Five-Day Cefdinir Treatment for Streptococcal Pharyngitis

Abstract

A multicenter, randomized, controlled, investigator-blind study was performed to evaluate the safety and efficacy of oral cefdinir versus oral penicillin V for the treatment of pharyngitis due to group A beta-hemolytic streptococci (GABHS). Patients 13 years of age and older were randomized to receive either oral cefdinir (300 mg twice a day) for 5 days followed by placebo for 5 days or oral penicillin V (250 mg four times a day) for 10 days. Throat cultures were obtained, and signs and symptoms of pharyngitis were recorded at study admission and follow-up visits on study days 11 to 15, 16 to 20, and 25 to 31. Patients kept a diary to record medication intake and their assessment of throat pain at admission and at each day of study treatment. Five hundred fifty-eight patients were enrolled, of whom 432 (77.4%) were clinically and microbiologically evaluable. The GABHS eradication rates 5 to 10 days after completion of therapy were 193 of 218 (88.5%) in the cefdinir group and 176 of 214 (82.2%) in the penicillin group (P = 0.053). Clinical cure rates were 89.0 and 84.6%, respectively (P = 0.80). By the time of the long-term follow-up visit, 2 to 3 weeks after completion of treatment, 156 of 191 (81.7%) of the assessable cefdinir patients and 152 of 195 (77.9%) of the penicillin patients remained free of GABHS. Both treatments were well tolerated, with adverse reaction rates of 18.3% in the cefdinir study arm and 15.0% in the penicillin study arm (P = 0.278). Five-day treatment with cefdinir is safe and effective therapy for GABHS pharyngitis. Based on its twice-a-day dosage and shorter course of therapy, leading to potentially greater patient compliance, cefdinir may be considered for use in the treatment of pharyngitis caused by GABHS.

Pharyngitis due to Streptococcus pyogenes (group A beta-hemolytic streptococci [GABHS]) is one of the most common bacterial infections seen in general medical practice, accounting for a significant number of physician office visits per year. Although patients recover clinically without antibiotic therapy, treatment is recommended to hasten clinical resolution, to prevent rheumatic fever (1), and to reduce the incidence of locally invasive infection.

Cefdinir is an extended-spectrum oral cephalosporin with potent antistreptococcal activity, with a MIC at which 90% of the isolates are inhibited (MIC₉₀) of 0.015 μg/ml for S. pyogenes (7).

Since its introduction in the 1940s, penicillin has been the “gold standard” treatment for streptococcal pharyngitis (1), and for many years it effected consistent microbiologic eradication rates of over 90% (2). However, in more recent years, the incidence of bacteriologic failure with oral penicillin therapy has increased to as much as 10 to 30% (3, 13). Alternatively, β-lactamase-stable oral cephalosporins and penicillins have been shown to be highly effective in the treatment of streptococcal pharyngitis (3, 13). In addition, trials of expanded- and broad-spectrum oral cephalosporins in Europe (10) and more recently in North America (8) suggest that a 5- to 7-day duration of therapy is as effective as or even more effective than the classical 10-day regimen of penicillin. Thus, we undertook to compare a 5-day course of oral cefdinir with a 10-day course of oral penicillin V for the treatment of streptococcal pharyngitis.

(Some of these data have been presented at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., 17 to 20 September 1995 [3a].)

MATERIALS AND METHODS

To enter the study, patients needed to be at least 13 years of age and were required to have throat pain and erythema. These and the signs and symptoms fever, cervical lymphadenitis, and pharyngeal tonsillar exudate and edema were monitored. Patients had to have a positive rapid streptococcal screening test (Abbott Testpack Plus Strep A; Abbott Laboratories, Abbott Park, Ill.). Patients allergic to β-lactams, with evidence of locally invasive disease, with significant concomitant disease (renal or hepatic dysfunction), or with a history of rheumatic fever were excluded. Culture for S. pyogenes was obtained at the admission visit by swabbing the oropharynx.

Patients were randomized to receive either 300-mg cefdinir capsules twice a day (b.i.d.) for 5 days or 250-mg penicillin V tablets four times a day (q.i.d.) for 10 days. The study was investigator blinded; medication was dispensed by a third party, who instructed the patient not to mention to the investigator any details about the appearance of the medication or the dosing schedule. To better maintain the blind, those patients who received cefdinir were dosed with an additional 5 days of placebo after completing the cefdinir treatment. Patients were scheduled to return for three additional visits, at which times assessment of clinical signs and symptoms was performed, as was repeat culturing for S. pyogenes. These visits took place on study days 11 to 15 (5 to 10 days after completion of cefdinir), 16 to 20 (5 to 10 days after completion of penicillin), and 25 to 31 for long-term follow-up. In addition to these visits, patients were contacted by telephone on day 3 of treatment to encourage compliance and inquire about adverse events. Identification of S. pyogenes, susceptibility testing, and routine laboratory testing for safety (complete blood count with differential, blood urea nitrogen, creatinine, liver enzymes, and urinalysis) were performed by a central laboratory (SciCor Labs, Inc., Indianapolis, Ind.). Susceptibility (MIC) testing was performed according to National Committee for Clinical Laboratory Standards guidelines (6). The following breakpoints for cefdinir were used: susceptible, ≤1 μg/ml; intermediate, 2 μg/ml; resistant, ≥4 μg/ml.

