not in a carrier state.
Notably, the rates of recurrence after penicillin or amoxicillin therapy--both within 30 days and 60 days--increased substantially during the early 1980s. A retrospective chart review of 1721 cases of acute GABHS pharyngotonsillitis treated with penicillin or amoxicillin from 1975 to 1996 showed that GABHS pharyngotonsillitis recurred within 30 days in 20.5% (n = 352) and within 60 days in 30.2% (n = 519) of children. (16) Moreover, the percentage of acute GABHS pharyngotonsillitis cases treated with penicillin or amoxicillin declined from 91% (1975 to 1979) to 67% (1995 to 1996) in this retrospective study. Many of the remaining cases were treated with cephalosporins and the 30-day recurrence rate was significantly lower after oral cephalosporin therapy (8.6%) than after penicillin (21.8%; P<0.0001) or amoxicillin (16.8%; P<0.04) treatment.
Despite the rising incidence of penicillin resistance, there has not been an overwhelming increase in the incidence of acute rheumatic fever. While the incidence and severity of acute rheumatic fever in the United States has declined significantly over the past 5 decades, reports beginning in the mid 1980s have cited a resurgence of this complication in several areas of the country. (17-19) Although the current incidence of acute rheumatic fever is still significantly lower than during the pre-antibiotic era, it still warrants consideration by physicians treating pediatric patients presenting with pharyngotonsillitis.
Economic Costs of GABHS Pharyngotonsillitis
Testing for and treating GABHS pharyngotonsillitis among children comprises a variety of economic costs. Most financial costs incurred during an episode of GABHS pharyngotonsillitis can be attributed to parental time lost from work. (20,21) One study estimated that parents' lost work productivity accounted for approximately 75% of the total cost of one such episode, whereas the cost of antibiotic therapy contributed only 3 %. (20) Because the costs of lost work time routinely outweigh the medical costs associated with GABHS pharyngotonsillitis, even a minimal change in the duration of the illness can have a major impact on overall costs. (21)
Causes for Penicillin Failure in GABHS Pharyngotonsillitis
Both clinical failure and bacteriologic failure still occur despite 100% susceptibility of GABHS to penicillin in vitro. Bacterial interactions among the organisms that inhabit the nasopharynx may contribute to treatment failure with penicillin.
Copathogenicity: One cause of penicillin failure
The pharynx may be co-colonized by bacterial pathogens that can inactivate penicillins and make them ineffective against GABHS. Copathogenicity in acute GABHS pharyngotonsillitis may occur when [beta]-lactamase-producing strains of Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Staphylococcus aureus colonize the inflamed pharynx. (5,22) Although these organisms are generally not pathogenic in the pharynx, they can produce the enzyme [beta]-lactamase, which inactivates penicillins that are not [beta]-lactamase-stable. (4)
A clear association has been established in the therapy of GABHS pharyngotonsillitis between the failure of patients to respond to penicillin and the preexistence of [beta]-lactamase-producing bacteria (BLPB) in their pharyngotonsillar flora. (22) More than 75% of tonsils were removed because of recurrent tonsillitis harboring BLPB. (23-29) Free [beta]-lactamase was detected in the core of most of those tonsils. (30) Antibiotics that are effective against GABHS and are also resistant to [beta]-lactamase, such as cefuroxime axetil, cefdinir, or cefpodoxime, attain higher success eradication rates in relapsing GABHS pharyngotonsillitis. (23)
The co-localization of these organisms with GABHS was shown in a recent study of 548 children with acute pharyngotonsillitis, 20% of whom had
GABHS isolated before treatment. (31) GABHS was isolated with a copathogen in 62% of the cases, most commonly H influenzae and M catarrhalis (29% and 22% of children, respectively) (FIGURE 3). Notably, all of the M catarrhalis isolates and about one third of the H influenzae isolates produced [beta]-lactamases. (31) The impact of [beta]-lactamase production in cases of penicillin failure is suggested by a recent study of 20 children with recurrent pharyngotonsillitis after penicillin V therapy. (32) [beta]-lactamase-producing pathogens were recovered in 85% of these cases. Thus, copathogenicity may be one reason for penicillin failure.
