Tigecycline-Induced Tooth Discoloration in Children Younger than Eight Years

ABSTRACT

Tetracycline may cause tooth discoloration when used in young children during tooth development. Whether tigecycline, a tetracycline derivative, has either a similar adverse event or not remains unclear. We assessed the discoloration of the permanent teeth of patients <8 years old after tigecycline exposure. These patients were identified through a retrospective chart review in a Chinese children’s hospital. Those who had at least one erupted permanent tooth after tigecycline exposure were interviewed, examined, and photographed by an experienced pediatric dentist and independently assessed by another senior dentist to detect tetracycline-like tooth discoloration. We identified 101 patients who were exposed to tigecycline, 12 of whom were included. The mean daily dose of tigecycline was 2.3 mg/kg of body weight (standard deviation, 0.6), and the median duration was 12.5 days (interquartile range [IQR], 8.0 to 19.3). The median age of exposure was 5.2 years (IQR, 4.5 to 7.4), and the median age of dental examination was 9.1 years (IQR, 9.0 to 10.3). Two patients (16.7%) developed yellow discoloration: a girl having yellow discoloration with white-to-yellow opacities in the upper lateral incisors and lower incisors and a boy with a suspicious buccal yellow discoloration and enamel dysplasia in the second molars. The incidence and extent of tigecycline-associated dental adverse events remain unclear due to the small sample size and inadequate follow-up period.

INTRODUCTION

Tigecycline is a broad-spectrum antibiotic that is active against many drug-resistant organisms (1, 2). As a tetracycline derivative, it is not recommended for children under 8 years of age, given its potential for tooth discoloration (3). However, when the potential benefits outweigh the uncertain impact on tooth development, tigecycline is still used in salvage therapy for severe infections in young children (4–10).

Tetracycline-induced tooth discoloration is caused by the accumulation of a colored tetracycline-calcium orthophosphate complex in the developing tooth (11). Therefore, tetracycline use historically has been limited during pregnancy and before 8 years of age (5, 12). However, not all tetracyclines cause tooth discoloration, as almost no tooth discoloration or enamel hypoplasia is caused by doxycycline in young children (13–16). Consequently, the American Academy of Pediatrics revised the recommendation that doxycycline can be used for short- or medium-term therapy (≤21 days) regardless of age (5).

Although no published data have described the risk of tooth discoloration, tigecycline is not recommended for use during tooth development. Since tigecycline has potential activity against multidrug-resistant bacteria infections, especially on severe infections in young children (4–10), we conducted this study to investigate the incidence of tooth discoloration by a preliminary follow-up in patients <8 years old who were exposed to tigecycline.

Design.

In this study, we retrieved the electronic medical records of patients <8 years old exposed to tigecycline (Tygacil) between 1 June 2012 and 30 November 2018 at the Children's Hospital, Zhejiang University School of Medicine. Patients >5 years old by 1 June 2019 were contacted telephonically for queries regarding any permanent tooth eruption after tigecycline therapy.

Patients were recruited if they met the following inclusion criteria: (i) exposure to tigecycline at an age of <8 years; (ii) at least one permanent tooth erupted after tigecycline therapy; and (iii) able to cooperate with a dental examination. Children exposed to other tetracyclines in utero and during childhood, disorders that affect tooth development, or those exhibiting practical impediments to participation were excluded.

Dental examination.

Patients were interviewed for a dental examination and given a questionnaire. During the interview, tooth discoloration was examined by an experienced pediatric dentist and independently verified by a senior dentist via photographs. Discrepancies were discussed and assessed by the chief pediatric dentist. The shade guide of the Vita Lumin Vacuum was used for color evaluation. Dental photography was performed using mouth mirrors and a Canon EOS 700D camera (Canon, Tokyo, Japan).

The WHO Oral Health Questionnaire for Children (17) was administered to investigate oral hygiene and the exposure history to other tetracyclines.

Ethics.

This study was approved by the Ethics Committee of the Children's Hospital, Zhejiang University School of Medicine (no. 2019-IRB-023), and registered in the Chinese Clinical Trial Registry (ChiCTR 1900022469). The patients and/or their parents provided informed consent (Fig. 1).

