Penicillin or cephalosporin for strep throat?

October 2004

The treatment of group A ß-hemolytic streptococcal (GABHS) tonsillopharyngitis is experiencing renewed controversy with the publication of recent studies and editorials. The chief medical editor of Infectious Diseases in Children, Philip Brunell, MD, has additionally weighed in on this issue in his July editorial.

Casey and Pichichero published this year (Pediatrics 2004) a meta-analysis of studies of several cephalosporins and penicillin administered orally for 10 days in the treatment of GABHS tonsillopharyngitis in children younger than 18 years of age. Trials included in this meta-analysis were published in 2000 or prior and were randomized and controlled. These trials had to meet the criteria of bacteriologic confirmation of GABHS infection by rapid test or culture and assessment of bacteriologic outcome with post-therapy culture. Outcomes sought were bacteriologic cure and clinical cure. When possible, the authors reanalyzed study data after eliminating GABHS carriers to calculate bacteriologic and clinical cure rates. Differences in bacteriologic cure rates with cephalosporin treatment as compared with treatment with penicillin were defined by an odds ratio (OR), with an OR of >1 indicting a higher bacteriologic cure rate for cephalosporin treatment. A total of 35 trials (7,125 patients) met the inclusion criteria. The authors used a rating scale (Jadad) to assess the quality of the trials, based upon a 0-5 rating. Most of the included trials were of lesser quality, as only 31% of the trials were considered higher quality (Jadad score >2). Six of the 35 trials were double blind and nine trials included investigator blinding. Eleven different cephalosporins and one carbacephem (lorcarbef [Lorabid, King]) were compared with penicillin in these trials. Carriers were defined and eliminated from study analysis in seven trials, and in 11 trials, data were available to allow Casey and Pichichero to reanalyze the data without carriers. Follow-up test-of-cure cultures were obtained at the optimal time of three to 14 days post therapy in nine trials. Twenty-six trials used some means to assess compliance with therapy (eg, tablet counts, urine testing). The summary OR for bacterial cure for all 35 trials was >1 (3.02), indicating a higher bacterial cure rate for cephalosporin therapy as compared with treatment with penicillin. Similarly, the summary OR for clinical cure was >1 (based upon 30 trials), also indicating a higher clinical cure rate with cephalosporin treatment. The authors additionally calculated sensitivity analyses and found that the OR was >1 when trials were grouped and reanalyzed as 1) double-blind trials, 2) higher quality trials (Jadad scale >2), 3) trials with detailed compliance monitoring, 4) trials that eliminated carriers, and 5) trials with a three- to 14-day post-therapy test-of-cure. The authors additionally separated the evaluated cephalosporins by class-generation: Each generation, first, second, and third, had a bacterial cure OR >1. There was no difference among the generations. This implies no advantage to the use of a second- or third-generation cephalosporin and yet includes disadvantages of increased cost and broader antimicrobial spectrum of activity. Individual compounds with an OR not surpassing 1 included cefaclor and lorcarbef.

In an editorial published two months later, Shulman and Gerber discussed several major concerns they harbor about the validity of Casey and Pichichero’s meta-analysis. They expressed doubt over the quality of many of the included studies, including a lack of double-blinding, compliance or lack of follow-up post-therapy cultures. To an extent, Casey and Pichichero had considered this by conducting additional sensitivity analyses. An additional concern expressed by Shulman and Gerber relates to the inclusion (or lack of exclusion) of chronic pharyngeal streptococcal carriers in some studies. This becomes important, as cephalosporins have previously been shown to be superior to penicillin in eradicating a chronic carrier state.

Treatment guidelines

The 2003 “Red Book” discusses penicillin given orally as the drug of choice for the treatment of GABHS tonsillopharyngitis. First-generation cephalosporins are described as an acceptable alternative, especially for children with an allergy to penicillin that is not immediate, anaphylactic hypersensitivity. Although some studies documenting the efficacy of a five-day cephalosporin treatment course have been published, the “Red Book” does not recommend these treatments for routine therapy.

The Infectious Diseases Society of America (IDSA) published its guidelines on the diagnosis and management of group A streptococcal pharyngitis in 2002. Penicillin is recommended as the agent of choice, despite the availability of published studies documenting the efficacy of various cephalosporins. The IDSA does not advocate the use of short-course cephalosporin therapy, as studies evaluating these agents have limited methodology.

Conclusion

How does the average clinician make use of the above information? Casey and Pichichero appear to make a strong case for the use of a cephalosporin with a complete and well-done meta-analysis. The combination of 35 trials with more than 7,000 study patients includes data that are difficult to ignore. However, Shulman and Gerber also present convincing arguments about the potential limitations of this meta-analysis. Because many (most) of the individual trials were of lower quality, it is reasonable for one to wonder about the ability of a meta-analysis to reach a valid conclusion with potentially unreliable data. Certainly, a meta-analysis of numerous studies (many of lesser quality) is not as dependable as large well-done controlled trials. The arguments for the use of penicillin as the antibiotic of choice as presented by the “Red Book” and other authoritative sources seem relatively clear. Penicillin is the only antibiotic (the caveat being that when it is given as an intramuscular injection) to have been shown by controlled trials to accomplish what all clinicians seek when treating GABHS tonsillopharyngitis – the prevention of rheumatic fever. The assumption that other drugs, such as cephalosporins, will similarly prevent rheumatic fever is based upon the drug’s ability to eradicate GABHS from the tonsillopharynx. Not only can penicillin accomplish this task, but it does so at a very minimal cost, safely, with the added advantage that no GABHS has been shown to be resistant to penicillin, and with minimal effects upon populations of other bacteria (ie, it has a narrow spectrum of activity). These are many of the attributes of an optimal antibiotic. Perhaps the most negative aspect of using penicillin is the requirement for a 10-day treatment course, which many may not be compliant with. Intramuscular penicillin, then, becomes the optimal antibiotic. But, of course, its administration is painful (so much for the “optimal antibiotic”).

So why use a cephalosporin? Casey and Pichichero contend that cephalosporins are more likely to eradicate GABHS from the infecting site, with the assumption, perhaps, that the ability for the prevention of rheumatic fever is greater. Why might this be if resistance to penicillin has not been documented? Casey and Pichichero discuss several reasons: ß-lactamase–producing flora in the infected area that destroy penicillin, penicillin more effectively eradicates -streptococci in the tonsillopharynx than do cephalosporins (-streptococci are local competitors of GABHS), and cephalosporins have pharmacokinetic and pharmacodynamic advantages over penicillin, resulting in superior blood and tissue levels. Thus, what should the clinician do? It seems appropriate to continue to use penicillin for most patients with documented GABHS tonsillopharyngitis. Penicillin does what we want it to do, at a very low cost, and with minimal adverse effects. The true clinical benefit of using a cephalosporin needs to be further defined.

For more information:

• Casey JR, Pichichero ME. Meta-analysis of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis in children. Pediatrics. 2004;113:866-882.
• Shulman ST, Gerber MA. So what’s wrong with penicillin for strep throat? Pediatrics. 2004;113:1816-1819.
• Bisno A, Gerber MA, Gwaltney JM, et al. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin Infect Dis. 2002;35:113-125.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children's Hospital, Des Moines, Iowa.