prryjones
29th July 2005, 09:44 PM
New Applications of Doxycycline Hyclate in Medicine and Dentistry
Mea A. Weinberg, DMD, MSD, RPh
Clinical Assistant Professor,
Professor of Periodontics,
New York University College of Dentistry
New York City
Tetracyclines are used in medicine and dentistry because of their unique properties as bacteriostatic antimicrobials.1 They function by inhibiting bacterial multiplication and growth. In addition to their antimicrobial effects, tetracyclines have anti-inflammatory properties. Another property of tetracyclines is their unexpected activity at su bantimicrobial doses. This property was discovered by Golub et al in 1983, when they administered minocycline to germ-free, diabetic rats with periodontal disease.2 The experiment resulted in a 65% to 70% reduction in collagenase activity in the gingival tissue and was associated with preventing alveolar bone loss. Subsequent studies by Golub with chemically modified tetracyclines (CMTs) helped to confirm their nonantimicrobial properties. By removing the dimethylamino group from the carbon-4 position of the "A" ring of the tetracycline molecule,3 Golub and his colleagues were able to show that tetracycline exerted a unique property that was independent of its antimicrobial effects. The CMTs showed no antimicrobial effect but rather inhibited an enzyme called collagenase, which is produced by host neutrophils (white blood cells) and structural cells (eg, fibroblasts and osteoclasts).
Collagenase is part of a family of proteinases called matrix metalloproteinases (MMPs). MMPs are involved in a number of physiological events, including tissue remodeling, and pathological processes such as periodontal disease, arthritis, atherosclerosis, diabetes, and osteoporosis. MMPs are normally under tight regulation not only at the level of gene expression but also extracellularly after secretion. Disruption of this regulation leads to pathologic breakdown of the connective tissues. Collagen is the major component of connective tissues in the body (eg, bone and soft tissue such as gingiva, eye, and skin). Collagenase is synthesized and released primarily from neutrophils in response to bacterial infection; it is responsible for breaking down collagen. Although the production of collagenase from infiltrating neutrophils is part of the natural host response to infection, in periodontal disease and other inflammatory diseases, there is an imbalance between the level of activated tissue-destroying MMPs and their endogenous inhibitors.
Early experimental studies showed that tetracyclines and CMTs effectively inhibited neutrophil-derived MMPs, and other tissue-degrading MMPs, including gelatinase and elastase. Human studies confirmed these findings. In pharmacokinetic and clinical studies, doxycycline 20 mg twice daily significantly reduced collagenase activity in the gingival crevicular fluid in adults with periodontal disease, while maintaining maximum plasma drug concentrations below the antimicrobial threshold of 1 mcg/mL.4,5 Doxycycline was selected over minocycline and tetracycline because it was found to be a more potent collagenase inhibitor.6 This discovery introduced the use of subantimicrobial dose doxycycline hyclate (SDD) in the enzyme modulation treatment of inflammatory periodontal diseases to prevent further breakdown of the bone and the gingival soft tissues.
Properties of Tetracyclines
Tetracycline and its analogues are among the most important broad-spectrum antibiotics used throughout the world today. Tetracycline was first produced in 1952 and its semisynthetic derivatives, doxycycline hyclate and minocycline HCl were produced in 1966 and 1972, respectively. All tetracyclines are bacteriostatic by inhibiting protein synthesis in bacteria. Specifically, tetracyclines enter the bacterial cell membrane and accumulate intracellularly through energy-dependent transport systems in the bacterial cell membrane. Once inside the bacterium, tetracycline may be transported out again, bind to cellular components, or be chemically modified so that efflux does not occur.7 If the drug stays inside the bacterium, it will bind to the 30s ribosomes, preventing the binding of tRNA (transfer RNA)*amino acid complex to the mRNA (messenger RNA), thereby inhibiting the growth of the pathogen. Broad-spectrum, gram-positive, and gram-negative pathogens are susceptible to tetracycline (TABLE 1).
Tetracyclines inhibit host-derived matrix metalloproteinase enzymes (eg, collagenases and other proteinases) that cause connective and bone tissue destruction through direct and indirect mechanisms.3,8 There are several types of human MMPs. Some important MMPs involved in diseases include the collagenases: MMP-1 (produced by fibroblasts), MMP-8 (produced by neutrophils), and MMP-13 (produced by bone cells).