FIG 1.

Flowchart of enrollment and dental examination.

Tigecycline was administered to 12 patients to treat severe pneumonia (n = 7), febrile neutropenia (n = 3), and abdominal infections (n = 2). It was administered at a mean daily dose of 2.3 mg/kg of body weight (standard deviation, 0.6) with a median duration of 12.5 days (interquartile range [IQR], 8.0 to 19.3). The patients were exposed to tigecycline at a median age of 5.2 years (IQR, 4.5 to 7.4) and underwent dental examination at 9.1 years (IQR, 9.0 to 10.3). The median intervals between tigecycline exposure and dental examination and the last eruption were 4.5 years (IQR, 3.6 to 5.1) and 3.9 years (IQR, 2.8 to 4.4), respectively. All patients denied having been exposed to other tetracyclines at any time.

A total of 88 permanent teeth had erupted at the time of examination, and 12 discolored teeth were identified in two children (16.7%). One was a 4-year-old girl who was administered tigecycline at 2.3 mg/kg/day for 27 days. After 4.5 years, 8 of the upper lateral incisors and lower incisors exhibited demarcated white-to-yellow opacities confined to the incisive 1/2 to 1/3 part, while the rest were yellowish (Fig. 2a). Notably, the lower left lateral incisor and canine had formed into a fused tooth. The extensive white spots of the upper incisors was not a discoloration but identified as demineralization due to poor oral hygiene. Another was a 7-year-old boy who was administered tigecycline at 2.2 mg/kg/day for 19 days. Four years after, four of his second molars erupted and exhibited suspicious buccal enamel dysplasia with yellow discoloration (Fig. 2b). As both patients showed substantial debris around their teeth before oral examination, suspicious discolorations due to demineralization were excluded.

FIG 2.

Tooth discoloration associated with tigecycline. (a) Yellowish discoloration of the upper lateral incisors and lower incisors. (b) Suspicious buccal enamel dysplasia with yellowish discoloration of second molars. Patients have given consent for the dental photographs to appear anonymously in the manuscript.

In this study, the extent of discoloration was mild. Dental events may be related to the type of tetracycline, dosage, duration, and age of exposure (5, 12–16, 18–21). Above all, the calcium-binding capacity of tetracycline partly determines the possibility of discoloration. For instance, doxycycline seldom leads to tooth discoloration due to its weak calcium-binding potency (13–16, 21–23). Similar to tetracycline, tigecycline can bind to metal ions (24, 25), but its potency has not been established. Typically, exposure to tetracyclines over a long duration, at large doses, and at a young age will lead to more distinct and severe dental events (12). The doses received by the patients were close to the recommended dosage for patients aged 8 to 11 years (1.2 mg/kg every 12 h). Only one patient was administered a high dose (4.2 mg/kg/day), but for a short duration. Both cases with discoloration experienced a long duration of tigecycline exposure for at least 19 days. However, two other patients received tigecycline for 20 and 24 days, and neither developed any discoloration.

The calcification of affected teeth followed the age of exposure. The calcification process of incisors, canines, and first molars begins after birth and ends after 4 to 5 years, whereas that of premolars and second molars begins at 2 to 3 years and ends at 7 to 9 years of age (12, 14, 15). Consistent with the age of calcification, the girl with affected anterior teeth and the boy with affected second molars were exposed to tigecycline at 4 and 7 years of age, respectively. In this study, most patients were exposed to tigecycline after the age of 4 years and underwent dental examination at 8 to 10 years (only two patients were 13 to 14 years old). Therefore, in most cases, the effect of tigecycline on the development of incisors, canines, and first molars was not observed; however, the effect on second molars could not be ruled out.

As a pilot study, some limitations should be addressed. Most importantly, the sample size was small, as tigecycline is rarely used in young children. Moreover, quite a few patients were lost to follow-up. Limited to only two cases, it was difficult to investigate potential factors linked to tigecycline-induced tooth discoloration, the incidence of which may be underestimated due to insufficient following-up periods.

Conclusions.

Our findings suggest that tigecycline causes yellow staining of permanent teeth with a moderate incidence rate, although this study still needs to be followed up until more patients complete permanent tooth development.