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Paediatr Child Health. 1998 Jul-Aug; 3(4): 281–282.
PMCID: PMC2851355

Re: The new macrolide antibiotics: Use them carefully

Mark Greenwald, MD FRCPC

Dear Editor:

There is no doubt that the article, “The new macrolide antibiotics: Use them carefully”, which appeared in the November/December issue (Paediatr Child Health 1997;2:385-6, Can J Infect Dis 1997;8:312–313), has the potential to carry a lot of weight. Some of the authority comes from the author himself but as heavily weighted is the real or perceived appearance of ‘official sanction’. This official sanction flows from the author being a member of various groups/committees within the Canadian Paediatric Society (CPS), Pediatric Investigators Collaborative Network on Infections in Canada, Paediatric Infectious Disease Society and others. Correspondence is directed to Infectious Diseases and Immunization Committee of the Canadian Paediatric Society. Publication in the Canadian Journal of Infectious Diseases, and especially in the “Paediatric Infectious Disease Notes” together and separately give credibility. In fact, noting that it was also published in Paediatrics & Child Health implies additional worthiness to republish and reprint. The author has an academic association with Centre Hospitalier Universitaire de Québec, but the article appears sanctioned by the listing, by name, of the members and liaisons of the Infectious Diseases and Immunization Committee of the CPS. Having such pedigrees, such an article is likely to influence the community, so we must “use them carefully”.

Regarding the content of the article there are certain statements where the advice should be used carefully. The author states that the agents discussed, clarithromycin and azithromycin, “have a very good record of safety and efficacy in the treatment of common paediatric infections”. He then reviews the pharmacology and states that the release of azithromycin from the tissues continues beyond the period of administration.

When discussing the indications for use, the author states that “only clarithromycin is approved for the treatment of acute sinusitis in children”. The Compendium of Pharmaceuticals and Specialties, 1997 (1) states that the indications for the Tablets include acute maxillary sinusitis caused by the expected organisms (streptococcus, Haemophilus influenzae and Moraxella catarrhalis). The tablets have not been studied in children under 12 years of age. Under indications for the Pediatric Granules for Suspension there is no stated indication for sinusitis. Even more confusing is the use of clarithromycin for specifically Streptococcus pneumonia sinusitis in children as shown in Table 2 of the note. Assuming for a moment that this is borrowed from authorized uses in other countries, why then the limitation to this organism? For example, indications in the United States for this specific disease entity in children include the three major organisms.

Additional aspects are misleading, especially because we are advised to “use them carefully”. The article recommends use in children six months to 16 years for otitis media, but the other approved indications do not carry ages ranges for use. By implication and in the absence of stated age ranges to the contrary for the other indications, one assumes the same applies. In fact, for pneumonia the granules were not studied for clarithromycin in children under three years of age, and for Mycobacterium avium complex under 20 months.

The author goes on in paragraph 4 “Extension of Use...” to note that common practice uses antibiotics for the “treatment of diseases...not officially approved”. Indeed this is often the case. Specifically the extension of use from otitis to sinusitis is common and does make sense because of the same pathogens and tissues. The author, however, categorically states that azithromycin “should not be prescribed for the treatment of sinusitis in children...”. Why the author should select this drug does not follow logically at all from anything referred to until this point.

When discussing toxicity, this class of drugs is deemed safe when used as recommended. Assuming nonindicated use, the author discusses the potential of more severe toxic side effects. He notes that for this class of drugs as a whole the “incidence of hearing disorders and of cholestatic jaundice appears to be related to the dose and duration of therapy”. There is no reason to isolate a single entity if the duration of exposure is approximately the same as another drug, albeit the number of doses and dosing duration would be less for azithromycin whose pharmacokinetics have been so studied.

In paragraph 7, the article by Tseng (2) is quoted extensively, presumably to explore this issue of toxicity; specifically ototoxicity. There are some serious problems with using this source and ‘extending’ conclusions to other areas. The study was in adults. The study was done on human immunodeficiency virus (HIV)-infected individuals. The mean dose used was 600 mg/day; 17% of patients experienced ototoxicity but the toxicity was mild to moderate and mostly reversible. The duration of exposure was greater than nine weeks. The author quoted does publish in the HIV and drug toxicity literature. In fact, this very same quoted author has written about the extremely common potential for drug interactions in this patient treatment scenario (HIV) (3).

To use this study to understand inductively the treatment of sinusitis or for that matter any respiratory tract infection does not follow. The subjects would be children and otherwise healthy, not HIV-infected. Conventional doses would be used, not 600 mg per day. In fact, it has been recommended in the scenario of the quoted article to use 300 mg per day (3). The duration of treatment for sinusitis in children would not be considered prolonged (one to four weeks versus nine weeks on average). Azithromycin may offer significant advantages in the treatment of sinusitis in all ages, with better compliance characteristics and at least equivalent or better clinical effect (4).