In the inflammatory process, macrophages secrete cytokines (such as interleukin-1 [IL-1], tumor necrosis factor-alpha [TNF-alpha]) and prostaglandins that stimulate the production of MMPs from neutrophils, fibroblasts, osteoclasts, and osteoblasts. These cytokines also inhibit alveolar bone formation and enhance bone resorption.9
Tetracyclines inhibit the inflammatory process and connective tissue breakdown through multiple mechanisms. These include directly inhibiting active MMPs and inhibiting the oxidative activation of pro-MMPs; decreasing the secretion of cytokines and prostaglandin synthase; increasing proanabolic collagen production; and increasing osteoblast activity and bone formation.3 MMPs are also involved in building and repairing connective tissue and bone. In particular, fibroblast-type collagenase (MMP-1) is responsible for the normal turnover of tissues. In in-vitro studies, the concentrations of tetracyclines necessary to inhibit MMP-1 were significantly higher than those required to inhibit MMP-8.10 Moreover, MMP-1 is the least sensitive to inhibition by tetracyclines. Based on these studies and other pharmacokinetic research on the 20-mg doxycycline hyclate tablet (Periostat), the concentrations of doxycycline achieved in the plasma and gingival crevicular fluid are not sufficient to inhibit MMP-1 activity in the periodontium. This suggests that 20-mg doxycycline hyclate tablets do not have undesirable effects on normal tissue turnover in other body systems.
The anti-inflammatory effects of SDD are thought to be related to the inhibitory effects of doxycycline (both direct and indirect) on proinflammatory cytokines--namely, IL-1 and TNF-alpha.8,11,12 These proinflammatory cytokines act by stimulating the release of MMPs and prostaglandins, and they induce bone resorption.9
Because SDD was shown effective in inhibiting the MMPs associated with the progression of periodontal disease, an SDD was specifically formulated with the intent of using 20-mg tablets twice a day. This drug, which is FDA-approved to be used in dentistry as an adjunct drug to scaling and root planing (deep cleaning of the gum pockets) in chronic periodontitis, is marketed under the name Periostat (doxycycline hyclate 20-mg tablets; CollaGenex Pharmaceuticals, Inc). One chemically modified tetracycline, COL-3, is currently being evaluated in Kaposi's sarcoma (in an NIH study) and most recently in rosacea.
Rosacea is a common skin condition that is primarily an inflammatory disease. Rosacea is characterized by a persistent erythema or redness of the skin that is intensified by spicy foods and alcohol. Coexisting bacterial infection may or may not be present. This erythematous pattern is usually seen on the nose, cheeks, and forehead.
In a rosacea study completed in 2003, 40 patients were randomized to receive metronidazole (MetroLotion, Galderma) and doxycycline hyclate 20 mg tablet (Periostat) twice daily or metronidazole and placebo tablets for 12 weeks.37 Patients then discontinued the metronidazole but continued to take doxycycline hyclate 20 mg tablets or placebo for an additional four weeks. In the preliminary data analysis, patients receiving doxycycline hyclate 20 mg had significantly fewer inflammatory lesions than those on placebo (P < .05) at all time points during the study. At week 12 there was a 59% reduction in lesion count in the group receiving metronidazole and doxycycline hyclate 20 mg tablets, compared with a 34% reduction in the group receiving metronidazole and placebo. The global clinical severity score was also significantly improved in the doxycycline hyclate 20 mg group, and there was a trend towards improvement in the erythema scores. In addition, patients who were maintained on doxycycline hyclate 20 mg for an additional four weeks retained the improvements observed at 12 weeks, whereas those on placebo began to deteriorate.
In another recent study, 50 rosacea patients (manifesting all stages of disease) received monotherapy with doxycycline hyclate 20 mg tablets twice daily for eight weeks.38 Most patients had no previous history of treatment for their rosacea symptoms. Patients were evaluated at the initial visit and again between two and eight weeks for erythema, inflammatory lesions, and telangiectasias (spider veins) (FIGURES 1A & 1B). After an average of four weeks of treatment with doxycycline hyclate 20 mg, patients experienced an 80% to 100% clearing of inflammatory lesions and a 50% reduction in erythema. A decrease in the size and diameter of telangiectasias was also observed, although complete clearing was not achieved. There were no reports of GI side effects, headaches, vaginitis, or photosensitivity (including for patients who had experienced such adverse effects on antimicrobial dosages of doxycycline).