Increased adherence of GABHS by coaggregation
The coaggregation of GABHS and M catarrhalis may contribute to penicillin failure in another way. Both organisms have appreciable carriage rates in the nasopharynx and depend on adherence to epithelial surfaces to express their pathogenicity. When tested on isolated human epithelial cells, the presence of M catarrhalis substantially increased the adherence of GABHS, but not of other bacterial species. (33) On microscopic evaluation, the organisms were co-localized on the same epithelial cell surface. The increased adherence of GABHS correlated with the ability of the 2 potential pathogens to coaggregate, an attribute which was not seen with other bacterial species and appeared to be mediated via proteins, known as adhesins, found on the M catarrhalis surface. It has been suggested that coaggregation may contribute to the pathogenicity of GABHS in the pharynx. Moreover, because most M catarrhalis strains produce [beta]-lactamases, GABHS found in the coaggregates may be more resistant to penicillin, and consequently, treatment failure with penicillin may be more likely.
Brook and Gober evaluated the recovery of M catarrhalis and H influenzae in association with GABHS in children with acute pharyngotonsillitis. (31) GABHS was recovered from 112 of 548 (20.4%) children with acute pharyngotonsillitis. Of the 114 isolates of H influenzae recovered, 32 were isolated in association with GABHS and 82 were recovered without GABHS (29% vs 19%, respectively; P<0.05). Similarly, 25 of the 69 isolates of M catarrhalis were recovered in association with GABHS and 44 were isolated without GABHS (22% vs 10%, respectively; P<0.05). This study demonstrates an association between the recovery of GABHS and H influenzae and M catarrhalis from pharyngotonsillar cultures of patients with acute pharyngotonsillitis.
Eradication of Protective Organisms
Penicillin failure may also be caused by the eradication of normally protective flora, particularly AHS. AHS protect the pharynx from GABHS colonization by producing antibiotic-like substances called bacteriocins that inhibit GABHS growth as well as other growth-inhibitory substances. (34) AHS may also suppress GABHS growth by utilizing the nutrients in the nasopharyngeal environment essential for GABHS colonization. Penicillin is known to potently suppress AHS, which may then impair its protective properties. Patients who have recolonization with AHS after a course of antibiotic therapy have been shown to be less likely to develop recurrent GABHS pharyngitis than those without recolonization. (5,35) In a recent study of 40 children with recurrent tonsillitis, AHS was recovered significantly less often following treatment with penicillin V than with cefdinir (30% vs 75%; P = 0.01). (32) Moreover, AHS with GABHS-inhibiting activity were isolated less frequently after treatment with penicillin (P = 0.014). The minimal eradication of protective organisms may support the use of cefdinir in clinical practice.
Poor compliance with the full 10-day course of oral penicillin therapy is an important cause of penicillin failure in GABHS pharyngotonsillitis. Several factors contribute to poor compliance. First, patients may stop taking the prescribed antibiotic once they start to feel better. In GABHS pharyngotonsillitis, significant clinical improvement may be seen within the first 2 to 3 days of penicillin therapy--before bacterial eradication has occurred. (5) Second, poor compliance in young children may be related to the lack of palatability of an antibiotic suspension. Clearly, the full dosage may not be given when a child rejects an unpalatable suspension. In such situations, it may be particularly tempting for parents to shorten the treatment course once symptoms start to resolve. In young children, therefore, amoxicillin is often used instead of penicillin because the suspension is somewhat more palatable. (3) Third, side effects may prompt patients to discontinue antibiotic therapy. Finally, poor compliance may be related to the inconvenience of the dosing regimen. (4) Medications that must be taken 3 or 4 times each day show lower compliance rates than those that can be taken once or twice per day. Missing doses or, particularly in twice-daily dosing regimens, not receiving the full dosage can be expected to reduce the effectiveness of antibiotic therapy. Penicillin V has a short half-life and administering it only twice daily may lead to a greater rate of failures. Amoxicillin once or twice daily may lead to better compliance while maintaining efficacy, and this approach warrants further study to explore microbiological outcomes. (36,37)
Managing Recurrent GABHS Pharyngotonsillitis
Recurrent GABHS pharyngotonsillitis following penicillin therapy is relatively common, but the incidence of recurrent disease may be lower with other types of antibiotics. As previously described, recurrent GABHS pharyngotonsillitis developed within 30 days of therapy completion in 21.8% of cases treated with penicillin, 16.8% of cases treated with amoxicillin, 14% of cases treated with macrolides, and 8.6% of cases treated with cephalosporins. (16) For patients with recurrent GABHS pharyngotonsillitis, it is important to determine the possible cause of recurrence, which may include an intercurrent viral illness in a persistent GABHS carrier; noncompliance with the originally prescribed antibiotic regimen; acquisition of a new GABHS infection through a family member, classmate, or community contact; or recurrence of the original infecting strain due to treatment failure. (3) In clinical practice, it may be difficult to distinguish a GABHS carrier with an intercurrent viral infection from a patient with acute GABHS pharyngotonsillitis. Helpful clues may be provided by the clinical signs and symptoms, as well as by certain epidemiologic considerations, such as patient age, season of the year, and local prevalence of respiratory viral illnesses. Random culture or end-of-therapy culture once the patient is asymptomatic may also be helpful, especially when eradication is documented prior to a clinical, culture-positive recurrence.
