General Information: Doxycycline is a tetracycline derived from oxytetracycline. It is classified as a long-acting tetracycline, although this classification scheme is somewhat artificial since tetracycline (classified as short-acting) can be dosed at longer intervals than usually occurs in clinical practice. While once daily dosing is an advantage for doxycycline, adverse reactions were less for minocycline when these two agents were compared in the treatment of urethritis and cervicitis.1 Nevertheless, doxycycline is one of the most frequently prescribed tetracyclines. Doxycycline, along with minocycline, can be administered without regard to meals, although some cations can still significantly reduce oral bioavailability. Clinically, doxycycline can be used to treat non-gonococcal urethritis and cervicitis, exacerbations of bronchitis in patients with COPD 2, and acne vulgaris. Doxycycline is considered the tetracycline of choice in patients with poor renal function due to its limited renal clearance. The Centers for Disease Control have suggested doxycycline be considered as an alternative to ciprofloxacin for the treatment of anthrax. Doxycycline was originally approved by the FDA in 1967. Atridox, a subgingival controlled-release product, was approved September 4, 1998 for the treatment of chronic adult periodontitis. Periostat capsules were approved by the FDA in October 1998 as adjunct to scaling and root planing for the treatment of adult periodontitis; Periostat tablets were approved February 2001 for the same indication. Doryx, a delayed-release enteric-coated oral formulation, was FDA approved in May 2005. A dual-release capsule (Oracea), containing immediate- and delayed-release beads, was approved May 2006 for treating inflammatory lesions (papules and pustules) of rosacea in adults.
Mechanism of Action: Doxycycline is generally bacteriostatic against a wide variety of organisms, both gram-positive and gram-negative. In gram-negative bacteria, transportation of the drug into the cell occurs either by passive diffusion or through an energy-dependent active transport system. The latter system is also believed to exist in gram-positive bacteria. Doxycycline and minocycline are more lipophilic than the other tetracyclines, which allows them to pass easily through the lipid bilayer of bacteria where reversible binding to the 30S ribosomal subunits occurs. Binding of doxycycline blocks the binding of aminoacyl transfer RNA (tRNA) to the messenger RNA (mRNA). Bacterial protein synthesis is inhibited, which ultimately accounts for the antibacterial action. High concentrations of antibiotic also can interfere with protein synthesis in mammalian cells, but these cells lack the active transport systems found in bacteria.345
Tetracycline resistance occurs via efflux, alterations in binding to the ribosome via ribosomal protection proteins, and decreased permeability. Tetracycline resistance in community-acquired MRSA (CA-MRSA) isolates is primarily associated with the tetK gene. The tetM resistance gene confers resistance to the entire class; however, the tetK gene confers resistance to tetracycline and an inducible resistance to doxycycline, but has no impact on minocycline susceptibility.3678
The susceptibility interpretive criteria for doxycycline are delineated by pathogen. The MICs for Enterobacteriaceae, Acinetobacter sp., other non-Enterobacteriaceae, Enterococcus sp., and Staphylococcus sp. are defined as susceptible at 4 mcg/mL or less, intermediate at 8 mcg/mL, and resistant at 16 mcg/mL or more. The MICs for Streptococcus pneumoniae are defined as susceptible at 0.25 mcg/mL or less, intermediate at 0.5 mcg/mL, and resistant at 1 mcg/mL or more.910
The action of tetracyclines in the treatment of acne vulgaris has not been fully established but is believed to be due in part to its antibacterial actions. Skin bacteria produce lipase that breaks down triglycerides present in sebum into free fatty acids, which are comedogenic and may be the cause of the inflammatory lesions of acne. Reduction in the number of lipase-producing bacteria or inhibition of lipase production are 2 possible mechanisms of tetracyclines. Several other mechanisms have been proposed but not studied. The second-generation tetracyclines, doxycycline, and minocycline, are preferred for the treatment of acne because of lower prevalence of resistant P. acnes strains as compared with tetracycline and their greater lipophilicity is believed to increase follicular penetration.11
