Children >8 years of age should receive 25-50 mg/kg daily in four divided doses. The total daily dose of intravenous tetracycline (no longer available in the U.S.) for most acute infections is 1 g (or 2 g for severe infection), divided into equal doses and administered at 6- or 12-hour intervals. The low pH of tetracycline, but not doxycycline or minocycline, invariably causes phlebitis if infused into a peripheral vein. The recommended dose of demeclocycline is 150 mg every 6 hours or 300 mg every 12 hours for adults and 6.6-13.2 mg/kg in two to four divided doses for children >8 years of age. Demeclocycline is used rarely as an antimicrobial agent because of its higher risks of photosensitivity reactions and nephrogenic diabetes insipidus. The oral or intravenous dose of doxycycline for adults is 100 mg every 12 hours on the first day and then 50 mg every 12 hours, 100 mg once a day, or 100 mg twice daily when severe infection is present; for children >8 years of age, the dose is 4-5 mg/kg per day in two divided doses the first day, then 2-2.5 mg/kg given once or twice daily. The dose of minocycline for adults is 200 mg orally or intravenously initially, followed by 100 mg every 12 hours; for children, it is 4 mg/kg initially followed by 2 mg/kg every 12 hours. Tigecycline is administered intravenously to adults as a 100-mg loading dose, followed by 50 mg every 12 hours. For patients with severe hepatic impairment, the loading dose should be followed by a reduced maintenance dose of 25 mg every 12 hours. Dosage data are not available for tigecycline in pediatrics.
Tetracyclines should not be administered intramuscularly because of local irritation and poor absorption. GI distress, nausea, and vomiting can be minimized by administration of tetracyclines with food. Generally, oral administration of tetracyclines should occur 2 hours before or 2 hours after co-administration with any of the agents listed. Cholestyramine and colestipol also bind orally administered tetracyclines and interfere with the absorption of the antibiotic.
Respiratory Tract Infections. Doxycycline's good activity against S. pneumoniae and H. influenzae and excellent activity against atypical pathogens such as Mycoplasma and Chlamydophilia pneumoniae make it an effective single agent for empirical therapy of community-acquired pneumonia in the outpatient setting or as an adjunct to cephalosporin-based therapy for inpatients (Mandell et al., 2007). Tigecycline has been demonstrated to be effective for use as a single agent for adults hospitalized with community-acquired bacterial pneumonia (Bergallo et al., 2009).
Skin and Soft-Tissue Infections. Community strains of methicillin-resistant S. aureus often are susceptible to tetracycline, doxycycline, or minocycline, which appear to be effective for uncomplicated skin and soft-tissue infections, although published data are limited (Cenizal et al., 2007). Tigecycline is approved by the Food and Drug Administration (FDA) for the treatment of complicated skin and soft-tissue infections.
Tetracyclines have been used to treat acne. They may act by inhibiting propionibacteria, which reside in sebaceous follicles and metabolize lipids into irritating free fatty acids. The relatively low doses of tetracycline used for acne (e.g., 250 mg orally twice a day) are associated with few side effects.
Intra-abdominal Infections. Increasing resistance among Enterobacteriaceae and gram-negative anaerobes limit the utility of the tetracyclines for intra-abdominal infections. However, tigecycline possesses excellent activity against these pathogens as well as Enterococcus and has demonstrated effectiveness in clinical trials for complicated intra-abdominal infections (Oliva et al., 2005).
GI Infections. Therapy with the tetracyclines is often ineffective in infections caused by Shigella, Salmonella, or other Enterobacteriaceae because of a high prevalence of drug-resistant strains in many areas. Resistance limits the usefulness of tetracyclines for travelers' diarrhea. Doxycycline (300 mg as a single dose) is effective in reducing stool volume and eradicating Vibrio cholerae from the stool within 48 hours. Antimicrobial agents, however, are not substitutes for fluid and electrolyte replacement in this disease. In addition, some strains of V. cholerae are resistant to tetracyclines.
Urinary Tract Infections. Tetracyclines are no longer recommended for routine treatment of urinary tract infections because many enteric organisms that cause these infections, including E. coli, are resistant. There is little experience in using tigecycline for urinary tract infections; based on its in vitro activity, it should be adequate.
Sexually Transmitted Diseases. Because of resistance, doxycycline no longer is recommended for gonococcal infections. If coinfection with C. trachomatis has not been excluded, then either doxycycline or azithromycin should be administered in addition to an agent effective for gonococcal urethritis (Workowski and Berman, 2006).