The posttherapy visit taking place 5 to 10 days after completion of therapy was the time point at which the cure was defined (test of cure [TOC]). To allow for regrowth of suppressed streptococci, microbiologic outcome was defined as persistence or eradication, depending on the throat culture for S. pyogenes at the posttherapy visit. In those cases in which an isolate was found at a postadmission visit, typing (T agglutination typing, M protein typing, and opacity factor typing, as appropriate) of the acute- and convalescent-phase strains was performed (5) (World Health Organization Collaborating Center for Reference and Research on Streptococci, Minneapolis, Minn.). If the acute- and convalescent-phase isolates had identical serotypes, they were considered the same strain, and an outcome of persistent infection was assigned; if not, the admission pathogen was considered eradicated. A clinical outcome of “cure” or “failure” was assigned at each visit; an outcome of “improved” was not used. Cure was defined as the absence or satisfactory remission of all signs and symptoms. Failure was defined as a less than satisfactory response or the need for alternative antimicrobial therapy.

To be evaluable, a patient must have had a culture positive for S. pyogenes at study admission, and the patient must have taken at least 80% of the assigned study medication. Compliance was assessed by questioning the patient, parent, or guardian, by use of a dosing diary, and by quantifying unused medication. The diary also solicited daily information on throat pain, to be characterized by the patient as absent, mild, moderate, or severe. Patients were not permitted to take other systemic antimicrobials and were required to return within the specified TOC window for follow-up, except in those cases in which a patient was clinically failing and returned earlier. Equivalence of outcomes was assessed by a two-tailed 95% confidence interval (CI) approach (11). Cochran-Mantel-Haenszel (CMH) testing was also performed to test for differences in outcomes. All patients receiving the study drug were evaluable for safety, which was monitored by reports of adverse reactions, changes in physical examination, and development of laboratory abnormalities. An adverse reaction was defined as any untoward occurrence during therapy or within 2 days of discontinuing treatment, which was considered by the investigator to be definitely, probably, or possibly due to study medication.

Written informed consent was obtained from each patient or, when appropriate, from the patient’s parent or guardian. This study was approved by an Investigational Review Board for each participating study site.

RESULTS

Efficacy.

Patients were recruited from 21 sites. Five hundred fifty-eight patients were enrolled. The patient demographics were similar in the two study arms: 59.7% of the patients were women, 87.5% were white, and the median age was 26 years (range, 13 to 76 years). Patient disposition is summarized in Table 1. The most common reason why a patient was not evaluable was a negative culture at study admission (74 patients). Other reasons were that the patient returned outside the specified window for evaluation (except for treatment failure) or did not return (46 patients), noncompliance (5 patients), and receipt of a concurrent antimicrobial (1 patient). The reasons for nonevaluability were similar in the two treatment groups. Most of the attrition between the numbers of patients in the posttherapy visit and the long-term follow-up represents patients who were failures posttherapy, who did not require additional follow-up to determine outcome.

TABLE 1.

Patient outcome with cefdinir versus penicillin therapy

Drug	No. (%) of patients
	Enrolled	Evaluable at TOCa	With S. pyogenes eradication	With clinical cure
Cefdinir	278	218	193 (88.5)	194 (89.0)
Penicillin	280	214	176 (82.2)	181 (84.6)

^aTOC was performed 5 to 10 days after completion of therapy. 

All 484 isolates of S. pyogenes were susceptible to both cefdinir and penicillin. The MIC₅₀, MIC₉₀, and MIC range of cefdinir were 0.015, 0.030, and 0.008 to 0.03 μg/ml, respectively. For penicillin V, the same parameters were 0.03, 0.03, and ≤0.015 to 0.03 μg/ml, respectively.

Microbiologic eradication rates and clinical cure rates for evaluable patients at the posttherapy visit 5 to 10 days after completion of therapy are shown in Table 1. The 95% CI for the difference in eradication rates of cefdinir − penicillin was −0.4%, 12.9%, indicating equivalence between the two treatments; CMH testing did not show a difference between the two groups (P = 0.053). The 95% CI for the difference in clinical cure rates of cefdinir − penicillin was −2.0%, 10.8%. CMH testing did not show a significant difference (P = 0.80). An analysis of data from patient diaries showed that the median and mean time to symptomatic resolution of throat pain in both treatment groups was 3 days. In the cefdinir group, eradication rates were slightly higher in patients 18 years of age or older (142 of 158 [89.9%]) than in those 17 years of age or younger (51 of 60 [85.0%]). In the penicillin group, the eradication rates were similar in the older (130 of 158 [82.3%]) and younger (46 of 56 [82.1%]) age groups.

