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Systemic Antibiotics and Tooth Loss in Periodontal Disease
1 University of Washington, Dental Public Health Sciences, B509, 1959 NE Pacific Street, Box 357475, Seattle, WA 98195-7475, USA; Correspondence: * corresponding author, silvajcc{at}u.washington.edu
Systemic antibiotics have been recommended for the treatment of destructive periodontal disease. Our goal was to relate antibiotic use for medical or dental reasons to subsequent tooth loss in a cohort of 12,631 persons with destructive periodontal disease. After adjustment for age, smoking, and other confounders, the dispensing of antibiotics for 1–13 days, 14–20 days, or 21 or more days was not associated with reduced tooth loss [Adjusted rate ratio (RR) = 1.0; 95% Confidence Interval (CI) = 0.8–1.1; RR = 1.2; 95% CI = 0.9–1.4, and RR =1.2, 95% CI =1.0–1.3, respectively]. Numerous subgroup analyses were consistent with these overall null findings, with two exceptions: Longer courses of tetracyclines were associated with reduced tooth loss among persons receiving periodontal care, and penicillin was associated with reduced tooth loss among persons with more severe disease. Long-term, larger randomized trials are needed to provide evidence that antibiotics reduce tooth loss when used in the management of destructive periodontal disease.
Key Words: antimicrobials • systemic antibiotics • tooth loss • cohort study
The hypothesis that destructive periodontal disease is an infection has prompted extensive research on identifying causative micro-organisms and the potential role of antimicrobials and antibiotics to improve outcomes by reducing putative pathogens in the oral flora and modulating the host response to inflammation. Several classes of antibiotics have been evaluated in clinical studies, and systematic reviews have indicated that systemic antibiotics for the treatment of destructive periodontal disease resulted in short-term improvements in clinical attachment and probing levels (Herrera et al., 2002; Haffajee et al., 2003). No studies have been identified reporting on the effects of systemic antimicrobials on true endpoints, such as tooth loss (Herrera et al., 2002). The aim of this study is to examine the association between systemic antibiotic use and the incidence of tooth loss.
Design and Data Sources We conducted a retrospective cohort study of 12,631 Health Maintenance Organization (HMO) members with destructive periodontal disease, 45 to 61 yrs old in 1999, who had complete medical, dental, and prescription drug coverage between 1996 and 2002. The participants had been diagnosed with early, moderate, or advanced chronic periodontal disease by a general dentist or a periodontist during 1999–2002. The study protocol was approved by the institutional review boards of the two research organizations involved in the study.
Outcome: Tooth Loss
Main Exposure: Antibiotic Use
Alternative Definitions of Antibiotic Use
Statistical Analyses
We performed subgroup analyses of the primary definitions of antibiotic use by restricting the analyses to participants undergoing periodontal treatment during the first three-year period, participants with moderate to advanced periodontal disease, and participants classified as active smokers. We tested interactions between these variables and antibiotic use by comparing the likelihood ratios of models with and without the interaction terms (Type 3 analysis in proc genmod). All reported p-values are based on two-sided tests. Analyses were performed with StataSE, version 8 and SAS, version 9.1 software.
Of the 12,631 participants, 3643 (29%) did not fill any antibiotic prescription during the first 3 yrs of the study; 2858 (23%) filled prescriptions for 1–13 days; 1633 (13%) for 14–20 days; and 4497 (36%) for 21 or more days (Table 1  ).
Primary Measures of Antibiotic Use
Before adjustment, tetracyclines were associated with a 20% reduced tooth loss rate (95%CI = 0.6–1.0). After adjustment for potential confounding factors, penicillin, metronidazole, tetracyclines, and macrolides used during the first 3 yrs were not associated with subsequent tooth loss. Relative to no clindamycin use, 1–13 days on clindamycin was associated with a 70% increased risk of tooth loss (95% CI = 1.3, 2.2), and a linear trend for increased tooth loss rate was observed (p < 0.05) (Table 3  ).
Subgroup Analyses of the Primary Measures of Antibiotic Use When analyses were restricted to participants undergoing periodontal treatment, any antibiotic use was not associated with decreased tooth loss rate, nor were the specific classes penicillins, clindamycin, metronidazole, and macrolides. At least 21 days of tetracyclines was associated with a 60% decreased tooth loss risk (RR = 0.4; 95%CI = 0.3–0.7), and a linear trend was present (p < 0.05). No interactions were observed between antibiotics and periodontal treatment, except for tetracyclines (p < 0.05) (Table 4 ).
When analyses were restricted to participants with moderate or advanced periodontal disease, both 21+ days of antibiotics and 21+ days of penicillins were associated with a 20% decreased tooth loss rate (95%CI = 0.7–1.0 and 0.6–1.0, respectively), after adjustment for confounding. Other specific classes were not associated with tooth loss among participants with moderate or advanced periodontal disease. Interactions between periodontal status and antibiotics were statistically significant for any antibiotics, penicillins, clindamycin, and macrolides (p < 0.05) (Table 4 ).