In an ongoing study, 150 patients with moderate to severe rosacea are randomized to receive doxycycline hyclate 20-mg tablets twice daily or placebo for four months.39 The primary efficacy parameters include change in total papule and pustule lesion counts and change in clinician's erythema scores from baseline.
Although doxycycline hyclate 20 mg tablets are not currently indicated for the treatment of rosacea or acne vulgaris, similarities between these diseases and periodontitis, as well as the encouraging results from studies of its use in acne and rosacea patients, have prompted FDA phase III studies involving orally administered SDD in rosacea patients.39 Ongoing and planned SDD studies include patients with blepharitis, postmenopausal osteopenia, periodontal implantitis, perioral dermatitis, and additional rosacea studies.
Adverse Events
Systemic antibiotic use is usually limited by dose-related adverse events. All drug-interactive precautions and contraindications for standard higher doses of doxycycline also apply to SDD (TABLE 3). The proposed mechanism of the interaction between oral contraceptives (synthetic estrogen and progestin combination) and some antibiotics is thought to be the reduction/elimination of gut bacteria necessary for enterohepatic recirculation of estrogens. Since SDD does not act as an antibiotic, it has no effect on gastrointestinal bacteria.18
Some common adverse events include gastrointestinal distress such as diarrhea, vomiting, and nausea. The incidence of candidiasis, and photosensitivity reactions are considered "class labeling" and are not reported in the clinical trials or by doctors.
Administration of doxycycline hyclate 20 mg with a high-fat/high-protein diet, which included dairy products, resulted in a decreased rate and extent of absorption and delayed maximum concentration. Thus, the dosing recommendations state that the drug should be taken at least one hour prior to or two hours after meals (TABLE 2).
One major disadvantage of using long-term antibiotics for the treatment of periodontal diseases, acne vulgaris, and rosacea is the development of antibiotic-resistant bacteria, whereby susceptible strains are eradicated while the resistant strains remain.20 SDD has not been linked to the emergence of antibiotic-resistant bacteria. Studies confirm that low-dose doxycycline has no effect on total anaerobic and facultative bacteria in plaque samples from patients receiving this dose regimen for up to 18 months.25
Instructions for the Pharmacist
The 20 mg dosage of doxycycline hyclate differs from other dosages of doxycycline hyclate used to treat a variety of bacterial infections. It is imperative that the pharmacist does not substitute other formulations of doxycycline, including 50-mg tablets or 50-mg tablets split in half, for the intent of cost-effectiveness. Splitting scored and unscored tablets has been documented to result in significant differences in the intended dosage.40-42 Furthermore, there are no data supporting the long-term safety of dosages of doxycycline that exceed 20 mg twice daily. Thus, patients taking higher doses may be at risk for antibiotic and bacterial resistance.
Conclusion
Pharmacologic advancements in the treatment of inflammatory and immune diseases including periodontitis, acne vulgaris, and rosacea have skewed toward host-modulation therapy rather than traditional antibiotic therapy. This new approach has not been documented to cause bacterial resistance because it uses low-enough doses of doxycycline hyclate to avoid eliciting bacterial resistance. It is directed toward inhibiting collagenase and other MMPs, which are responsible for the pathological destruction of collagen, the major component of bone and soft tissues in the body. Many clinical studies demonstrate that doxycycline hyclate 20 mg is safe and effective in the adjunctive treatment of chronic periodontitis, and one completed clinical study in acne patients show that this formulation is also safe and effective in controlling inflammatory lesions.36 Currently, clinical studies are being conducted to evaluate the effectiveness of doxycycline hyclate 20 mg tablets in the treatment of rosacea. Other studies will involve patients with blepharitis, periodontal implantitis, postmenopausal osteopenia, and perioral dermatitis.
It is important for pharmacists to realize that the indications for doxycycline hyclate 20 mg tablets are not the same as for the tetracyclines, which are used as antibiotics. Rather than acting as an antimicrobial, doxycycline hyclate 20 mg is a nonantimicrobial that is used in subantimicrobial, low-dose formulation. Thus, this product should not be substituted for a less expensive, generic doxycycline formulation (eg, either used as 50-mg or split 50-mg tablets or capsules). Currently, there is no substitute for doxycycline hyclate 20 mg tablets (Periostat), and the product should be dispensed as written on the prescription. Substitution with other formulations of doxycycline may place the patient at risk for the emergence of antibiotic and bacterial resistance. Studies have demonstrated that doxycycline hyclate 20 mg tablets can be used safely and effectively for nine to 12 months.