In the treatment of periodontitis, it is thought that doxycycline works by inhibiting collagenase. Collagenase breaks down connective tissue which leads to the separation of the gum from the tooth. Products (e.g., Periostat) used for treatment of periodontitis contain lower amounts of doxycycline. Doxycycline concentrations produced by Periostat are too low to exert a direct antibacterial effect. Clinical studies of patients receiving Periostat for 9 to 18 months show that Periostat has no effect on total anaerobic and facultative bacteria in plaque samples. Periostat should not be used as an antibiotic in the treatment of periodontitis.12
Pharmacokinetics: Doxycycline is administered orally, intravenously, and via the subgingival route. Protein binding ranges from 80% to 90%. Distribution is extensive due to the relatively high lipid solubility of doxycycline compared to other tetracyclines, although only small amounts diffuse into CSF. Only minocycline is more lipid-soluble.413
Doxycycline is not hepatically metabolized. The major route of doxycycline excretion is via the feces with minimal amounts excreted renally (e.g., the renal clearance of doxycycline is roughly 30 to 35 mL/minute). Doxycycline undergoes enterohepatic recirculation; it may be partially inactivated by chelation with iron or other cations in the intestine. In patients with normal renal function, excretion of the active drug is about 30% to 40% in the urine with the remainder eliminated in the feces within 48 hours of dosage. Serum half-life ranges from 12 to 25 hours, depending on single or multiple dosage, in adults with normal renal function.3413
Oral Route: Oral absorption of doxycycline from immediate- and delayed-release products is 90% to 100%. Peak serum doxycycline concentrations of 1.5 to 3.6 mcg/mL occur after usual oral doses of regular- or delayed-release products and are achieved in approximately 3 hours in adults.45 Of all the tetracyclines, doxycycline has the least affinity for calcium ions. Therefore, overall absorption is not significantly affected when the immediate- or delayed-release doxycycline products are taken with milk or other dairy products, but absorption may be delayed.14315 A single-dose study of Periostat given with a 1,000-calorie, high-fat, high-protein meal, which included dairy products, resulted in a decrease in the rate and extent of absorption and delay in the time to maximum concentrations.12 When the delayed-release doxycycline tablets were given with a high-fat meal, the Cmax and AUC were reduced by 24% and 13%, respectively, after a single dose of 100 mg, while the mean Cmax was 19% lower and the AUC was unchanged after single dose administration of 150 mg; the clinical significance of these reductions is unknown.15 After administration of a single dose of the Doryx MPC formulation under fasting conditions in healthy adult subjects, the 120 mg MPC formulation was found to bioequivalent to the regular delayed-release 100 mg tablets. When a single dose of Doryx MPC was administered with a high-fat, high-calorie meal, the Cmax was approximately 30% lower, but there was no significant difference in AUC compared to fasting conditions.16 The dual-release capsules (Oracea) are not bioequivalent to other doxycycline products; absorption may be decreased when given with meals. In a single-dose food effect study, the Cmax and AUC of doxycycline (given as Oracea) were reduced by about 45% and 22%, respectively, in healthy volunteers fed a 1,000-calorie, high-fat, high-protein meal which included dairy products. These reductions in AUC and Cmax can be clinically significant. After dosing with dual-release capsules, peak serum concentrations were 510 ng/mL after a single-dose and 600 ng/mL after 7 days (steady-state). Chelation does occur with other cations; administration with bismuth subsalicylate, proton pump inhibitors (PPIs), aluminum-, calcium-, or magnesium-containing antacids, or with iron-containing products will decrease absorption significantly. The bioavailability of doxycycline may be reduced in patients with high gastric pH or achlorhydria (e.g., PPI therapy, gastrectomy, gastric bypass surgery).17
Hepatic Impairment: Pharmacokinetic data for doxycycline are unavailable in patients with hepatic impairment. However, like all other tetracyclines except minocycline, doxycycline is not hepatically metabolized. Mild hepatic impairment should have no effect on doxycycline pharmacokinetics. However, in patients with severe hepatic disease, hepatic excretion into bile may be delayed and elimination half-life extended.13
Renal Impairment: Although urinary clearance of doxycycline is reduced to about 1% to 5% in patients who have impaired creatinine clearance, in general, accumulation of doxycycline does not occur in renal failure due to the fact that the renal pathway is an insignificant route of elimination. Studies have shown no significant difference in serum half-life of doxycycline (range: 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life.316
