Tetracycline and Doxycycline Applications

RESIDENT COMPETITION: HONORABLE MENTION TETRACYCLINE AND DOXYCYCLINE APPLICATIONS

Sean F. Lynn, MD ELSEVIER

Tetracycline and doxycycline fre- sive antimicrobials. (Prim Care ABSORPTION AND EXCRETION quently are prescribed to women Update Ob/Gyns 1996;3:224-227) for a number of diflerent infec- Tetracycline is absorbed incom- tious diseases. Although both are pletely from the gastrointestinal tract; only 60% is absorbed under considered to be broad spectrum, The optimal and judicious selection optimal conditions. Plasma concen- many common pathogens have ac- of antimicrobial agents for the trations of doxycycline, however, quired resistance to them, leaving therapy of infectious disease is a essentially are equivalent whether a fairlyfinite list of indicated uses. complex procedure that requires This list includes the treatment of given orally or intravenously be- clinical judgment and detailed cause the drug’s absorption is several sexually transmitted dis- knowledge of pharmacological and nearly complete. The absorption of eases, pelvic inflammatory dis- microbiological factors. The goal is to both drugs is much greater in the ease and endometritis, and acne. choose a drug that is selectively ac- fasting state and is impaired sub- The principal contraindications to tive for the most likely infecting mi- stantially by food, milk products, their use are breast feeding, preg- croorganism(s) and that has the least antacids, calcium, and iron prepa- nancy, age less than 8 years, and potential to cause toxicity or allergic rations. Tetracycline is affected impaired renal or hepatic func- reactions in the individual being much more by these factors than tion. The main toxicities are stain- treated. Tetracycline and doxycy- doxycycline. Both tetracycline and ing of teeth, stippling of bones, and cline are antibiotics commonly pre- doxycycline should be taken 3 photosensitivity. Renal, central scribed by primary care physicians in hours before, or 2 hours after, taking nervous system, hepatic, and gas- the treatment of a number of infec- iron or antacids, and tetracycline trointestinal disturbances also tions. The objective of the following should not be taken with meals. have been documented. When Once in the serum, the half-lives of taken with food or certain medi- discussion is to review the pharma- tetracycline and doxycycline are cations, tetracycline is poorly ab- cology, toxicity, spectrum of activity, 6-1.2 hours and 16-18 hours, resorbed, making adequate serum clinical application, and cost of these spectively. Hence, tetracycline re- concentrations dificult to attain. important, and occasionally mis- quires four-times-a-day dosing, Doxycycline is better absorbed. used, antimicrobial agents. whereas doxycycline only needs to The volume of distribution for both be taken twice daily.2.3 drugs is essentially that of the The volume of distribution of tet- body’s serum, including small racyclines includes not only that of amountsin breastmilk, secretions, Pharmacology the extracellular serous fluid but the cerebrospinal fluid, and amniotic ORIGIN AND STRUCTURE tears, saliva, cerebrospinal fluid, fluid. The drugs are metabolized and amniotic fluid. Concentrations in the liver and then eliminated in The development of tetracycline an- in these secretions and fluids are the urine (tetracycline) or feces tibiotics was the result of a system- only IO-25% of those found in the (doxycycline). Subtle diflerences atic screening of soil specimens col- serum, and only doxycycline is in the metabolism and side eflects lected from many parts of the world known to accumulate in the cere- of the two medications favor the for antibiotic-producing organisms. brospinal fluid. All tetracyclines are use of doxycycline over tetracy- A number of tetracyclines exist, all concentrated in the liver and ex- cline in most instances. In spite Of very much alike in structure and creted by way of the bile into the their limitations, when used prop- function. Tetracycline and doxycy- intestine. Because of the effects of erly, tetracycline and doxycycline cline are semisynthetically pro- the enterohepatic circulation, the are safe, egective, and inexpen- duced from a species of Streptomy- tetracyclines are excreted and ces and differ only by the position of resorbed continually and thus may a single hydroxy moiety on carbon be present in the blood for a long From the Department of Obstetrics/Gynecology. tTniversity of Florida. Gainesville. Florida. #5.l time after cessation of therapy. Tet-