The IDSA considers any of the first-line treatment options to be suitable for single episodes of recurrent GABHS pharyngotonsillitis. (3) If patient compliance with an initial oral penicillin regimen was poor, then consideration may be given to the use of intramuscular benzathine penicillin G. IDSA guidelines recommend second- or third-generation cephalosporins for use in patients who fail first-line therapy with penicillin or amoxicillin. Additionally, it may be useful to substitute a [beta]-lactamase-stable antibiotic, such as a second-generation (eg, cefuroxime axetil) or extended-spectrum third-generation (eg, cefdinir, cefpodoxime) cephalosporin, if copathogenicity is suspected in treatment failure. (32)
An advantage of the cephalosporins is that they are generally resistant to the enzyme [beta]-lactamase. However, their efficacy against BLPB is generation-dependent (TABLE 1). First-generation cephalosporins (eg, cephalexin, cefadroxil) are effective only against S aureus; second-generation (cefuroxime axetil and cefprozil) and extended-spectrum third-generation (cefdinir and cefpodoxime) cephalosporins are effective against S aureus, H influenzae, and M catarrhalis; and third-generation (eg, cefixime, ceftibuten) cephalosporins are only effective against H influenzae and M catarrhalis. However, as a group, the cephalosporins are capable of overcoming BLPB (including M catarrhalis which allows for microbial coaggregation) when they are present, preserving the interfering organisms, and eradicating GABHS. Managing a patient with recurrent pharyngotonsillitis presents challenges and opportunities for optimal therapy (CASE 2).
Patients Allergic to Penicillin
Up to 10% of patients may be allergic to penicillin. (38) Allergic reactions to penicillin may be classified by their timing. Immediate-type reactions occur within the first hour after administration and are mediated by immunoglobulin E (IgE). These reactions may progress to anaphylaxis, with symptoms of wheezing, laryngeal edema, hypotension, and dysphagia. Accelerated allergic reactions that occur within 1 to 72 hours may also be IgE-mediated and may reflect the previous sensitization of the patient to penicillin. Penicillin-induced anaphylaxis has been reported at a rate of 1 in 5000 to 10,000 courses of therapy. (39) However, the most common reaction to penicillin is an idiopathic maculopapular rash, which emerges during treatment and does not appear related to IgE. Skin testing may be helpful in identifying which patients are likely to have a penicillin allergy. Skin testing is typically conducted with a mixture of penicillin derivatives that encompass both its major and minor determinants. In approximately 80% to 95% of patients who report a history of penicillin allergy, skin test results will be negative. (39,40) This finding indicates that the previous reaction to penicillin was not IgE-mediated or that IgE antibodies are no longer present. When skin test results are positive, they are predictive of allergic reactions in about 60% of cases. (38)
Skin reactions with cephalosporins occur less frequently than with penicillins--in about 1% to 3% of patients. Most reactions are not mediated by IgE. (40) Severe reactions and anaphylaxis are also rare with cephalosporins. Because penicillins and cephalosporins are both [beta]-lactam antibiotics, the issue of cross-reactivity between the 2 antibiotic classes has been raised. However, penicillins and cephalosporins differ sufficiently in structure and develop distinct degradation products, consequently immunologic cross-reactivity is actually low. (38) Some early reports suggested that the rate of cross-allergenicity between penicillins and cephalosporins was 7% to 18%. (40) Subsequent review of more than 15,000 patients treated with cephaloridine, cephalexin, cephalothin, cefazolin, or cefamandole found that skin reactions occurred in 8.1% of patients with a history of penicillin allergy, as compared with 1.9% of patients without such history. (38,40) However, the early first-generation cephalosporins included in this analysis were produced by the Cephalosporium mold and actually contained trace amounts of penicillin. Accordingly, the cross-reactivity data in these reports is likely overestimated. It now appears that the cross-reactivity between penicillin and most second- and third-generation cephalosporins is very low and may actually be lower than the cross-reactivity between penicillin and other classes of antibiotics. (38)
Optimizing Antibiotic Efficacy in GABHS Pharyngotonsillitis