Indications: Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Acinetobacter sp., Actinomyces israelii, Bacillus anthracis, Bacteroides sp., Balantidium coli, Bartonella bacilliformis, Borrelia recurrentis, Brucella sp., Campylobacter fetus, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium sp., Entamoeba histolytica, Entamoeba sp., Enterobacter aerogenes, Enterococcus sp., Escherichia coli, Francisella tularensis, Fusobacterium fusiforme, Haemophilus ducreyi, Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Klebsiella granulomatis, Klebsiella sp., Leptospira sp., Listeria monocytogenes, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Nocardia sp., Orientia tsutsugamushi, Plasmodium falciparum, Propionibacterium acnes, Rickettsia akari, Rickettsia prowazekii, Rickettsia rickettsii, Shigella sp., Staphylococcus aureus (MSSA), Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci), Streptococcus sp., Treponema pallidum, Treponema pertenue, Ureaplasma urealyticum, Vibrio cholerae, Viridans streptococci, Yersinia pestis
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
This drug may also have activity against the following microorganisms: Bartonella quintana, Bordetella pertussis, Borrelia burgdorferi, Burkholderia mallei, Burkholderia pseudomallei, Coxiella burnetii, Helicobacter pylori, Legionella pneumophila, Leptotrichia buccalis, Mycobacterium fortuitum, Mycoplasma hominis, Pasteurella multocida, Propionibacterium propionicum, Spirillum minus, Staphylococcus aureus (MRSA), Streptobacillus moniliformis, Vibrio parahaemolyticus, Wuchereria bancrofti, Yersinia enterocolitica
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug’s activity against the organism.
Contraindications and Precautions: Doxycycline and other tetracycline antibiotics are contraindicated in patients with known tetracyclines hypersensitivity.
Use caution when prescribing doxycycline to patients with severe hepatic disease because hepatic excretion into bile may be delayed and elimination half-life extended.
Doxycycline is associated with photosensitivity reactions after sunlight (UV) exposure, with these reactions occurring somewhat less frequently than with demeclocycline. Photosensitivity reactions are believed to be due to accumulation of the drug in the skin and are mostly phototoxic in nature, but photoallergic reactions also can occur with select drugs.18 Reactions can develop from within a few minutes to up to several hours after exposure and will last for 1 to 2 days after discontinuation of the drug. Advise drug recipients to avoid excess sunlight/artificial ultraviolet light whenever possible, use sunscreens, and to discontinue therapy if phototoxicity occurs (i.e., skin eruption).19
Doxycycline calcium oral suspension contains sodium metabisulfite. Sulfites cause an allergic reaction in some people and this product should be used with caution in patients with a known sulfite hypersensitivity. This sensitivity reaction is more common in patients with asthma than in non-asthmatic patients.3
Increases in gastric pH may reduce the absorption of doxycycline. For example, the bioavailability of doxycycline may be reduced in patients on proton pump inhibitor therapy or with achlorhydria.
Adequate and well-controlled studies of doxycycline use in pregnant women are lacking. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for treatment of anthrax exposure.16 Tetracyclines have been noted to have a detrimental effect on the skeletal development and bone growth of the fetus; only use tetracyclines during pregnancy, especially during the second half of pregnancy, if benefits from treatment outweigh the risks.17 In a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, tetracycline use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 2.59, 95% CI: 1.97 to 3.41, 67 exposed cases); residual confounding by severity of infection may be a potential limitation of this study.20 Additionally, in a large population-based cohort study (n = 139,938 live births) assessing antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, doxycycline was associated with an increased risk of circulatory system malformation, cardiac malformations, and ventricular/atrial septal defect (aOR 2.38, 95% CI: 1.21 to 4.67, 9 exposed cases; aOR 2.46, 95% CI: 1.21 to 4.99, 8 exposed cases; aOR 3.19, 95% CI: 1.57 to 6.48, 8 exposed cases, respectively). Possible study limitations include potential unmeasured confounders (i.e., smoking, folic acid, and alcohol intake) as well as that the study was underpowered to detect associations between individual antibiotics and specific malformations due to the small number of exposed cases.21 In another case-control study (n = 32,804 controls; 18,515 cases), there was a weak but marginally statistically significant association with total malformations and use of doxycycline (n = 64 (0.19%) of the controls and 56 (0.3%) of the cases treated with doxycycline) anytime during pregnancy. No association was seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases.22 Guidelines suggest doxycycline may be used for the treatment of uncomplicated malaria during pregnancy in rare instances if other options are not available or are not tolerated and benefit of use outweighs risks.23
