Experts debate GAS treatment

July 2004

---Philip A. Brunell, MD

There has been a recent exchange in Pediatrics concerning the treatment of streptococcal pharyngitis, with Mike Pichichero, MD, proposing first-generation cephalosporins be added to the current options for treatment (Pediatrics. 2004;113:866) and Stan Schulman, MD, and Mike Gerber, MD, stating the reasons why we should stick with the current recommendations, a preference for penicillin V with cephalosporins relegated to a secondary role in case of penicillin allergy (Pediatrics. 2004;113:1816).

This may be a propitious time for this argument to take place. We have just had presented to us the first case of rheumatic fever that I have seen in a number of years. A 10-year-old with a new murmur, shown by ultrasonography to be due to mitral regurgitation; a preceding streptococcal infection, proven by a positive antigen test; and an elevated sedimentation rate and fever. In addition, we have seen cases of invasive streptococcal disease at two sites that I regularly visit in the D.C. area. Dick Schwartz, MD, also in our area, described the isolation of group A streptococcus (GAS) from middle ear fluid in his commentary in the June issue. Thus, I am concerned that we may be in for a resurgence of severe streptococcal disease. I would think it might decrease the threshold at which one does a throat culture. The decision to culture (or antigen test) should be based on age, season, exposure and the frequency of finding positive tests for GAS, as well as physical signs, eg, the presence of tonsillopharyngitis, exudates and tender cervical nodes, and the absence of coryza, cough and other respiratory signs and symptoms. At this time, I would add the presence of an unusual number of cases of GAS in the community.

There are two major lessons that can be learned by reviewing the debate between the protagonists. The first is to review in our minds why we are treating GAS pharyngitis, and the second is a lesson in meta-analysis. Many of us look upon the latter as a panacea for resolving conflicting data and distilling mountains of information to a simple conclusion. However, there have been books written on meta-analysis including its limits as well as how to do and interpret it.

Schulman and Gerber are very critical of Pichichero’s meta-analysis. I must admit that, having limited skills in this area, I am very dependent upon the authors of these studies, but also upon the journal and its editors and reviewers to assure that what I read is accurate. The critique of Dr. Pichichero’s article shakes my confidence a bit. It does dissect a meta-analysis, which is a good exercise in how the conclusions can be influenced by how this type of study is performed.

Seeing a case of rheumatic fever reminds one of the most important reason for treating GAS pharyngitis, ordinarily a self-limited infection: the prevention of rheumatic fever. It is for this reason that therapy that will achieve an adequate blood level of penicillin for 10 days is prescribed. The course of the disease has been shown to be shortened, but it is well to remember that papers on whether penicillin shortens the course of illness were still being published four decades after the introduction of penicillin.

If people were doing studies this long, the effects of therapy must not have been that obvious. Indeed, in the classic study done by Jim Bass, MD, and his colleagues (JAMA. 1985;253:1271) there was a measurable effect on the rate of difference of symptoms during the first two days following treatment, but by 72 hours, the treated and untreated groups were indistinguishable. Untreated patients do get better. I always cite the mother who called in for the strep culture report the morning after I had seen her child; I confidently predicted the culture had been negative as the patient now was afebrile and perfectly well. The plate had a florid culture of GAS and 10 days of penicillin was prescribed, not to alleviate symptoms but to prevent rheumatic fever. Treatment was withheld until culture results were in hand, as this does not appear to increase the risk of rheumatic fever, even if therapy is initiated nine days after onset of illness. There also are disputed claims that delay might reduce the risk of recurrences, as early therapy could inhibit the immune response. Many “recurrences” on closer examination are infection with different strains.

Rapid tests vs. culture

With the advent of rapid diagnostic tests, you can argue that treatment should be given as soon as possible for alleviation of symptoms. Many CLIA-waived tests now are available. Although backing up negative antigen tests with a throat culture has been recommended, it is recognized that some of the later-generation tests are quite sensitive. However, if you decides to go the rapid test route, it is suggested that before using them as a sole diagnostic test, you should concurrently do throat cultures until you have enough confidence in the specificity and sensitivity in your own office. You cannot stress enough the importance of obtaining an adequate specimen for whatever test is used: both tonsils in addition to the pharynx.

Since throat cultures generally become negative after 24 hours of therapy, and that is why we permit children to attend school a day after therapy is started, children may return to school sooner if treated. Studies of the effect of treatment on spread in households are hard to find and somewhat conflicting. The number of household members who are found to be positive at the time the index case is diagnosed might adumbrate the effect of therapy. Although therapy probably reduces the suppurative complications — eg, lymphadenitis, peritonsillar or retropharyngeal abscesses, otitis, sinusitis — these commonly occur in the absence of pharyngitis.