racycline is eliminated primarily showed concentrations less than ing, and diarrhea may occur. Sev- through the kidney. Doxycycline, the lower limit of the sensitivity of eral studies cite tetracycline and on the other hand, is eliminated the assay. Nevertheless, the stan- doxycycline as the cause of revers- almost exclusively in the feces and dard of care presently is that tetra- ible esophageal ulcerations, pre- is, therefore, one of the safest of the cyclines should not be used by ventable, in part, by taking the med- antibiotics in the presence of renal breastfeeding mothers because al- ications in a sitting position and failure.lX3 ternative therapies are available and with a full glass of water. Alter- the potential implications are sig- ations in bowel flora may also cause MECHANISM OF ACTION nificant.’ bacterial overgrowth that can be life-threatening (see Superinfec- The site of action of tetracycline and CALCIFIED TISSUES tions). Overall, doxycycline is less doxycycline is the bacterial ribo- irritating to the gastrointestinal tract some. The drugs bind primarily to Retardation of bone growth and dis- than tetracycline.“,6.7 30 S ribosomes and block access of coloration of teeth may occur in bacterial aminoacyl tRNA to the children due to the formation of SUPERINFECTIONS acceptor sites on mRNA, preventing a tetracycline- or doxycycline- the addition of amino acids to the calcium complex. Whereas the ef- Like all antimicrobial agents, the growing peptide chain. Resistance fects on bone are reversible with tetracyclines may lead to superin- is mediated by a plasmid that pre- cessation of treatment, the tooth fections caused by resistant bacteria vents the intracellular accumula- discoloration is permanent. Tetra- or yeasts. The incidence of these tion of tetracyclines. These drugs cyclines are impregnated into tooth infections appears to be much are primarily bacteriostatic, pre- dentin and will fluoresce a bright higher with the tetracyclines than venting the organism from repro- yellow when exposed to ultraviolet with the penicillins. Pseudomem- ducing but not killing it outright. radiation and later stain a darker branous enterocolitis may occur Thus, an intact immune system is yellow or brown. Deciduous tooth with either oral or intravenous ad- necessary for eradication of the in- calcification occurs from the 14th ministration of tetracycline and fection.1.4 week in utero to 2-3 months of age. doxycycline.’ Tetracycline exposure during this time will affect only the deciduous HEPATIC Toxicity teeth. Permanent tooth calcification In general, tetracyclines should be takes place between the ages of 4 avoided in patients with hepatic REPRODUCTION months and 8 years?,” disease because of the catabolic or Tetracyclines are pregnancy cate- antianabolic effects that may yield a gory D, mainly due to their effects on SKIN nitrogen load requiring hepatic me- fetal bone and teeth (see below). Phototoxicity was noted to occur in tabolism. Fine vacuoles, cytoplas- Tetracyclines may reduce the effec- 40 of 2,682 (1.6%) patients treated mic changes, and increased deposi- tiveness of oral contraceptives; with tetracycline and six of 15 tion of fat have been noted to occur however, this effect has not been (40%) using doxycycline? This in the liver of patients treated with confirmed in all investigations.5B6 photosensitivity was evident only these drugs. Pregnant women are when skin was exposed to sunlight particularly susceptible to severe BREASTFEEDING containing rays in the range of tetracycline-induced hepatic inju- 270-320 nm range. This type of ry.2 Available data suggest that an insig- radiation is filtered out by ordinary nificant amount of tetracycline is window glass. All photosensitiza- NERVOUS SYSTEM excreted into breast milk. In addition effects are reversible, and per- tion, one study showed that the Dizziness, tinnitus, and vertigo manent injury to the skin does not drug that is excreted is bound to have been reported and are com- occur.1*2.6 calcium, which retards its absorp- pletely reversible. Case reports of tion in the fetus. Review of the pseudotumor cerebri have also been literature shows that no cases of GASTROINTESTINAL associated with tetracycline use.’ tooth staining in breastfed infants The high antibiotic concentrations RENAL subsequent to maternal ingestion of reached in the intestine alter enteric tetracyclines have been well docu- flora, and stools may become soft, Tetracyclines may aggravate uremia mented. Assays on infants breastfed odorless, and yellow-green in color. in patients with renal disease be- by mothers using tetracyclines all Epigastric burning, nausea, vomit- cause, at higher concentrations, the