Tetracyclines, including doxycycline, are distributed in small amounts into breast milk. According to the manufacturer, because of the potential for serious adverse reactions in nursing babies, a decision should be made whether to discontinue nursing or to discontinue the drug.3 In general, manufacturers recommend that tetracycline antibiotics not be used in breast feeding mothers due to a theoretical risk of causing tooth discoloration, enamel hypoplasia, inhibition of linear skeletal growth, oral and vaginal thrush, or photosensitivity reactions in the nursing infant.3 However, because tetracyclines bind to calcium in the maternal breast milk, the risk for oral absorption by the infant is minimal.24 Data are available regarding doxycycline milk concentrations in breast-feeding women; however, infant serum concentrations and effects are nursing babies were not reported. In one study, doxycycline (100 mg PO daily) was given to 10 mothers. On the second day of treatment, milk doxycycline averaged 0.82 mg/L (range 0.37 to 1.24 mg/L) 3 hours after the dose, and 0.46 mg/L (range 0.3 to 0.91 mg/L) 24 hours after the dose. Using the average of the peak and trough milk concentrations in this study, the estimated average intake of an exclusively breast-fed infant would be about 6% of the maternal weight-adjusted dosage.25 Further available data indicate that after doses of 100 to 200 mg PO, milk concentrations do not exceed an average of 1.8 mg/L.26272829 Studies of long-term tetracycline use in breast-feeding are lacking. Doxycycline does not have a listed American Academy of Pediatrics breast-feeding category, but another tetracycline antibiotic, tetracycline, is rated as usually compatible with breast-feeding.30 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Tetracyclines, like doxycycline, may have a serious effect on the bones and teeth in young children. Tetracyclines are incorporated into bones and teeth that are undergoing calcification. This may cause permanent yellow or brown discoloration and enamel hypoplasia in developing teeth. Use doxycycline in neonates, infants, and children younger than 8 years only when the potential benefits are expected to outweigh the risks in severe or life-threatening infections (e.g., anthrax, Rocky Mountain spotted fever), particularly when no other alternative therapies are available.316 However, studies have failed to demonstrate dental staining, enamel hypoplasia, or tooth color differences in children who have received short-term courses of doxycycline at younger than 8 years of age and suggest that this concern may be unwarranted.3132 Doxycycline is the treatment of choice for children of any age for certain infections (i.e., anthrax prophylaxis, rickettsial diseases).333435 Guidelines suggest doxycycline may be used for the treatment of uncomplicated malaria in children younger than 8 years in rare instances if other options are not available or are not tolerated and benefit of use outweighs risks.23
Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.
Doxycycline subgingival formulation (Atridox) has not been clinically evaluated in patients with dental disease/periodontal disease involving extremely severe periodontal defects with very little remaining periodontium. Also, it has not been clinically tested for use in the regeneration of alveolar bone, either in preparation for or in conjunction with the placement of endosseous (dental) implants or in the treatment of failing implants. Periostat and similar oral formulations for peridontitis produce doxycycline concentrations too low to exert a direct antibacterial effect. Clinical studies of patients show that the products have no effect on total anaerobic and facultative bacteria in plaque samples. These products should not be used as an antibiotic in the treatment of periodontitis/periodontal disease.
Doxycycline subgingival (Atridox) and periodontal oral formulations (Periostat, others) have not been clinically tested in patients with predisposition to oral candidiasis, such as patients with immunosuppression due to diabetes mellitus, chemotherapy, or human immunodeficiency virus (HIV) infection.
