US Pharm. 2019;44(5):HS2-HS7.
ABSTRACT: Doxycycline is recommended for up to 60 days in the management of anthrax in children. Because tetracycline is associated with tooth staining in children under 8 years old, doxycycline is also avoided in this age group. The incidence of tooth staining from doxycycline use in children was reviewed. A literature search was performed to identify English-language studies in children younger than 8 years old. Five studies that fit the inclusion criteria investigated 161 children aged 4 days to 7.9 years who were treated with doxycycline for approximately 10 days. One case of tooth staining was documented; otherwise, tooth staining occurred equally in matched control groups. The rare incidence of tooth staining with doxycycline use in pediatric patients is encouraging.
Bioterrorism has grown to become a significant threat to the public. In 2001 in the United States, 22 cases of anthrax were identified, five of which were fatal. Powdered anthrax spores were placed in letters that were mailed through the U.S. postal system.1 This occurrence led to heightened awareness of the need to be prepared in case of a repeat incident. One of the concerns of an outbreak is the required therapy in special populations. In particular, pediatric patients are faced with barriers because some lifesaving antibiotics, such as doxycycline, have warnings against use in this patient population. This article chronicles a literature review that was undertaken in order to analyze the safety of doxycycline use in pediatric patients and determine doxycycline’s role in tooth staining in pediatric patients under 8 years of age.
Bacillus anthracis is a gram-positive, rod-shaped bacterium that causes anthrax, which can result in a life-threatening infection. Bacterial spores remain dormant in the environment for a prolonged period of time until entering a human or animal host, at which point they are activated and begin to grow. Incubation ranges from 1 to 43 days. Active cells multiply, spread, and produce toxins that result in severe illness.1 Exposure can occur via the cutaneous, gastrointestinal, and inhalational routes. Inhalational exposure is associated with the highest mortality rate.1,2
Pharmacotherapy of B anthracis Infection
According to the CDC and the American Academy of Pediatrics’ 2014 guideline, antibiotics such as ciprofloxacin, doxycycline, and penicillin are the mainstays of treatment and prophylaxis for infection that is caused by B anthracis. Although the guideline notes that doxycycline therapy for 10 to 14 days is not expected to cause tooth staining, postexposure prophylaxis is recommended with antibiotics for a minimum of 60 days. Owing to the risk of beta-lactamase–induced resistance, the preferred antibiotic for the first 10 days of postexposure therapy is ciprofloxacin or doxycycline. Antibiotic therapy may be continued or changed for the remaining 50 days of postexposure therapy based on susceptibility testing. For strains that are sensitive to penicillin, amoxicillin is safe in pediatric patients and is preferred; however, penicillin VK may be used.3 Alternatives include clindamycin and levofloxacin, depending on medication availability. In addition, a vaccine is available for exposed adults and children older than 6 months, promoting immunogenicity to B anthracis and providing protection against symptomatic infection.3
For cutaneous anthrax cases in which the infection is localized and uncomplicated, initial treatment with doxycycline or ciprofloxacin is recommended on an outpatient basis for 7 to 10 days pending susceptibility results. Patients should be monitored for signs and symptoms of systemic involvement, which necessitates hospitalization and IV antibiotic therapy.3 Systemic exposure through the inhalational or gastrointestinal route requires hospitalization and treatment with two IV bactericidal agents in addition to a protein synthesis inhibitor—one of which is doxycycline—for 14 days or longer, until the patient is clinically stable. After treatment of the acute infection, postexposure prophylaxis is indicated for a total of 60 days from exposure in all patients whose exposure was cutaneous, inhalational, or gastrointestinal, as outlined previously.
Providers are hesitant to prescribe doxycycline in pediatric patients because of the potential tooth-staining effects associated with the tetracycline class in children.4 Tetracycline readily binds to calcium, which can lead to permanent yellow, gray, and brown staining of developing teeth if administered during tooth crown calcification.4 This event is dose- and duration-dependent and most commonly occurs between birth and 8 years for most permanent teeth except third molars.4 Although only tetracycline was proven to be the offender, as a precaution, the entire class of antibiotics was issued a warning about use in children under 8 years old. Compared with tetracycline, doxycycline binds less readily to calcium (19% for doxycycline vs. 39.5% for tetracycline), which led to the hypothesis that tooth staining may not be a deterrent to using this particular medication in young children.5
Literature Review of Doxycycline and Tooth Staining in Children
A PubMed and Embase literature search was conducted using the terms “child,” “doxycycline,” and “staining.” This search identified five studies that examined dental staining and doxycycline use in children exposed to the drug before the age of 8 years. None of these studies evaluated children who were treated for anthrax.