The potential may actually be less for drug interactions with azithromycin (5), and the same and/or additional toxicities may be found with clarithromycin in the scenario use (6).

The bottom line is that absolutely no evidence, direct or by inference, is offered to support the recommendations. The rudimentary requirements for scientific speculation are not met.

The specific cautions concerning use of the newer macrolides, and in particular that contraindication to use azithromycin in sinusitis, have not been carefully made, and ‘official support’ has not been carefully placed.

REFERENCES

1. Gillis MC. Compenium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association; 1997.
2. Tseng AL, Dolovich L, Salit IE. Azithromycin-related ototoxicity in patients infected with human immunodeficiency virus. Clin Infect Dis. 1997;24:76–7. [PubMed]
3. Tseng AL, Foisy MM. Management of drug interactions in patients with HIV. Ann Pharmocother. 1997;31:1040–58. [PubMed]
4. Brown BA, Griffith DE, Girard W, et al. Relationship of adverse events to serum drug levels in patients receiving high-dose azithromycin for mycobacterial lung disease. Clin Infect Dis. 1997;24:958–64. [PubMed]
5. Hayle R, Lingaas E, Hoivik HO, et al. Efficacy and safety of azithromycin versus phenoxymethylpenicillin in the treatment of acute maxillary sinusitis. Eur J Microbiol Infect Dis. 1996;15:849–53. [PubMed]
6. Nahata M. Drug interactions with azithromycin and the macrolides: An overview. J Antimicrob Chemother. 1996;37(Suppl C):133–42. [PubMed]
7. Shafran S, Deschenes J, Miller M, et al. Uveitis and pseudojaundice during a regimen of clarithromycin, rifabutin and ethambutol. MAC Study Group of the Canadian HIV Trials Network. N Engl J Med. 1994;330:438–9. [PubMed]
Paediatr Child Health. 1998 Jul-Aug; 3(4): 282.

Response

We appreciate Dr Greenwald’s comments on our Paediatric Infectious Disease Note, “The new macrolide antibiotics: Use them carefully” (Paediatr Child Health 1997;2:385-6). The note was drafted in response to two problems of inappropriate use of antibiotics that were recently observed in paediatric patients: prescription of erythromycin as therapy of acute otitis media and sinusitis; and prescription of azithromycin for 10 days or more for the treatment of acute sinusitis.

So-called ‘off-label’ use of antibiotics has been a common practice in the treatment of paediatric infections for a long time, often because paediatric data are not available at the time of approval. Although this is probably acceptable in certain circumstances, it has become increasingly problematic, frequently leading to observable instances of inappropriate use of antibiotics, such as the two situations described above.

Erythromycin is not an acceptable therapy for upper respiratory tract infections of children, because it is not active against Gram-negative bacteria, such as Haemophilus influenzae, which often cause these infections.

Dr Greenwald takes issue mainly with the statement that azithromycin should not be prescribed for acute sinusitis in children. The appropriate duration of antibiotic therapy for acute sinusitis in children is not known. In a recent review, Ellen Wald (1), a well-respected specialist in this field, suggests that antibiotics should be administered for 10 days past the termination of acute symptoms, which is somewhat awkward to prescribe. The Canadian Consensus Conference on Therapy of Acute Sinusitis (2) recommended 10 days of antibiotics for common cases of sinusitis. However, many physicians treating acute sinusitis in children opt for a therapy of 14 to 21 days because shorter courses are often associated with failure or early recurrence. While one randomized study suggested that three days of azithromycin might be sufficient for the treatment of acute sinusitis (3), this study only included adults and no cultures of the sinus secretions were performed in order to assess efficacy.

Thus, we are left with no data upon which to base a recommendation for use of azithromycin in acute sinusitis of children. Many physicians have adopted azithromycin for the treatment of common upper airway infections, such as acute otitis media in children, because of its wide spectrum of activity, proven efficacy and good safety record, when prescribed for three to five days. However, we believe that prescription of this agent for the treatment of acute sinusitis has the potential to lead to significant toxicity if it is used for the longer durations often prescribed for this condition.

In conclusion, we feel that physicians choosing to prescribe azithromycin for the treatment of acute sinusitis in children should be careful to restrict the duration of therapy to three to five days, and avoid early repeat prescriptions to prevent accumulation of the drug in tissues with possible toxic side effects.

REFERENCES

1. Wald ER. Diagnosis and management of sinusitis in children. Adv Pediatr Infect Dis. 1996;12:1–20. [PubMed]
2. Low DE, Desrosiers M, McSherry J, et al. A practical guide for the diagnosis and treatment of acute sinusitis [see comments] CMAJ. 1997;156(Suppl 6):S1–14. [PubMed]
3. Hayle R, Lingaas E, Hoivik HO, et al. Efficacy and safety of azithromycin versus phenoxymethylpenicillin in the treatment of acute maxillary sinusitis. Eur J Clin Microbiol Infect Dis. 1996;15:849–53. [PubMed]

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