Doxycycline does not treat fungal infection or viral infection (e.g., common cold). Prescribing doxycycline in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria (antimicrobial resistance). Patients should be told to complete the full course of treatment, even if they feel better earlier. Antibiotic therapy can result in superinfection or suprainfection with nonsusceptible organisms, such as candidiasis. Patients should be monitored closely.19
Doxycycline has been associated with increased intracranial pressure in adults and bulging fontanels in infants. Women of childbearing age with obesity or a prior history of intracranial hypertension are at higher risk for developing doxycycline-associated intracranial hypertension. Since blurred vision, diplopia, and permanent vision loss are potential clinical manifestations of intracranial hypertension, ophthalmologic evaluations (i.e., fundoscopy) are advised for patients developing visual symptoms while receiving doxycycline. Stopping the drug usually resolves intracranial hypertension; however pressures may remain elevated for weeks after treatment discontinuation. Continue to monitor patients until they stabilize. In addition, avoid concurrent use of doxycycline with isotretinoin, as isotretinoin is also associated with increased intracranial pressures.319
While doxycycline may be used to treat certain sexually transmitted diseases (STD), the drug may mask or delay the symptoms of incubating syphilis when given as part of an STD treatment regimen. All patients with a diagnosed or suspected STD should be tested for other STDs, which may include HIV, syphilis, chlamydia, and gonorrhea, at the time of diagnosis. Initiate appropriate therapy and perform follow-up testing as recommended based upon sexually transmitted disease diagnosis.336
In general, doxycycline dose selection for the geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.16 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.37
Doxycycline may cause severe serious rash and other severe cutaneous adverse reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). If patients develop skin reactions, discontinue doxycycline and institute appropriate therapy.3
Administration of doxycycline may result in laboratory test interference. False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.3 Additionally, antimicrobials are known to suppress H. pylori; thus, ingestion of these agents within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of doxycycline in the 4 weeks prior to the test.3839
Pregnancy: Adequate and well-controlled studies of doxycycline use in pregnant women are lacking. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for treatment of anthrax exposure.16 Tetracyclines have been noted to have a detrimental effect on the skeletal development and bone growth of the fetus; only use tetracyclines during pregnancy, especially during the second half of pregnancy, if benefits from treatment outweigh the risks.17 In a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, tetracycline use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 2.59, 95% CI: 1.97 to 3.41, 67 exposed cases); residual confounding by severity of infection may be a potential limitation of this study.20 Additionally, in a large population-based cohort study (n = 139,938 live births) assessing antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, doxycycline was associated with an increased risk of circulatory system malformation, cardiac malformations, and ventricular/atrial septal defect (aOR 2.38, 95% CI: 1.21 to 4.67, 9 exposed cases; aOR 2.46, 95% CI: 1.21 to 4.99, 8 exposed cases; aOR 3.19, 95% CI: 1.57 to 6.48, 8 exposed cases, respectively). Possible study limitations include potential unmeasured confounders (i.e., smoking, folic acid, and alcohol intake) as well as that the study was underpowered to detect associations between individual antibiotics and specific malformations due to the small number of exposed cases.21 In another case-control study (n = 32,804 controls; 18,515 cases), there was a weak but marginally statistically significant association with total malformations and use of doxycycline (n = 64 (0.19%) of the controls and 56 (0.3%) of the cases treated with doxycycline) anytime during pregnancy. No association was seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases.22 Guidelines suggest doxycycline may be used for the treatment of uncomplicated malaria during pregnancy in rare instances if other options are not available or are not tolerated and benefit of use outweighs risks.23