The efficacy of penicillin and amoxicillin in GABHS pharyngotonsillitis has waned over the past 3 decades, even though the incidence of acute rheumatic fever has not increased with the continued use of penicillin. In a meta-analysis of 35 randomized, controlled trials comparing penicillins, primarily penicillin V, with cephalosporins, the bacterial cure rate with penicillins declined from 83.4% for trials conducted in the 1970s to 79.4% for those conducted in the 1990s (FIGURE 4). (41) Over the same period, the bacterial cure rate remained essentially unchanged with cephalosporins, with rates ranging from 91% in the 1970s to 92.8% in the 1990s. Overall, the likelihood for bacterial cure of GABHS was 3 times higher when a cephalosporin was administered than when penicillin V was given (summary odds ratio of 35 trials analyzed = 3.02; 95% CI: 2.49 to 3.67; P<0.00001). (41) The cephalosporins showed a trend for increasing superiority over penicillin over the 3 decades (P = 0.09); 8 of the cephalosporins evaluated in the meta-analysis (cephalexin, cefadroxil, cefuroxime, cefpodoxime, cefprozil, cefixime, ceftibuten, and cefdinir) showed higher bacterial cure rates compared with penicillin. (41)
The explanation for the ability of cephalosporins to perform so well is that they are as effective as penicillin in eradicating GABHS. However, penicillin, which is also effective against both aerobic- and anaerobic-interfering organisms, has the potential of ridding the pharyngotonsillar area of these beneficial organisms and depriving the patient of their potential beneficial effects. Cephalosporins, however, are less effective against both aerobic- and anaerobic-interfering organisms; therefore, these organisms are more likely to be preserved following cephalosporin therapy. (42) The higher their generation, the less effective are the cephalosporins against both aerobic- and anaerobic-interfering organisms. In a paradoxical way, the lesser efficacy of cephalosporins against interfering organisms is their potential advantage. Consequently, the administration of a cephalosporin has a selective effect: preserving both the patient's aerobic- and anaerobic-interfering organisms while eradicating their GABHS (TABLE 2). The extended-spectrum third-generation cephalosporins, as well as cefuroxime, possess unique antibacterial features that make their use optimal for eradication of GABHS and [beta]-lactamase producing bacteria while preserving the interfering organisms (TABLE 1).
The clinical and bacteriologic efficacy of several extended-spectrum third-generation cephalosporins as compared with penicillin have been evaluated in the treatment of GABHS pharyngotonsillitis. A pooled analysis of 4 multicenter, randomized, controlled trials explored the efficacy of cefdinir compared with penicillin in the treatment of GABHS pharyngotonsillitis. (43) In total, these studies enrolled 2751 patients, of whom 569 patients received cefdinir once daily for 10 days, 568 patients received cefdinir twice daily for 10 days, 518 patients received cefdinir twice daily for 5 days, and the remaining 1096 patients received penicillin 4 times per day for 10 days. Overall, cefdinir produced a significantly higher microbiologic eradication rate than penicillin (92% vs 77%; P<0.001), which is consistent with the aforementioned meta-analysis. The eradication rates with the 10-day and 5-day regimens of cefdinir were 93% and 89%, respectively. Both therapies were well tolerated, with diarrhea, nausea, and headache reported as the most common adverse events (AEs) in both treatment groups. (43) Similarly, in another investigator-blinded study of pediatric patients aged 1 to 12 years, cefdinir administered at a dose of 7 mg/kg twice daily for 5 days produced higher eradication rates measured 4 to 10 days after completion of treatment than penicillin V 10 mg/kg 4 times daily for 10 days (89.7% vs 71.8%; P<0.001). (44) In this study, the incidence of AEs was similar between treatment groups (12.5% in the cefdinir group vs 13.6% in the penicillin V group; P = 0.69). Most AEs were considered mild to moderate, and diarrhea was the most common AE reported by patients receiving cefdinir, while vomiting ranked highest among the penicillin group. (44)
High rates of GABHS eradication have also been seen with other cephalosporins. (45) Cefpodoxime administered twice daily for 5 days or cefpodoxime once a day for 10 days produced higher GABHS eradication rates than penicillin V given 3 times per day for 10 days in a multicenter, randomized, investigator-blinded study of 377 children aged 2 to 17 years. (46) At the end of therapy, the eradication rates for the 5- and 10-day regimens of cefpodoxime were 90% and 95%, respectively, compared with 78% for penicillin (P = 0.02 and P = 0.003, respectively). When assessed 32 to 38 days after treatment, bacteriologic failure was seen in 17% of children treated with cefpodoxime for 10 days and 19% of children treated with cefpodoxime for 5 days, compared with 35% of the penicillin V-treated children (P [less than or equal to] 0.005). Treatment-related AEs were infrequent and similar in all 3 treatment groups, with gastrointestinal side effects being the most commonly reported. (46)