C. trachomatis often is a coexistent pathogen in acute pelvic inflammatory disease, including endometritis, salpingitis, parametritis, and/or peritonitis. Doxycycline, 100 mg intravenously twice daily, is recommended for at least 48 hours after substantial clinical improvement, followed by oral therapy at the same dosage to complete a 14-day course. Doxycycline usually is combined with cefoxitin or cefotetan (Chapter 53) to cover anaerobes and facultative aerobes.
Acute epididymitis is caused by infection with C. trachomatis or N. gonorrhoeae in men <35 years of age. Effective regimens include a single injection of ceftriaxone (250 mg) plus doxycycline, 100 mg orally twice daily for 10 days. Sexual partners of patients with any of these conditions also should be treated.
Nonspecific urethritis is often due to Chlamydia trachomatis. Doxycycline, 100 mg every 12 hours for 7 days, is effective; however, azithromycin is usually preferred because it can be given as a single 1-g dose. Doxycycline (100 mg twice daily for 21 days) is first-line therapy for treatment of lymphogranuloma venereum. The size of buboes decreases within 4 days, and inclusion and elementary bodies entirely disappear from the lymph nodes within 1 week. Rectal pain, discharge, and bleeding of lymphogranulomatous proctitis are decreased markedly. When relapses occur, treatment is resumed with full doses and is continued for longer periods.
Nonpregnant penicillin-allergic patients who have primary, secondary, or latent syphilis can be treated with a tetracycline regimen such as doxycycline, 100 mg orally twice daily for 2 weeks. Tetracyclines should not be used for treatment of neurosyphilis.
Rickettsial Infections. Tetracyclines are effective and may be lifesaving in rickettsial infections, including Rocky Mountain spotted fever, recrudescent epidemic typhus (Brill's disease), murine typhus, scrub typhus, rickettsialpox, and Q fever. Clinical improvement often is evident within 24 hours after initiation of therapy. Doxycycline is the drug of choice for treatment of suspected or proven Rocky Mountain spotted fever in adults and in children, including those <9 years of age, in whom the risk of staining of permanent teeth is outweighed by the seriousness of this potentially fatal infection (Masters et al., 2003).
Anthrax. Doxycycline, 100 mg every 12 hours (2.2 mg/kg every 12 hours for children weighing <45 kg), is indicated for prevention or treatment of anthrax. It should be used in combination with another agent when treating inhalational or GI infection. The recommended duration of therapy is 60 days for exposures occurring as an act of bioterrorism.
Local Application. Except for local use in the eye, topical use of the tetracyclines is not recommended. Their use in ophthalmic therapy is discussed in previous versions of this text. Minocycline sustained-release microspheres for subgingival administration are used in dentistry as an adjunct to scaling and root planing procedures to reduce pocket depth in patients with adult periodontitis.
Other Infections. Tetracyclines in combination with rifampin or streptomycin are effective for acute and chronic infections caused by Brucella melitensis, Brucella suis, and Brucella abortus. Effective regimens are doxycycline, 200 mg per day, plus rifampin, 600-900 mg daily for 6 weeks, or the usual dose of doxycycline plus streptomycin 1 g daily, intramuscularly. Relapses usually respond to a second course of therapy. Although streptomycin is preferable, tetracyclines also are effective in tularemia (Ellis et al., 2002). Both the ulceroglandular and typhoidal types of the disease respond well. Actinomycosis, although most responsive to penicillin G, may be successfully treated with a tetracycline. Minocycline is an alternative for the treatment of nocardiosis, but a sulfonamide should be used concurrently. Yaws and relapsing fever respond favorably to the tetracyclines. Tetracyclines are useful in the acute treatment and for prophylaxis of leptospirosis (Leptospira spp.). Borrelia spp., including B. recurrentis (relapsing fever) and B. burgdorferi (Lyme disease), respond to therapy with a tetracycline. The tetracyclines have been used to treat susceptible atypical mycobacterial pathogens, including M. marinum.
Gastrointestinal. All tetracyclines can produce GI irritation, most commonly after oral administration. GI distress is also characteristic of tigecycline administration. Epigastric burning and distress, abdominal discomfort, nausea, vomiting, and diarrhea may occur. Tolerability can be improved by administering these drugs with food, but tetracyclines should not be taken with dairy products or antacids. Tetracycline has been associated with esophagitis, esophageal ulcers, and pancreatitis.
Many of the tetracyclines are incompletely absorbed from the GI tract, and high concentrations in the bowel can markedly alter enteric flora. Sensitive aerobic and anaerobic coliform microorganisms and gram-positive spore-forming bacteria are suppressed markedly during long-term tetracycline regimens. As the fecal coliform count declines, overgrowth of tetracycline-resistant microorganisms occurs, particularly of yeasts (Candida spp.), enterococci, Proteus, and Pseudomonas. Moniliasis, thrush, or Candida-associated esophagitis may arise during therapy with tetracyclines. Tetracyclines and glycylcyclines may occasionally produce pseudomembranous colitis caused by Clostridium difficile; pseudomembranous colitis caused by overgrowth of C. difficile is a potentially life-threatening complication.