No consistent associations of antibiotic use and tooth loss were observed for active smokers, and interactions between smoking and antibiotics were not found (Table 4
Alternative Measures of Antibiotic Use
We found no evidence in this cohort study that systemic antibiotics prescribed for medical or dental reasons were associated with a decreased tooth loss rate. Evaluation of specific antibiotic classes, such as tetracycline, metronidazole, and macrolide, similarly did not show consistent patterns for reduced tooth loss. The effects of antibiotics on tooth loss were further evaluated in groups of persons considered to be at higher risk of tooth loss. Individuals receiving periodontal treatments, individuals with more severe destructive periodontal disease, and smokers did not have a lower tooth loss rate associated with antibiotic use, except for lower tooth loss rates associated with tetracycline use among persons undergoing periodontal treatment during baseline and penicillin use among participants with moderate or advanced destructive periodontal disease. Our findings on tooth loss conflict to some extent with the observed short-term benefits on pocket depth. The lack of a beneficial effect of antibiotics on tooth loss may be due to several reasons. Possibly, a higher tooth loss incidence among participants using antibiotics may have resulted from antibiotic use to treat acute dental conditions, such as periapical and periodontal abscesses (Newman et al., 2001) related to teeth requiring extraction. Participants receiving antibiotics might have differed from those not receiving antibiotics in ways not captured by the information available in this study. For example, we did not have information on socio-economic status (SES); this shortcoming may have confounded the association between antibiotics and tooth loss, since antibiotics may be prescribed more often to low-SES patients—a group already at increased risk of tooth loss. Or antibiotics may have truly no association with, or a slight adverse effect on, tooth loss. A large proportion of destructive periodontal disease cases may have a non-infectious etiology, and antibiotics would therefore show little effect when used in a non-targeted fashion (Bergström, 2004). Alternatively, the elimination of susceptible oral micro-organisms may disturb the normal commensal flora and allow pathogenic oral bacteria to proliferate (Whitney et al., 2000; Tlaskalova-Hogenova et al., 2004; Loo et al., 2005). Baseline dental characteristics of the participants were strongly associated with tooth loss incidence, which can be observed in the rate ratios and differences of periodontal status and tooth loss during baseline. Factors such as diabetes, smoking, and caries treatment had a stronger association with tooth loss than did antibiotics. Overall, classes of antibiotics varied somewhat in their association with tooth loss. Tetracyclines and metronidazole were not associated with lower adjusted tooth loss rates. These antibiotic classes are frequently recommended as adjunctive periodontal therapy, due to reported reductions in the need for surgery and extraction (Loesche et al., 2002) and improvements in surrogate endpoints (Haffajee et al., 1995; Berglundh et al., 1998; Sigusch et al., 2001; Rooney et al., 2002; Rodrigues et al., 2004; Ehmke et al., 2005; Mombelli et al., 2005). Macrolides and penicillins were not associated with tooth loss, and clindamycin was associated with higher tooth loss incidence. These antibiotic classes are frequently used to treat acute dental conditions that might reflect unsalvageable teeth (Newman et al., 2001). Given that dentists’ prescriptions of antibiotics to treat chronic dental conditions vary greatly (Lewis et al., 1989; Palmer et al., 2000), and that evidence for specific antibiotic regimens is lacking (Loesche, 1999), we evaluated antibiotic usage in different ways. We searched for dose-response relationships, effects of repeated courses of antibiotics across time, and both short-term (one year later) and longer-term (up to 4 yrs later) effects of antibiotic use on tooth loss. In addition, several other representations of antibiotic usage, such as antibiotic duration (continuous variable), were tested. None of these analyses provided convincing evidence of a lower incidence of tooth loss among persons receiving antibiotics. When evaluating high-risk subgroups of the population, we observed similar trends, except in two circumstances. Antibiotic therapy has been recommended as a dental treatment for persons at increased risk of dental diseases (Herrera et al., 2002), as an adjunct to conventional periodontal therapy (Haffajee et al., 2003), and for smokers, because the response to conventional periodontal therapy may be compromised in these persons (Palmer et al., 1999). However, tooth loss rates of participants who received or did not receive antibiotic prescriptions within each of these three subgroups were not appreciably different. The two exceptions were for longer courses of tetracyclines among persons receiving periodontal treatment and longer courses of penicillins among participants with moderate or advanced destructive periodontal disease being associated with lower tooth loss rates. The finding regarding tetracyclines is noteworthy, due to both the strength of the association and the evidence on non-antibiotic host-modulating properties of this class (Ingman et al., 1993). Independent confirmation of these findings in another cohort would provide a clearer picture of whether our observations were spurious or reflected real trends. Strengths of the present study include the sample size, long-term follow-up, the ability to control for diabetes and smoking status, and the availability of comprehensive pharmacy and dental treatment information. Limitations of this study include the exclusion of subjects younger than 45 years old and the lack of information on important risk factors, such as the number of teeth at risk and the indication for the antibiotic prescriptions. This study could not assess the impact of antibiotics, such as metronidazole, in younger destructive periodontal disease patients who present with suppuration and other signs of clinical inflammation. Similarly, some have advocated that specific diagnostic testing should be done on persons with destructive periodontal disease to determine the need for antibiotics, and that antibiotics should be prescribed only to those individuals in whom a specific periodontal infection is diagnosed (Loesche et al., 1992, 1996). With no data on diagnosis or reason for antibiotic prescription, we cannot assess whether such a targeted strategy might be effective. In summary, systemic antibiotic use was not associated with a lower incidence of tooth loss. It is possible that our inability to identify a beneficial effect was due to a variety of biases, including confounding, selection biases, and misclassification biases. Participants treated with antibiotics may have had different numbers of teeth present at the start of this study, may have had different disease conditions, or may have had other risk factors present that actually caused their teeth to be lost more often than those participants not treated with antibiotics. Further epidemiological studies should explore the consistency of our findings, and if consistent trends emerge with respect to specific classes of antibiotics and specific risk groups, a long-term large randomized clinical trial should be planned. Meanwhile, our findings of lack of association between antibiotics and tooth loss and the growing concerns about antibiotic resistance reinforce that prescription of antibiotics for chronic destructive periodontal diseases should be made with caution.
This investigation was supported by Research Grants R21 DE015619 and R01 DE13192 from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. Received for publication May 15, 2006. Revision received February 4, 2008. Accepted for publication May 29, 2008.
Journal of Dental Research, Vol. 87, No. 9,
871-876 (2008)
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