Similar trends have also been observed for macrolides. Erythromycin is recommended as an alternative for patients allergic to penicillin, and its benefits include a relatively narrow activity spectrum, low cost, and low risk of serious AEs. (4) Azithromycin represents another viable alternative for second-line treatment of pharyngotonsillitis. In a multicenter, randomized study that involved 484 children aged 2 to 12 years, GABHS eradication rates observed at the end of therapy were highest in children receiving azithromycin administered at 20 mg/kg once daily for 3 days (94.2%), compared with children given penicillin V for 10 days (84.2%) or a lower (10 mg/kg/d) dosage of azithromycin for 3 days (57.8%). (47) Significantly fewer treatment-related AEs were reported in the penicillin V group (3%) compared with azithromycin 10 mg (18.3%) and 20 mg (23%) groups. (47) Most AEs were mild-to-moderate gastrointestinal events. (41) Comparable results have been reported in studies with clarithromycin, which is approved for treating pharyngitis due to Streptococcus pyogenes. (48)
Even though the macrolides are an alternative therapeutic choice, the increased use of macrolides for the treatment of respiratory tract and various other infections has been associated with increased GABHS resistance to these agents. Resistance of GABHS to macrolides reached up to 60% in Finland, Italy, Japan, and Turkey. (49) Of particular concern is the recent significant increase of such resistance in the United States that reached 48% in specific populations. (50,51) It is therefore advisable to avoid the routine use of macrolides for GABHS pharyngotonsillitis and save these agents for patients who manifest a type I penicillin allergy.
Optimizing Compliance With Treatment Regimen
Treatment compliance may be improved by using short-course antibiotic therapy instead of the conventional 10-day regimen and by providing more palatable antibiotic preparations for pediatric patients. Currently, 3 antibiotics are approved for use in short-course therapy of GABHS pharyngotonsillitis in children: cefdinir 7 mg/kg twice daily, cefpodoxime 5 mg/kg twice daily, and azithromycin 12 mg/kg once daily, each for 5 days. These agents, when administered in short-course therapy, provide superior GABHS eradication rates compared with penicillin V given 3 or 4 times per day for 10 days. (44,46,47)
The palatability of antibiotic suspensions has been evaluated by both children and health care providers in many studies. In one study, 86 physicians and health care personnel randomly sampled 12 antibiotic suspensions, including the 3 antibiotics available for short-course treatment of GABHS pharyngotonsillitis. (52) Their ranking of these 3 antibiotics in order of overall palatability from highest to lowest was as follows: cefdinir, azithromycin, cefpodoxime. A preference for cefdinir was also seen in a pooled analysis of 7 randomized, single-blind, crossover studies, which compared the taste and smell acceptability of the cefdinir oral suspension with oral suspensions of amoxicillin, amoxicillin/clavulanate potassium, azithromycin, and cefprozil. (53) In these studies, 965 children aged 4 to 8 years used a visual smile-face scale to compare the taste and smell of 2 different antibiotic suspensions. Ratings were then converted to numeric scores ranging from 5 (really good) to 1 (really bad). Overall, the taste of the cefdinir suspension was rated as "really good" or "good" significantly more often than the other antibiotic suspensions (82.7% vs 73.8%, respectively; P<0.001). Cefpodoxime was not included in the pooled analysis, but it has generally scored low in taste tests, particularly because of its poor aftertaste. (54,55)
Once GABHS pharyngotonsillitis has been appropriately diagnosed, prevention of rheumatic fever is the goal of antibiotic treatment. Bacterial eradication is also seen as an important goal. While penicillin remains the first-line therapy for GABHS pharyngotonsillitis, treatment failure with penicillin has become more common, with 30-day recurrence rates now approaching 35%. Among the important factors contributing to the increasing rate of penicillin failure are polymicrobial interactions of the pharyngotonsillar flora, such as copathogenicity with [beta]-lactamase-producing pathogens, coaggregation with M catarrhalis, and suppression of the protective actions of AHS against GABHS infection.