Photosensitivity. Demeclocycline, doxycycline, and other tetracyclines and glycylcyclines to a lesser extent may produce mild-to-severe photosensitivity reactions in the skin of treated individuals exposed to sunlight. Onycholysis and pigmentation of the nails may develop with or without accompanying photosensitivity.
Hepatic Toxicity. Hepatic toxicity has developed in patients with renal failure receiving ≥2 g of drug per day parenterally, but this effect also may occur when large quantities are administered orally. Cases of hepatotoxicity have been reported rarely with doxycycline, minocycline, and tigecycline administration. Pregnant women are particularly susceptible to tetracycline-induced hepatic damage.
Renal Toxicity. Tetracyclines may aggravate azotemia in patients with renal disease because of their catabolic effects. Doxycycline, minocycline, and tigecycline have fewer renal side effects than other tetracyclines. Nephrogenic diabetes insipidus has been observed in some patients receiving demeclocycline, and this phenomenon has been exploited for the treatment of the syndrome of inappropriate secretion of antidiuretic hormone (Chapter 25).
Fanconi syndrome, characterized by nausea, vomiting, polyuria, polydipsia, proteinuria, acidosis, glycosuria, and aminoaciduria, has been observed in patients ingesting outdated and degraded tetracycline. These symptoms presumably result from a toxic effect of the degradation products on proximal renal tubules. Under no circumstances should outdated tetracyclines be administered.
Effects on Teeth. Children receiving long- or short-term therapy with a tetracycline or glycylcycline may develop permanent brown discoloration of the teeth. The larger the drug dose relative to body weight, the more intense the enamel discoloration. The duration of therapy appears to be less important than the total quantity of antibiotic administered. The risk of this untoward effect is highest when a tetracycline is given to neonates and infants before the first dentition. However, pigmentation of the permanent teeth may develop if the drug is given between the ages of 2 months and 5 years when these teeth are being calcified. The deposition of the drug in the teeth and bones probably is due to its chelating property and the formation of a tetracycline–calcium orthophosphate complex.
Treatment of pregnant patients with tetracyclines may produce discoloration of the teeth in their children. The period of greatest danger to the teeth is from midpregnancy to ~4-6 months of the postnatal period for the deciduous anterior teeth, and from a few months to 5 years of age for the permanent anterior teeth when the crowns are being formed. However, children up to 8 years old may be susceptible to this complication of tetracycline therapy.
Other Toxic and Irritative Effects. Tetracyclines are deposited in the skeleton during gestation and throughout childhood and may depress bone growth in premature infants. This is readily reversible if the period of exposure to the drug is short.
Thrombophlebitis frequently follows intravenous administration. This irritative effect of tetracyclines has been used therapeutically in patients with malignant pleural effusions, where drug is instilled into the pleural space in a procedure called pleurodesis.
Long-term tetracycline therapy may produce leukocytosis, atypical lymphocytes, toxic granulation of granulocytes, and thrombocytopenic purpura.
The tetracyclines may cause increased intracranial pressure (pseudotumor cerebri) in young infants, even when given in the usual therapeutic doses. Except for the elevated pressure, the spinal fluid is normal. The pressure promptly returns to normal when therapy is discontinued, and this complication rarely occurs in older individuals.
Patients receiving minocycline may experience vestibular toxicity, manifested by dizziness, ataxia, nausea, and vomiting. The symptoms occur soon after the initial dose and generally disappear within 24-48 hours after drug administration is stopped. Long-term use of minocycline can pigment the skin, producing a brownish discoloration. Various skin reactions, including morbilliform rashes, urticaria, fixed drug eruptions, and generalized exfoliative dermatitis, rarely may follow the use of any of the tetracyclines. Among the more severe allergic responses are angioedema and anaphylaxis; anaphylactoid reactions can occur even after the oral use of these agents. Other hypersensitivity reactions are burning of the eyes, cheilosis, atrophic or hypertrophic glossitis, pruritus ani or vulvae, and vaginitis. Although the exact cause of these reactions is unknown, they can persist for weeks or months after cessation of tetracycline therapy. Fever of varying degrees and eosinophilia may occur when these agents are administered. Asthma also has been observed. Cross-sensitization among the various tetracyclines is common.
Tetracyclines have a variety of effects on mammalian cells unrelated to their capacity to inhibit bacterial protein synthesis. Doxycycline is being studied as an inhibitor of matrix metalloproteinases (Villareal et al., 2003).