Forti and Benincori: The researchers described 25 premature neonates who received doxycycline in their first 4 to 55 days of life. Dosing was 2 mg/kg/day for the first day followed by 1 mg/kg/day for a duration of 6 to 17 days. Teeth examinations, which were conducted 1 year after treatment, involved direct observation and fluorescence using Wood’s light. One child developed discoloration of the upper incisors. Data were not provided on gestational age at exposure or on the number of teeth that had erupted by the time of examination.5
Lochary and Colleagues: This retrospective study evaluated tooth staining and doxycycline use in children with Rocky Mountain spotted fever. Age at exposure ranged from 4 years, 4 months to 8 years, 3 months. The dosage was 30 mg to 200 mg divided into twice-daily administration for 7 to 10 days, except in three patients for whom duration of exposure was not reported; for one subject, no dosing or duration information was available. Each subject was compared with a control subject matched for age, dental development, and fluoride exposure. Five dentists blinded to exposure evaluated photographs of the teeth, with one to four teeth examined. Staining was rated on a scale of 0 (normal) to 3 (severe discoloration). It was concluded that the difference in discoloration between exposed subjects and controls was not significant; however, results were mixed. Four exposed subjects and three controls had discoloration, and three exposed subjects had no difference in color scores versus controls. In 47 teeth (63%) there was a 1-point difference in color grading, and in 17 teeth (23%) there was a 2-point difference. Limitations of this study include examination of a limited number of teeth, lack of knowledge of oral or dental hygiene, and absence of weight-based dosing.6
Volovitz and Colleagues: A randomized, controlled, blinded study was conducted in a pediatric outpatient asthma clinic that used doxycycline to treat atypical pneumonia. Sixty-one children exposed to doxycycline before 8 years of age who had completed a 10-day treatment course were included (30 doxycycline patients and 31 matched controls). Children were first exposed to doxycycline at a mean age of 4.1 ± 1.6 years (2-7.7 years) and were examined at a mean of 6.3 ± 1.6 years after the first course (2-12 years). Children received an average of two courses of doxycycline, with a maximum of four courses administered in four children. Doxycycline syrup was used at a dosage of 4 mg/kg twice daily on day 1, followed by 2 mg/kg/day on days 2 through 10. Dental care, hygiene, and consumption of dark-colored beverages were statistically similar between groups; however, there was a trend toward poor oral hygiene in the doxycycline group versus controls (24% vs. 16.6%, respectively). Examinations, which were carried out by dentists who were blinded to treatment groups, involved visual inspection, a dental light unit, and a dental explorer. Tooth discoloration was graded from 1 to 16 for white to gray coloration using a Lumin Vacuum shade guide. There was no significant difference in tooth discoloration in children exposed to doxycycline; 72% versus 80% of children in the doxycycline and placebo groups, respectively, had a darker (grade 6-11) shade (not significant [NS]; P = .53).7
Todd and Colleagues: In this retrospective cohort study, 58 children on an American Indian reservation received doxycycline at a dosage of 2.3 mg/kg (range 0.3 mg/kg-2.9 mg/kg) twice daily for 0.5 to 10 days for treatment of Rocky Mountain spotted fever. Patients had a mean age of 4.5 years (range, 2 months-7.9 years), and doxycycline was administered during the tooth-calcification period. Some patients were exposed to multiple courses of doxycycline, with an average of 1.8 courses per patient. Controls were 213 children who never received doxycycline and were an average of 2 years older than the doxycycline group. Five licensed dentists blinded to exposure examined all children using the VITA Easyshade Compact instrument and a grading scale of tooth shades ranging from 1 to 16. There was no significant difference in tooth discoloration, fluorosis, or enamel hypoplasia between groups. Tooth shades tended to be slightly darker in the doxycycline group, with an average of 9.5 (range, 3-16) versus 9 (range, 2.1-15) in the unexposed group (NS; P = .20). No significant differences were observed in children who brushed their teeth or in those who consumed dark-colored drinks or used tobacco. Strengths of this study included an objective evaluation method for tooth staining and controlling for dental hygiene and consumption of potentially staining liquids. However, results are limited to short durations of doxycycline exposure.8