The choice of antimicrobial for the treatment of GABHS pharyngotonsillitis should be individualized. Cephalosporins should be considered in patients if the risk of penicillin failure is high, or if there are compelling medical, economic, or social reasons to utilize more effective agents as first-line therapy (TABLE 3). Cephalosporins have been shown to offer higher GABHS eradication rates than penicillins in numerous clinical studies of children, as well as of adolescents and adults. Cephalosporins inhibit microbial pathogenicity and coaggregation, and are superior to penicillin in preserving protective pharyngotonsillar flora. Because of these properties, the use of cephalosporins may help reduce treatment failures and GABHS recurrence. Factors that impact treatment compliance, such as dosing frequency and palatability, also need to be considered in order to achieve optimal success with antibiotic therapy. The availability of highly palatable antibiotics that can be administered in short-course therapy promises to improve the treatment of GABHS pharyngotonsillitis.
TABLE 3 Indications for the use of a cephalosporin to treat GABHS pharyngotonsillitis Presence of [beta]-lactamase-producing bacteria Absence of "interfering flora" (recent antibiotic treatment) Recurrent GABHS pharyngotonsillitis Past failures to eradicate GABHS High failures of penicillins in the community Comorbidities When failure is a medical, economic, or social hardship Penicillin allergy (non-type 1)
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(10.) Brook I. Failure of penicillin to eradicate group A [beta]-hemolytic streptococci tonsillitis: causes and management. J Otolaryngol. 2001;30:324-329.
(11.) Brook I. The role of [beta]-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Rev Infect Dis. 1984;6:601-607.
(12.) Brook I, Hirokawa R. Treatment of patients with a history of recurrent tonsillitis due to group A [beta]-hemolytic streptococci. A prospective randomized study comparing penicillin, erythromycin, and clindamycin. Clin Pediatr. 1985;24:331-336.
(13.) Casey JR, Pichichero ME. Metaanalysis of short course antibiotic treatment for group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 2005;24:909-917.
(14.) Bradley JS, Nelson JD. Nelson's Pocket Book of Pediatric Antimicrobial Therapy. 16th ed. Miami, Fla: AWWE Medical Publishers; 2006.
(15.) Kaplan EL, Johnson DR. Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and of oral penicillin V in eradication of group A streptococci from children with acute pharyngitis. Pediatrics. 2001;108:1180-1186.
(16.) Pichichero ME, Green JL, Francis AB, et al. Recurrent group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 1998;17:809-815.
(17.) Lee GM, Wessels MR. Changing epidemiology of acute rheumatic fever in the United States. Clin Infect Dis. 2006;42:448-450.
(18.) Wolfe RR. Incidence of acute rheumatic fever: a persistent dilemma. Pediatrics. 2000;105:1375.
(19.) Kavey RE, Kaplan EL. Resurgence of acute rheumatic fever. Pediatrics. 1989;84:585-586.
(20.) Roos K, Claesson R, Persson U, Odegaard K. The economic cost of a streptococcal tonsillitis episode. Scand J Prim Health Care. 1995;13:257-260.
(21.) Van Howe RS, Kusnier LP. Diagnosis and management of pharyngitis in a pediatric population based on cost-effectiveness and projected health outcomes. Pediatrics. 2006;117:609-619.
(22.) Brook I. The role of [beta]-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Rev Infect Dis. 1984;6:601-607.
(23.) Brook I. Role of [beta]-lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococci. Pediatr Infect Dis. 1985;4:491-495.
(24.) Brook I, Yocum P, Friedman EM. Aerobic and anaerobic bacteria in tonsils of children with recurrent tonsillitis. Ann Otol Rhinol Laryngol. 1981;90:261-263.
(25.) Reilly S, Timmis P, Beeden AG, Willis AT. Possible role of the anaerobe in tonsillitis. J Clin Pathol. 1981;34:542-547.
(26.) Tuner K, Nord CE. [beta]-lactamase-producing anaerobic bacteria in recurrent tonsillitis. J Antimicrob Chemother. 1982;10(suppl A):153-156.
(27.) Chagollan J, Macias JR, Gil JS. Flora indigena de las amigdales. Invest Med Int. 1984; 11:36-39.
(28.) Kielmovirch IH, Keleti G, Bluestone CD, Wald ER, Gonzalez C. Microbiology of obstructive tonsillar hypertrophy and recurrent tonsillitis. Arch Otolaryngol Head Neck Surg. 1989;115:721-724.