Mea A. Weinberg, DMD, MSD, RPh
Clinical Assistant Professor,
Professor of Periodontics,
New York University College of Dentistry
New York City
Tetracyclines are used in medicine and dentistry because of their unique properties as bacteriostatic antimicrobials.1 They function by inhibiting bacterial multiplication and growth. In addition to their antimicrobial effects, tetracyclines have anti-inflammatory properties. Another property of tetracyclines is their unexpected activity at su bantimicrobial doses. This property was discovered by Golub et al in 1983, when they administered minocycline to germ-free, diabetic rats with periodontal disease.2 The experiment resulted in a 65% to 70% reduction in collagenase activity in the gingival tissue and was associated with preventing alveolar bone loss. Subsequent studies by Golub with chemically modified tetracyclines (CMTs) helped to confirm their nonantimicrobial properties. By removing the dimethylamino group from the carbon-4 position of the "A" ring of the tetracycline molecule,3 Golub and his colleagues were able to show that tetracycline exerted a unique property that was independent of its antimicrobial effects. The CMTs showed no antimicrobial effect but rather inhibited an enzyme called collagenase, which is produced by host neutrophils (white blood cells) and structural cells (eg, fibroblasts and osteoclasts).
Collagenase is part of a family of proteinases called matrix metalloproteinases (MMPs). MMPs are involved in a number of physiological events, including tissue remodeling, and pathological processes such as periodontal disease, arthritis, atherosclerosis, diabetes, and osteoporosis. MMPs are normally under tight regulation not only at the level of gene expression but also extracellularly after secretion. Disruption of this regulation leads to pathologic breakdown of the connective tissues. Collagen is the major component of connective tissues in the body (eg, bone and soft tissue such as gingiva, eye, and skin). Collagenase is synthesized and released primarily from neutrophils in response to bacterial infection; it is responsible for breaking down collagen. Although the production of collagenase from infiltrating neutrophils is part of the natural host response to infection, in periodontal disease and other inflammatory diseases, there is an imbalance between the level of activated tissue-destroying MMPs and their endogenous inhibitors.
Early experimental studies showed that tetracyclines and CMTs effectively inhibited neutrophil-derived MMPs, and other tissue-degrading MMPs, including gelatinase and elastase. Human studies confirmed these findings. In pharmacokinetic and clinical studies, doxycycline 20 mg twice daily significantly reduced collagenase activity in the gingival crevicular fluid in adults with periodontal disease, while maintaining maximum plasma drug concentrations below the antimicrobial threshold of 1 mcg/mL.4,5 Doxycycline was selected over minocycline and tetracycline because it was found to be a more potent collagenase inhibitor.6 This discovery introduced the use of subantimicrobial dose doxycycline hyclate (SDD) in the enzyme modulation treatment of inflammatory periodontal diseases to prevent further breakdown of the bone and the gingival soft tissues.
Properties of Tetracyclines
Tetracycline and its analogues are among the most important broad-spectrum antibiotics used throughout the world today. Tetracycline was first produced in 1952 and its semisynthetic derivatives, doxycycline hyclate and minocycline HCl were produced in 1966 and 1972, respectively. All tetracyclines are bacteriostatic by inhibiting protein synthesis in bacteria. Specifically, tetracyclines enter the bacterial cell membrane and accumulate intracellularly through energy-dependent transport systems in the bacterial cell membrane. Once inside the bacterium, tetracycline may be transported out again, bind to cellular components, or be chemically modified so that efflux does not occur.7 If the drug stays inside the bacterium, it will bind to the 30s ribosomes, preventing the binding of tRNA (transfer RNA)*amino acid complex to the mRNA (messenger RNA), thereby inhibiting the growth of the pathogen. Broad-spectrum, gram-positive, and gram-negative pathogens are susceptible to tetracycline (TABLE 1).
Tetracyclines inhibit host-derived matrix metalloproteinase enzymes (eg, collagenases and other proteinases) that cause connective and bone tissue destruction through direct and indirect mechanisms.3,8 There are several types of human MMPs. Some important MMPs involved in diseases include the collagenases: MMP-1 (produced by fibroblasts), MMP-8 (produced by neutrophils), and MMP-13 (produced by bone cells).