The case for cephalosporins as well as alternatives to the classical therapy, viz. penicillin V three times a day for 10 days, is made on the basis of the efficacy of eradication of GAS from the pharynx. One might argue that this might not be a reasonable surrogate for successful therapy. The main criterion should be the prevention of rheumatic fever, and it is doubtful whether we will ever be able to test this in the United States.

Identifying carriers

One of the main pitfalls in our management of GAS pharyngitis is the carrier state. Almost all agree that it is of no clinical consequence. Deciding which positive results of GAS testing represent a carrier and which are actually related to the pharyngitis is problematic. Very often a positive test result in a patient with pharyngitis represents a carrier in someone with viral pharyngitis. This is one of the reasons it is suggested that testing not be done in those with clinical evidence of viral infection, eg, cough or rhinitis, nor should cultures ordinarily be done at the completion of therapy.

It has been noted that the carrier state is much more difficult to eradicate than organisms actually causing acute illness (J Pediatr. 1980;97:337). Some antibiotics are more effective at eradicating the carrier state, eg, clindamycin and probably the cephalosporins, than is penicillin. I like to chide those who support eradication as a correlate of efficacy of therapy with the comment that if I were to design a vaccine against GAS, I would want an organism that can confer immunity without causing disease. Carriers usually have high titers of antibody.

Carriers can be a problem in managing patients with recurrent pharyngitis. One cannot readily discern whether this represents new episodes of viral pharyngitis in a carrier or a recurrence or new infection due to GAS. Although this is not one of the recommended options, I had treated these patients with clindamycin for 10 days and recultured them. This can be expected to result in a greater than 90% clearance of carrier GAS (J Pediatr. 1991;119:123). After treatment, the children are recultured to assure there has been eradication. Then when there are recurrences of pharyngitis, which are found in the presence of a negative GAS test, one can assure the parents that the child had been a carrier. This will diminish the need for repeated culturing and courses of antimicrobials as well as the need for other, more complex methods of managing the problem, eg, treating the dog (which is not useful).

Penicillin

The optimal therapy for GAS is 10 days of penicillin V in appropriate dosage by weight. This is based on extrapolated data that indicated that parenteral penicillin would prevent rheumatic fever, the most important reason for treating GAS pharyngitis. For some reason, only partly due to the introduction of penicillin, this disease virtually disappeared from the United States about half a century ago. However, we have had localized outbreaks on several occasions. With the risk relatively low, we have been less stringent about the use of alternative therapy and the accuracy of detection. Most of the recommended treatment regimens never have been evaluated for prevention of rheumatic fever. This is not to say that penicillin was perfect. The child I mentioned had been given “a shot of penicillin,” but at the time of this writing, we are unsure as to whether it was an injection of ceftriaxone (Rocephin, Roche) or something else. It is important that one be able to maintain a suitable blood level of penicillin for at least 10 days. If parenteral therapy is used, this requires an adequate dose of benzathine G penicillin; this child, weighing more than 60 pounds, would have required 1.2 million units. Procaine or aqueous included in some preparations of bicillin are not counted in calculating this dose. Macrolides have been suggested as an alternative in penicillin-allergic individuals. However, resistance has been reported sporadically in some areas. First-generation cephalosporins also can be used in penicillin-allergic patients.

I believe that we have gotten away with some regimens in the treatment of these mostly self-limited infections. Macrolides, five-day courses and once-a-day azithromycin (Zithromax, Pfizer) all have been used. When rheumatic fever is a real threat, we should probably stay as close as possible to more proven regimens as well as be punctilious about culturing. At this point, a “belt-and-suspenders” approach probably is prudent. Penicillin has been tried and true. We have many years of experience in treating GAS with this drug. It is inexpensive, resistance is nil, it has a narrow spectrum of antimicrobial activity and it is relatively safe. My old professor of neurology (a wonderful Scotsman) used to say “hasten ye to use the new remedies fore they go out of style.”

For more information:

• Casey JR, Pichichero ME. Meta-analysis of cephalosporin versus penicillin treatment of group A streptococcal tonsillopharyngitis in children. Pediatrics. 2004;113(4):866-882.
• Shulman ST, Gerber MA. So what's wrong with penicillin for strep throat? Pediatrics. 2004 Jun;113(6):1816-1819.
• Bisno AL, Gerber MA, Gwaltney JM Jr, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin Infect Dis. 2002;35:113-125.
• Committee on Infectious Diseases. 2003 Red Book. 26th ed. American Academy of Pediatrics. 2003.