(29.) Brook I, Yocum P, Foote PA Jr. Changes in the core tonsillar bacteriology of recurrent tonsillitis: 1977-1993. Clin Infect Dis. 1995;21:171-176.
(30.) Brook I, Yocum P. Quantitative measurement of [beta]-lactamase in tonsils of children with recurrent tonsillitis. Acta Otolaryngol. 1984;98:556-559.
(31.) Brook I, Gober AE. Increased recovery of Moraxella catarrhalis and Haemophilus influenzae in association with group A [beta]-haemolytic streptococci in healthy children and those with pharyngotonsillitis. J Med Microbiol. 2006;55:989-992.
(32.) Brook I, Foote PA. Efficacy of penicillin versus cefdinir in eradication of group A streptococci and tonsillar flora. Antimicrob Agents Chemother. 2005;49:4787-4788.
(33.) Lafontaine ER, Wall D, Vanlerberg SL, Donabedian H, Sledjeski DD. Moraxella catarrhalis coaggregates with Streptococcus pyogenes and modulates interactions of S. pyogenes with human epithelial cells. Infect Immun. 2004;72:6689-6693.
(34.) Brook I. The role of bacterial interference in otitis, sinusitis and tonsillitis. Otolaryngol Head Neck Surg. 2005;133:139-146.
(35.) Roos K, Holm SE, Grahn-Hakansson E, Lagergren L. Recolonization with selected alpha-streptococci for prophylaxis of recurrent streptococcal pharyngotonsillitis--a randomized placebo-controlled multicentre study. Scand J Infect Dis. 1996;28:459-462.
(36.) Clegg HW, Ryan AG, Dallas SD, et al. Treatment of streptococcal pharyngitis with once-daily compared with twice-daily amoxicillin: a noninferiority trial. Pediatr Infect Dis J. 2006;25:761-767.
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(38.) Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics. 2005;115:1048-1057.
(39.) Gruchalla RS, Pirmohamed M. Antibiotic allergy. N Engl J Med. 2006;354:601-609.
(40.) Kelkar PS, Li J'T. Cephalosporin allergy. N Engl J Med. 2001;345:804-809.
(41.) Casey JR, Pichichero ME. Meta-analysis of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis in children. Pediatrics. 2004;113:866-882.
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(43.) Brook I. A pooled comparison of cefdinir and penicillin in the treatment of group A [beta]-hemolytic streptococcal pharyngotonsillitis. Clin Ther. 2005;27:1266-1273.
(44.) Tack KJ, Hedrick JA, Rothstein E, et al. A study of 5-day cefdinir treatment for streptococcal pharyngitis in children. Arch Pediatr Adolesc Med. 1997;151:45-49.
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(46.) Pichichero ME, Gooch WM, Rodriguez W, et al. Effective short-course treatment of acute group A [beta]-hemolytic streptococcal tonsillopharyngitis. Ten days of penicillin V vs 5 days or 10 days of cefpodoxime therapy in children. Arch Pediatr Adolesc Med. 1994;148:1053-1060.
(47.) Cohen R, Reinert P, De La Rocque F, et al. Comparison of two dosages of azithromycin for three days versus penicillin V for ten days in acute group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 2002;21:297-303.
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(54.) Demers DM, Chan DS, Bass JW. Antimicrobial drug suspensions: a blinded comparison of taste of twelve common pediatric drugs including cefixime, cefpodoxime, cefprozil and loracarbef. Pediatr Infect Dis J. 1994;13:87-89.
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An 8-year-old patient presents in January with a 1-day history of sore throat, severe pain on swallowing, fever, and headache. The child is otherwise healthy and has been taking ibuprofen to control the symptoms. Physical examination reveals tonsillopharyngeal erythema with exudate, and tender, enlarged anterior cervical lymph nodes along with a scarlatiniform rash. A RADT result was negative for Group A streptococcus infection. A second throat swab was obtained and sent for culture. The patient's mother was given a prescription for amoxicillin and asked to refrain from filling the prescription until the culture results were available. The following day, the culture result was found to be positive and the patient's mother was called and instructed to fill the prescription. Eleven days later, the mother called and stated that the child had completed the entire course of amoxicillin. Although symptoms were markedly improved, the child's "neck glands" were still quite swollen and tender to touch and, at night, the child continued to experience a low-grade fever of 100[degrees]F. Further, the patient's 6-year-old sister had just begun to complain of sore throat and was being kept out of school. The children were seen in the office and RADT results were positive for GABHS in both children. Each child was treated with cefdinir 7 mg/kg twice daily for a total of 5 days. At the follow-up visit 1 week later, both children were asymptomatic, had normal physical examinations, and follow-up throat culture results were negative. A macrolide antibiotic would have been a poor choice in this case because of the increasing resistance of GABHS to macrolides in the United States.