Reinfection and recolonization were uncommon among patients who achieved eradication at the posttherapy visit. At the long-term follow-up visit, 15 to 21 days after completion of therapy, 166 cefdinir patients and 157 penicillin patients whose S. pyogenes cultures had been negative at TOC were available for reculture. Of these, 156 (93.9%) cefdinir patients and 152 (96.8%) penicillin patients still had cultures negative for S. pyogenes.

Safety.

All 558 patients enrolled were evaluated for safety. Both cefdinir and penicillin V were well tolerated in this study. Adverse reactions occurred in 51 of 278 (18.3%) patients in the cefdinir group and 42 of 280 (15.0%) patients in the penicillin group (P = 0.28). The most common adverse reaction in both drug groups was diarrhea (cefdinir, 31 of 278 [11.2%] patients; penicillin V, 18 of 280 [6.4%] patients; P = 0.04). Other relatively common adverse reactions were nausea (cefdinir, 2.2%; penicillin, 3.9%), headache (cefdinir, 1.8%), abdominal pain (cefdinir, 1.4%; penicillin, 0.7%), dyspepsia (cefdinir, 1.4%; penicillin, 1.1%), and vaginal moniliasis (cefdinir, 0.7%; penicillin, 1.1%). Most adverse reactions were mild to moderate in intensity. The incidences of adverse reactions were similar in patients 13 to 17 years of age and those 18 years and older, except that diarrhea in the older group was experienced at approximately twice the rate in the younger group. There was no association between sex and incidence of adverse reactions (data not shown for demographic breakdowns).

Six patients (2.2%) discontinued cefdinir because of adverse reactions: three patients for diarrhea and one patient each for rash, nausea, and a combination of light-headedness, headache, and emesis. Four patients (1.4%) discontinued penicillin for adverse events: three for rash and one for numbness of the arm.

Monitoring of screening laboratory data revealed a trend towards lower peripheral leukocyte counts and neutrophilia in both treatment groups, consistent with resolution of infection. Transient elevation of liver enzymes was seen posttherapy in both groups and was of no clinical significance.

DISCUSSION

This study was designed to determine if a 5-day course of a new oral cephalosporin, cefdinir, was equivalent to the standard 10-day regimen of oral penicillin V in the treatment of patients with GABHS pharyngitis. Statistical testing for equivalence showed that the two treatment regimens were equivalent (P = 0.053) in terms of microbiologic eradication. Clinical cure rates were also equivalent in the two groups. The overall rates of adverse reactions were similar in cefdinir- and penicillin-treated patients.

An alternate and perhaps more stringent measure of outcome may be to require eradication of S. pyogenes at both the 5- to 10-day posttherapy and long-term follow-up visits. Overall, 25 of 25 (posttherapy visit) and 10 of 166 (long-term visit), or 35 of 191 (18.3%), cefdinir-treated patients and 38 of 38 and 5 of 157, or 43 of 195 (22.1%), penicillin-treated patients had streptococcal reisolation at some point. The difference in these eradication rates is not statistically significant.

In this study, there was a higher observed rate of eradication of GABHS in the cefdinir-treated group than in the penicillin-treated group, although the difference did not reach statistical significance at the P < 0.05 level. The observed difference in microbiologic responses cannot be attributed to a decreased susceptibility of S. pyogenes to penicillin, because all isolates were susceptible to penicillin by in vitro testing. Similarly, it cannot be explained by a difference in compliance, since noncompliant patients were excluded from the analysis. The phenomenon of higher S. pyogenes eradication rates for cephalosporins has been previously noted. Pichichero and Margolis have reviewed a number of studies comparing cephalosporin with penicillin for the treatment of streptococcal pharyngitis (9). Based on their meta-analysis, they concluded that the cephalosporins are generally more efficacious, presumably due to their resistance to degradation by β-lactamases. This may be especially true for patients with recurrent streptococcal pharyngitis who have been treated with penicillin within the previous 3 months (4). This opinion is not shared universally, however. Shulman and colleagues have also reviewed the studies included in the Pichichero meta-analysis, and concluded that the available literature does not show that cephalosporins are superior to penicillin for treatment of streptococcal pharyngitis (12).

The Food and Drug Administration in the United States has approved the use of a 5-day course of cefdinir for the treatment of streptococcal pharyngitis and had previously approved cefpodoxime proxetil for 5-day therapy as well. Other β-lactams have been approved for 10-day treatment. Whatever the duration of treatment, eradication of S. pyogenes should theoretically reduce the risk of nonsuppurative complications, such as rheumatic fever. The infrequency of these complications today, however, has made it impossible to determine in clinical trials whether treatments other than intramuscular injection of penicillin actually prevent sequellae of streptococcal infection.

In summary, this study showed that 5-day treatment with oral cefdinir is safe and effective therapy for GABHS, with microbiological and clinical cures equal to 10-day treatment with oral penicillin V. The b.i.d. dosage and shorter course of therapy, leading to potentially greater patient compliance, must be balanced with other considerations, such as cost, when considering cefdinir for the treatment of streptococcal pharyngitis.