Breast-Feeding: Tetracyclines, including doxycycline, are distributed in small amounts into breast milk. According to the manufacturer, because of the potential for serious adverse reactions in nursing babies, a decision should be made whether to discontinue nursing or to discontinue the drug.3 In general, manufacturers recommend that tetracycline antibiotics not be used in breast feeding mothers due to a theoretical risk of causing tooth discoloration, enamel hypoplasia, inhibition of linear skeletal growth, oral and vaginal thrush, or photosensitivity reactions in the nursing infant.3 However, because tetracyclines bind to calcium in the maternal breast milk, the risk for oral absorption by the infant is minimal.24 Data are available regarding doxycycline milk concentrations in breast-feeding women; however, infant serum concentrations and effects are nursing babies were not reported. In one study, doxycycline (100 mg PO daily) was given to 10 mothers. On the second day of treatment, milk doxycycline averaged 0.82 mg/L (range 0.37 to 1.24 mg/L) 3 hours after the dose, and 0.46 mg/L (range 0.3 to 0.91 mg/L) 24 hours after the dose. Using the average of the peak and trough milk concentrations in this study, the estimated average intake of an exclusively breast-fed infant would be about 6% of the maternal weight-adjusted dosage.25 Further available data indicate that after doses of 100 to 200 mg PO, milk concentrations do not exceed an average of 1.8 mg/L.26272829 Studies of long-term tetracycline use in breast-feeding are lacking. Doxycycline does not have a listed American Academy of Pediatrics breast-feeding category, but another tetracycline antibiotic, tetracycline, is rated as usually compatible with breast-feeding.30 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Adverse Reactions/Side Effects: Diarrhea (5% to 6%), nausea (8%), vomiting, dyspepsia (6%), glossitis, dysphagia, enterocolitis, abdominal pain (1%), upper abdominal pain (2%), abdominal distention (1%), stomach discomfort (1%), acid indigestion (4%), xerostomia (1%), toothache (7%), periodontal abscess (4%), gum pain (< 1%), pancreatitis, and anorexia are all possible gastric adverse reactions associated with doxycycline.31240 GI complaints are common with doxycycline and occur in roughly 39% of patients receiving oral doxycycline in the general population; complaints can be mitigated by administering the drug with food.13 Rare cases of esophagitis and esophageal ulceration have been reported in patients receiving capsule and tablet dosage forms of tetracycline antibiotics; however, many of these patients took the medication immediately before going to bed or lying down.3 Of all tetracycline antibiotics, doxycycline, especially in capsule form, is most likely to cause GI effects and esophagitis.5 Doxycycline-induced esophagitis is characterized by sudden onset odynophagia, retrosternal pain, and dysphagia and may be alleviated by taking with sufficient water and avoiding dosage at bedtime. Symptoms usually resolve within days to weeks after stopping the medication. Abdominal complaints may suggest hepatotoxicity (e.g., elevated hepatic enzymes, hepatitis), although serious liver reactions are relatively uncommon. Elevated aspartate aminotransferase (2%) was reported in some clinical trials.317 In 1 analysis, the number of patient cases developing acute symptomatic liver disease resulting in hospitalization for each million adult patients treated with a 10-day course of a tetracycline was 1.56 cases.41 The drugs are very rarely associated with hepatic failure (hepatotoxicity).3
As with other antibiotic preparations, use of doxycycline may result in overgrowth of nonsusceptible organisms and superinfection. Oral or parenteral tetracycline therapy, like doxycycline, can result in oral, rectal, or vaginal candidiasis because of changes in the normal balance of microbial flora. Candidal infections are more likely to occur in debilitated patients, those taking the drug over prolonged periods, and the elderly. The condition usually resolves upon discontinuation of the drug. Pseudomembranous colitis has been reported with the use of doxycycline and may range from mild diarrhea to fatal colitis.3 Fungal infection (2%) and general infection (2%) have been reported in some clinical trials in adult patients. The common cold (22%) and influenza or flu-like symptoms (2% to 11%) have also been reported.171240
Photosensitivity can appear within minutes of taking doxycycline, if the patient is exposed to direct sunlight or UV light.3 Photosensitivity is manifested by an exaggerated sunburn reaction and doxycycline should be discontinued at the first evidence of skin erythema. Red rashes and onycholysis have been reported on those areas exposed to sunlight. Paresthesias (tingling and burning) in the hands, feet, and nose may indicate latent photosensitivity. If the drug is discontinued, symptoms usually are alleviated within 1 to 2 days. Sunscreens seem to provide only limited protection, and severe response may necessitate treatment with corticosteroids or antihistamines. Photosensitivity is a toxic, rather than an allergic, reaction.1842
Hypersensitivity reactions to tetracyclines, including doxycycline, have been reported as urticaria, angioedema, anaphylaxis, anaphylactoid reactions such as anaphylactoid purpura, serum sickness, pericarditis, exacerbation of systemic lupus erythematosus (lupus-like symptoms), and drug reaction with eosinophilia and systemic symptoms (DRESS). Maculopapular rash, erythematous rashes, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, and erythema multiforme have also been reported. Exfoliative dermatitis has been reported but is uncommon. Rash (unspecified) has been reported in 4% of adult patients in some clinical trials.3161243