An 8-year-old male presents with a history of recurrent GABHS pharyngotonsillitis. He had been treated with oral penicillin for 10 days and improved initially but had a recurrence of symptoms 4 days after the end of therapy. His 4-year-old sibling was treated with amoxicillin 2 weeks earlier for an ear infection. Tonsillar culture on the 8-year-old was positive for GABHS. This patient's failure to respond to penicillin is most likely due to the inability of the antibiotic to eradicate the organism. Even though his symptoms initially subsided, the organisms that were not completely eradicated by therapy re-emerged to renew the infection. The most likely explanation for this failure is the presence of [beta]-lactamase-producing organisms in the child's nasopharynx that were acquired from his sibling who was recently treated with a [beta]-lactam antibiotic. These could "shield" GABHS from the penicillin. The child was re-treated for 10 days with an oral extended-spectrum third-generation cephalosporin and had complete bacteriologic and clinical cure.
Itzhak Brook, MD
Professor of Pediatrics Georgetown University School of Medicine Washington, DC
Joseph E. Dohar, MD
Associate Professor of Otolaryngology University of Pittsburgh School of Medicine; Clinical Director of the Voice, Resonance and Swallowing Center; Research Director of the Airway Center; Co-Director of the Wound Healing Program Children's Hospital of Pittsburgh Pittsburgh, Pa
FIGURE 2 Treatment failure in children with acute GABHS pharyngotonsillitis Patients with concordant serotype GABHS cultures (%) Time of assessment after IM Benzathine starting treatment Penicillin V (n=284) penicillin G (n=271) Days 10-14 24.6 26.9 Days 29-31 16.2 24.7 Either visit 35.2 37.3 Percentage of children with acute GABHS pharyngotonsillitis who had failed treatment with either penicillin V or intramuscular benzathine penicillin G in 2 multicenter, randomized, single-blind studies conducted in 1994 and 1995. Throat cultures were evaluated at visits on days 10-14 and 29-31 after the start of penicillin treatment. (15) FIGURE 3 Acute GABHS pharyngotonsillitis and other pathogens Children with co-isolate (%) H influenzae 28.6 M catarrhalis 22.3 S pneumoniae 17.9 S aureus 17.0 N=548 Percentage of children with acute GABHS pharyngotonsillitis who also had other bacterial pathogens isolated on throat culture. All isolates of M catarrhalis and S aureus and 35% of H influenzae were [beta]-lactamase-producing strains. (31) FIGURE 4 Comparative cure rates of GABHS pharyngotonsillitis Patients achieving bacteriologic cure (%) Penicillin Cephalosporin 1970s (6 studies) 83.4 91.0 1980s (11 studies) 82.4 92.7 1990s (18 studies) 79.4 98.8 Bacterial cure rates with penicillin and cephalosporins in acute GABHS pharyngotonsilitis. These results are from a meta-analysis of 35 randomized, ontrolled trials conducted in the 1970, 1980s, and 1990s, which compared enicillin therapy with cephalosporin therapy. (41) TABLE 1 Antibacterial activity of cephalosporins Cephalosporins [beta]-lactamase- producing First-generation Second-generation bacteria (cephalothin) (cefuroxime) S aureus Yes Yes H influenzae No Yes M catarrhalis No Yes Cephalosporins [beta]-lactamase- Extended-spectrum producing (cefdinir, Third-generation bacteria cefpodoxime) (cefixime, ceftibuten) S aureus Yes No H influenzae Yes Yes M catarrhalis Yes Yes Antibacterial activity of cephalosporins against aerobic and anaerobic [beta]-lactamase-producing bacteria. TABLE 2 Comparative antibacterial activity Antimicrobial activity Penicillins Cephalosporins Aerobic [beta]-lactamase-producing bacteria No Yes Interfering organisms Yes No GABHS Yes Yes Antibacterial activity of penicillin compared with cephalosporins in the management of acute GABHS pharyngotonsillitis.
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|Author:||Brook, Itzhak; Dohar, Joseph E.|
|Publication:||Journal of Family Practice|
|Article Type:||Disease/Disorder overview|
|Date:||Dec 1, 2006|
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