In the inflammatory process, macrophages secrete cytokines (such as interleukin-1 [IL-1], tumor necrosis factor-alpha [TNF-alpha]) and prostaglandins that stimulate the production of MMPs from neutrophils, fibroblasts, osteoclasts, and osteoblasts. These cytokines also inhibit alveolar bone formation and enhance bone resorption.9
Tetracyclines inhibit the inflammatory process and connective tissue breakdown through multiple mechanisms. These include directly inhibiting active MMPs and inhibiting the oxidative activation of pro-MMPs; decreasing the secretion of cytokines and prostaglandin synthase; increasing proanabolic collagen production; and increasing osteoblast activity and bone formation.3 MMPs are also involved in building and repairing connective tissue and bone. In particular, fibroblast-type collagenase (MMP-1) is responsible for the normal turnover of tissues. In in-vitro studies, the concentrations of tetracyclines necessary to inhibit MMP-1 were significantly higher than those required to inhibit MMP-8.10 Moreover, MMP-1 is the least sensitive to inhibition by tetracyclines. Based on these studies and other pharmacokinetic research on the 20-mg doxycycline hyclate tablet (Periostat), the concentrations of doxycycline achieved in the plasma and gingival crevicular fluid are not sufficient to inhibit MMP-1 activity in the periodontium. This suggests that 20-mg doxycycline hyclate tablets do not have undesirable effects on normal tissue turnover in other body systems.
The anti-inflammatory effects of SDD are thought to be related to the inhibitory effects of doxycycline (both direct and indirect) on proinflammatory cytokines--namely, IL-1 and TNF-alpha.8,11,12 These proinflammatory cytokines act by stimulating the release of MMPs and prostaglandins, and they induce bone resorption.9
Because SDD was shown effective in inhibiting the MMPs associated with the progression of periodontal disease, an SDD was specifically formulated with the intent of using 20-mg tablets twice a day. This drug, which is FDA-approved to be used in dentistry as an adjunct drug to scaling and root planing (deep cleaning of the gum pockets) in chronic periodontitis, is marketed under the name Periostat (doxycycline hyclate 20-mg tablets; CollaGenex Pharmaceuticals, Inc). One chemically modified tetracycline, COL-3, is currently being evaluated in Kaposi's sarcoma (in an NIH study) and most recently in rosacea.
Rosacea is a common skin condition that is primarily an inflammatory disease. Rosacea is characterized by a persistent erythema or redness of the skin that is intensified by spicy foods and alcohol. Coexisting bacterial infection may or may not be present. This erythematous pattern is usually seen on the nose, cheeks, and forehead.
In a rosacea study completed in 2003, 40 patients were randomized to receive metronidazole (MetroLotion, Galderma) and doxycycline hyclate 20 mg tablet (Periostat) twice daily or metronidazole and placebo tablets for 12 weeks.37 Patients then discontinued the metronidazole but continued to take doxycycline hyclate 20 mg tablets or placebo for an additional four weeks. In the preliminary data analysis, patients receiving doxycycline hyclate 20 mg had significantly fewer inflammatory lesions than those on placebo (P < .05) at all time points during the study. At week 12 there was a 59% reduction in lesion count in the group receiving metronidazole and doxycycline hyclate 20 mg tablets, compared with a 34% reduction in the group receiving metronidazole and placebo. The global clinical severity score was also significantly improved in the doxycycline hyclate 20 mg group, and there was a trend towards improvement in the erythema scores. In addition, patients who were maintained on doxycycline hyclate 20 mg for an additional four weeks retained the improvements observed at 12 weeks, whereas those on placebo began to deteriorate.
In another recent study, 50 rosacea patients (manifesting all stages of disease) received monotherapy with doxycycline hyclate 20 mg tablets twice daily for eight weeks.38 Most patients had no previous history of treatment for their rosacea symptoms. Patients were evaluated at the initial visit and again between two and eight weeks for erythema, inflammatory lesions, and telangiectasias (spider veins) (FIGURES 1A & 1B). After an average of four weeks of treatment with doxycycline hyclate 20 mg, patients experienced an 80% to 100% clearing of inflammatory lesions and a 50% reduction in erythema. A decrease in the size and diameter of telangiectasias was also observed, although complete clearing was not achieved. There were no reports of GI side effects, headaches, vaginitis, or photosensitivity (including for patients who had experienced such adverse effects on antimicrobial dosages of doxycycline).