Pöyhönen and Colleagues: This retrospective cohort study performed between 1994 and 2015 involved 38 children who received doxycycline for a suspected or confirmed central nervous system infection. Average age at doxycycline exposure was 4.7 years (range, 0.6-7.9 years), length of treatment was 12.5 days (range, 2-28 days), and mean age at dental examination was 14.2 years (8.3-22.6 years). One subject received two courses of doxycycline; the remaining subjects received one course. The average loading dose was 10 mg/kg/day (8-10 mg/kg/day) for the first 2 or 3 days, followed by an average of 5 mg/kg/day (2.5-10 mg/kg/day) administered once or twice daily (orally and/or IV). For examination of subjects’ teeth, two independent pediatric dentists assessed photographs of five perspectives of the teeth. Tetracycline-like discoloration or enamel hypoplasia was not found in the teeth of any subject, and it was concluded that doxycycline does not cause staining of permanent teeth in children. This study differs from others in its evaluation of various routes of administration and its use of slightly higher doses, and its strengths are the concordance between dentists on the findings and adequate documentation of doxycycline dosage. Information was not provided on subjects’ dental hygiene or socioeconomic class. The investigators noted that only visible effects of teeth were observed and that only two children were exposed to doxycycline before the age of 1 year. Since only one subject received more than one course of doxycycline, it is difficult to draw a conclusion about the effect of prolonged or multiple courses on tooth staining.9
Boast and Colleagues: This expert opinion paper concluded that there is no risk of tooth staining in children younger than 8 years who receive short courses of doxycycline for up to 10 days. However, further studies are required on adverse effects of longer courses or doses exceeding 5.8 mg/kg/day.10
Discussion
In summary, existing data reported on a total of 161 children exposed to doxycycline at age 4 days to 7.9 years. Maintenance weight-based doses were 1 to 10 mg/kg/day, with most children receiving the drug for 10 days. There were just two instances of longer therapy (17 and 28 days, respectively). Most children received one to two courses of doxycycline prior to 8 years of age. In most cases, doxycycline was administered orally. To date, only one case of tooth discoloration has been documented in an infant. Interestingly, similar rates of darkened tooth shades were reported in the doxycycline and control groups in three studies, with one case series showing slightly darker tooth-color shades in the doxycycline group; however, no results were statistically significant.6-8 Each study employed a different methodology for tooth evaluation, which limits generalization of the results. The treatment lengths in these studies were very short compared with the expected time frame for anthrax management, in which treatment length ranges from 10 days to 60 days for prophylaxis. None of these studies matched this exposure period, and the number of doxycycline courses was limited.
Conclusion
It is reassuring that in the literature to date, only one case of tooth staining in children younger than 8 years was directly related to doxycycline. In these studies, therapy duration was typically 10 days; however, in the management of anthrax, doxycycline therapy may extend to 60 days. In case of an emergency, such as anthrax exposure, children younger than 8 years who receive doxycycline must be monitored closely, and prolonged exposure of more than 10 days should be avoided if possible. Based on susceptibility testing, alternative therapies such as amoxicillin, which is effective against B anthracis and is safe in pediatric patients, should be considered. Should an emergency dictate the use of more than 10 days of doxycycline, a dentist trained to evaluate teeth staining should perform a meticulous tooth assessment using a standardized method for evaluating tooth darkening and enamel hypoplasia and document the children’s dental hygiene. Obtaining such data may shed greater light on the safety of doxycycline relative to discoloration of teeth in children exposed to the drug before the age of 8 years.
REFERENCES
1. CDC. Anthrax. www.cdc.gov/anthrax. Accessed April 5, 2019.
2. American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.
3. Bradley JS, Peacock G, Krug SE, et al. Pediatric anthrax clinical management. Pediatrics. 2014;133(5):e1411-e1436.
4. Wallman IS, Hilton HB. Teeth pigmented by tetracycline. Lancet. 1962;1(7234):827-829.
5. Forti G, Benincori C. Doxycycline and the teeth. Lancet. 1969;1(7598):782.
6. Lochary ME, Lockhart PB, Williams WT Jr. Doxycycline and staining of permanent teeth. Pediatr Infect Dis J. 1998;17(5):429-431.
7. Volovitz B, Shkap R, Amir J, et al. Absence of tooth staining with doxycycline treatment in young children. Clin Pediatr (Phila). 2007;46(2):121-126.
8. Todd SR, Dahlgren FS, Traeger MS, et al. No visible dental staining in children treated with doxycycline for suspected Rocky Mountain Spotted Fever. J Pediatr. 2015;166(5):1246-1251.
9. Pöyhönen H, Nurmi M, Peltola V, et al. Dental staining after doxycycline use in children. J Antimicrob Chemother. 2017;72(10):2887-2890.
10. Boast A, Curtis N, Gwee A. Question 1: teething issues: can doxycycline be safely used in young children? Arch Dis Child. 2016;101(8):772-774.
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