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Outbreaks, Alerts and Hot Topics

June, 2018

Highlights from The American Academy of Pediatrics Report of the Committee of Infectious Diseases: Red Book™ 2018 


Mary Anne Jackson, MD | Division Director, Infectious Diseases | Medical Editor, The Link Newsletter | Professor of Pediatrics

By now, you should have received your copy of the 31st edition of the Red Book™. More than 500 content experts and reviewers were engaged in ensuring that every chapter was updated. Twenty-seven chapters have been eliminated, many in the Active and Passive Immunization section where links to current resources have been added. Chikungunya and Zika virus chapters have been added. Among the 172 changes outlined in the introduction, one major change is notable, and relates to the recommendations for doxycycline.

Tetracyclines and Dental Staining


Discovered in the 1940s, tetracycline agents were introduced and represented one of the first broad-spectrum antibiotics available that provided activity against gram-positive and negative bacteria, chlamydia, mycoplasma, rickettsiae and parasites. Aureomycin, oxytetracycline and tetracycline were the first such agents introduced in 1948, 1949 and 1953 respectively, and use in pediatrics became widespread despite the first reports of dental staining in children by the early 1960s. Further research established that chelation of calcium to form a complex that is incorporated into the teeth during the calcification stage of dental development accounted for the staining, which was dependent on dose and duration of use. As of 1970, all tetracycline products manufactured in the U.S. included a warning that permanent discoloration of teeth (yellow-gray-brown) “occurs in those exposed in the latter half of pregnancy, in infancy and up to 8 years, and therefore tetracycline class agents should not be used” in those age groups. The label warnings and journal reports did not appear to reduce use of such agents, and Scheckler and Bennett reported years after the first reports of the risk that community hospital use was three times greater than use at a teaching hospital, where antibiotics were required to be approved by the infectious disease physicians (JAMA 213:264, 1970). Yaffe, et al., under the auspices of the Committee on Drugs (Pediatrics 55:142, 1975) stated that there were few indications for tetracycline drugs, and called for physicians to use every effort to discourage use in children. Every Red Book thereafter, included the warning against use of tetracyclines in those 8 years and under. 

 

New Red Book™ 2018 Recommendation
Amid the warnings that called for abandoning the use of tetracyclines in children, doxycycline was FDA approved in 1967. Although doxycycline was noted to have a reduced ability to chelate calcium, and suspected to be less likely to cause dental staining, precautions persisted even though the 1997 Red Book™ confirmed doxycycline as the drug of choice for Rocky Mountain Spotted Fever and in 1998, Peter Lockhart and his associates at the Department of Dentistry at Carolinas Medical Center, suggested that short-course doxycycline used to treat RMSF was not associated with dental staining based on clinical examination of 10 doxycycline-exposed children and 26 non-exposed children (PIDJ 17: 429, 1998). The concern regarding the underuse of doxycycline was well founded, as a 2012 national survey of doxycycline use for RMSF noted that 80 percent of clinicians correctly selected doxycycline for those 8 and older, but only 35 percent in the younger child; and noted that while those under 10 years accounted for less than 6 percent of cases, that 22 percent of deaths were in the younger age group.
  

Why the change in the 2018 Red Book™?

More recent comparative data confirms a safety profile for doxycycline that is distinct from tetracycline, with no correlation between use and dental staining in children. The new recommendation states that doxycycline should be used for all diseases where it is the drug of choice, without regard to patient’s age as there is no risk of dental staining. This recommendation is noted in 42 disease notations with the caveat that use not be extended beyond 21 days. Antimicrobial stewardship principles continue to apply: use the right drug, for the right duration, and only when an infection is present that necessitates the use of an antibiotic.

 

Drug Patients Exposed Dental staining Reference
Chlortetracycline and oxytetracycline (long term) Cystic fibrosis 50 40 (80%) Schwachman, et al., 1958
Tetracycline (short term) Neonates 50 46 (92%) Wallman, et al., 1962
Chlortetracycline, oxytetracycline, tetracycline (long term) Cystic fibrosis
 
63 24 (38%) Conchie, et al., 1970
Mixed Children < 6 yrs, eval at 8-11 yrs 238 55 (23%) Rebich, et al., 1983
Doxycycline (short term) Asthma 31 0 (0%) Volovitz, et al., 2007
Doxycycline (short term) RMSF before 8 yrs, as many as 8 courses 58 0 (0%) Todd, et al., 2015
Doxycycline (mean 12.5 d) <8 yrs (mean 4.7 yrs) 38 0 (0%) Pöyhönen, et al., 2017