In an ongoing study, 150 patients with moderate to severe rosacea are randomized to receive doxycycline hyclate 20-mg tablets twice daily or placebo for four months.39 The primary efficacy parameters include change in total papule and pustule lesion counts and change in clinician's erythema scores from baseline.
Although doxycycline hyclate 20 mg tablets are not currently indicated for the treatment of rosacea or acne vulgaris, similarities between these diseases and periodontitis, as well as the encouraging results from studies of its use in acne and rosacea patients, have prompted FDA phase III studies involving orally administered SDD in rosacea patients.39 Ongoing and planned SDD studies include patients with blepharitis, postmenopausal osteopenia, periodontal implantitis, perioral dermatitis, and additional rosacea studies.
Adverse Events
Systemic antibiotic use is usually limited by dose-related adverse events. All drug-interactive precautions and contraindications for standard higher doses of doxycycline also apply to SDD (TABLE 3). The proposed mechanism of the interaction between oral contraceptives (synthetic estrogen and progestin combination) and some antibiotics is thought to be the reduction/elimination of gut bacteria necessary for enterohepatic recirculation of estrogens. Since SDD does not act as an antibiotic, it has no effect on gastrointestinal bacteria.18
Some common adverse events include gastrointestinal distress such as diarrhea, vomiting, and nausea. The incidence of candidiasis, and photosensitivity reactions are considered "class labeling" and are not reported in the clinical trials or by doctors.
Administration of doxycycline hyclate 20 mg with a high-fat/high-protein diet, which included dairy products, resulted in a decreased rate and extent of absorption and delayed maximum concentration. Thus, the dosing recommendations state that the drug should be taken at least one hour prior to or two hours after meals (TABLE 2).
One major disadvantage of using long-term antibiotics for the treatment of periodontal diseases, acne vulgaris, and rosacea is the development of antibiotic-resistant bacteria, whereby susceptible strains are eradicated while the resistant strains remain.20 SDD has not been linked to the emergence of antibiotic-resistant bacteria. Studies confirm that low-dose doxycycline has no effect on total anaerobic and facultative bacteria in plaque samples from patients receiving this dose regimen for up to 18 months.25
Instructions for the Pharmacist
The 20 mg dosage of doxycycline hyclate differs from other dosages of doxycycline hyclate used to treat a variety of bacterial infections. It is imperative that the pharmacist does not substitute other formulations of doxycycline, including 50-mg tablets or 50-mg tablets split in half, for the intent of cost-effectiveness. Splitting scored and unscored tablets has been documented to result in significant differences in the intended dosage.40-42 Furthermore, there are no data supporting the long-term safety of dosages of doxycycline that exceed 20 mg twice daily. Thus, patients taking higher doses may be at risk for antibiotic and bacterial resistance.
Conclusion
Pharmacologic advancements in the treatment of inflammatory and immune diseases including periodontitis, acne vulgaris, and rosacea have skewed toward host-modulation therapy rather than traditional antibiotic therapy. This new approach has not been documented to cause bacterial resistance because it uses low-enough doses of doxycycline hyclate to avoid eliciting bacterial resistance. It is directed toward inhibiting collagenase and other MMPs, which are responsible for the pathological destruction of collagen, the major component of bone and soft tissues in the body. Many clinical studies demonstrate that doxycycline hyclate 20 mg is safe and effective in the adjunctive treatment of chronic periodontitis, and one completed clinical study in acne patients show that this formulation is also safe and effective in controlling inflammatory lesions.36 Currently, clinical studies are being conducted to evaluate the effectiveness of doxycycline hyclate 20 mg tablets in the treatment of rosacea. Other studies will involve patients with blepharitis, periodontal implantitis, postmenopausal osteopenia, and perioral dermatitis.
It is important for pharmacists to realize that the indications for doxycycline hyclate 20 mg tablets are not the same as for the tetracyclines, which are used as antibiotics. Rather than acting as an antimicrobial, doxycycline hyclate 20 mg is a nonantimicrobial that is used in subantimicrobial, low-dose formulation. Thus, this product should not be substituted for a less expensive, generic doxycycline formulation (eg, either used as 50-mg or split 50-mg tablets or capsules). Currently, there is no substitute for doxycycline hyclate 20 mg tablets (Periostat), and the product should be dispensed as written on the prescription. Substitution with other formulations of doxycycline may place the patient at risk for the emergence of antibiotic and bacterial resistance. Studies have demonstrated that doxycycline hyclate 20 mg tablets can be used safely and effectively for nine to 12 months.