Headache (26% reported with some capsule/tablet formulations for periodontitis, compared to 26% placebo) and anxiety (2%) have been reported in some clinical trials of doxycycline in adult patients.171240 Headache may be due to elevated intracranial pressure.3
Doxycycline has been associated with acute generalized exanthematous pustulosis (AGEP). The non-follicular, pustular, erythematous rash starts suddenly and is associated with fever above 38 degrees C. Drugs are the main cause of AGEP. A period of 2 to 3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days.44
Historically, the routine use of the tetracycline class in children less than 8 years has not been recommended due to tooth discoloration that has been seen in children exposed to a tetracycline during the last half of pregnancy, during infancy, or during childhood to the age of 8 years. Superficial discoloration of permanent teeth has been reported as reversible with professional dental cleaning after treatment discontinuation; however, permanent discoloration may occur.34 Studies with doxycycline use in young children have reported an absence of tooth staining and indicate that this concern may be unwarranted, particularly with short-term use.314532 In a retrospective study of 58 children who received doxycycline for Rocky Mountain Spotted Fever at less than 8 years of age, no difference was seen in dental staining, enamel hypoplasia, or tooth color compared with the control group. Children received an average of 1.8 courses of doxycycline for a mean duration of 7.3 days (range: 1 to 10 days) at a mean age of 4.5 years (range: 0.2 to 7.9 years).32 In another study (n = 61) in which 31 children received doxycycline before the age of 8 years (mean 4.1 years; range: 2 to 7.7 years), no tooth staining was detected in the doxycycline-treated children compared to the control group.31 Drugs in the tetracycline class are known to cause hyperpigmentation, which may affect many organs/tissues, including nails, bone, skin (skin hyperpigmentation), eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclera, and heart valves.46 These adverse reactions are more common during long-term use of the drugs but skin and oral hyperpigmentation can occur independently of treatment time or amount of drug administered. Enamel hypoplasia has also been reported.3 Brown nail discoloration was reported in an 11-year-old boy treated with doxycycline; normal nail color returned approximately 1 month after stopping doxycycline.47
Hematologic reactions such as hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported with doxycycline. Tetracyclines may also depress plasma prothrombin activity.3 Neutropenia and eosinophilia are more likely to occur during long-term therapy with doxycycline. Patients should be evaluated regularly in these instances.
Adverse renal effects of tetracyclines are usually a problem only for patients with seriously impaired renal function. Tetracyclines may cause an increase in BUN (azotemia) in such patients due to the antianabolic actions of the drugs; with doxycycline, the effect on BUN may be dose-related.3
Phlebitis is a frequent side effect after IV administration of doxycycline, especially if the therapy is long-term or the same vein is used. Avoid rapid administration. Extravasation can result in a serious reaction, and whenever possible the oral route of administration should be used. Observe patients receiving parenteral doxycycline for any injection site reaction.43
Benign increased intracranial pressure (pseudotumor cerebri) has been associated with the use of tetracyclines, including doxycycline. Clinical manifestations include headache, blurred vision, diplopia, vision loss, and papilledema. Symptoms are usually reversible following discontinuation of the drug; however, permanent vision loss can occur. Bulging fontanels in infants can occur with doxycycline.3
Respiratory adverse reactions noted in some clinical trials with doxycycline in adult patients include naso-pharyngitis (5%), pharyngolaryngeal pain (1%), sinusitis (3%), nasal congestion (2%), sore throat/throat irritation (5%), sinus congestion (5%), sinus headache (1% to 4%), cough (4%), and bronchitis (3%). These reactions were reported at a similar incidence in patients receiving placebo.171240
Musculoskeletal adverse reactions were reported in some doxycycline clinical trials in adult patients and include back pain (1% to 3%), backache (2%), menstrual cramp (4%), general pain (2% to 4%), injury (5%), and muscle and joint pain (musculoskeletal pain) (1% to 6%).171240
Hypertension (3%) and increased blood pressure (2%) have been reported in some clinical trials with doxycycline in adult patients.17
Increased blood glucose (hyperglycemia) (1%) and increased blood lactate dehydrogenase (2%) were reported in some doxycycline clinical trials in adult patients.17
Storage: Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.
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