225 LYNN

Table 1. Clinical Application of Tetracycline and Doxycycline in Obstetrics and Gynecology Dose and Duration of Condition Causative Organisms Therapy Remarks Acne (inflammatory Skin flora TCN 250-500 mg BID for Alternatives: topical tretinoin and type) 6-8 wk 10% benzoyl peroxide, erythromycin 256-500 mg BID- TID, or minocycline 100 mg BID Actinomycosis Actinomyces israelii DCN 100 mg BID for 2-6 mo Alternative: penicillin V 500 mg TCN 500 mg QID for 2-6 mo QD Cervicitis Chlamydia trachomatis, DCN 100 mg BID for 7 d Alternatives: erythromycin 500 mg Neisseria gonorrhoeae TCN 500 mg QID for 7 d QID for 7 d, ofloxacin 300 mg BID for 7 d, or azithromycin 1 g in a single oral dose. Ceftriaxone, 125-500 mg IM, or cefixime, 400 mg in a single oral dose, are recommendedto eradicate gonorrhea Endometritis Vaginal flora DCN 100 mg BID for 7 d Alternatives: TCN 500 mg QID for 7 d amoxicillin/clavulanate 500 mg TID or erythromycin 500 mg QID for 7 d Granuloma inguinale Calymmatobacterium DCN 100 mg BID for 3-5 wk Erythromycin 500 mg QID for (donovanosis) granulomatis TCN 500 mg QID for 3-5 wk 3-5 wk is usedin pregnancy Treatment with TMP-SMZ has been reported to be effective Lymphogranuloma C. trachomatis DCN 100 mg BID for 21 d Alternative: erythromycin 500 mg venereum QIDfor21 d Lyme disease Borrelia burgdorferi DCN 100 mg BID for 10-20 d Alternatives: penicillin V or TCN 500 mg QID for lo-20 d erythromycin, both 500 mg QID for 10-20 d Nongonococcal Ureaplasma urealyticum, DCN 100 mg BID for 7 d Alternatives: see those listed for urethritis C. trachomatis TCN 500 mg QID for 7 d cervicitis (above) Pelvic inflammatory C. trachomatis, N. Outpatient: cefoxitin 2 g IM Spectinomycin 2 g IM given once disease gonorrhoeae, Gram- plus probenecid 1 g po may be substituted for the negative rods, Anaerobes once or ceftriaxone 250 mg cephalosporin in penicillin- IM once, followed by DCN allergic patients 100 mg po BID or TCN 500 mg po QID for IO-14 d Inpatient: cefotetan 2 g IV An alternative inpatient regimen every 12 h or cefoxitin 2 g consistsof gentamicin and IV every 6 h plus DCN clindamycin until afebrile, 100 mg IV or po every 12 h; followed by DCN 100 mg BID for DCN should be continued a total of 10-14 d of antibiotic for 10-14 d therapy

TCN, tetracycline; BID, two times a day; TID. three times a day; DCN, doxycycline; QID. four times a day; IM, intramuscularly; TMP-SMZ. trimethoprim- sulfamethoxazole; po. orally; IV, intravenously.

drugs may cause alterations of hu- cycline or doxycycline overdosage ALLERGIC man protein synthesis. If treatment is supportive only; dialysis is of no Accounts of severe hypersensitive of a patient with renal insufficiency benefit’s6 reactions are rare but have been is necessary, dosing should be in- known to occur.’ creased to every 18-24 hours for doxycycline and every 8-12 hours HEMATOLOGIC for tetracycline. Outdated tetracycline also has been associated with Tetracycline can depress plasma Spectrum of Activity Fanconi syndrome (cystine storage prothrombin activity, requiring ad- and Clinical Applications disease associated with renal tubu- justment of dosing of anticoagu- lar defects) due to an acid excipient lants. It also can cause severe throm- The use of tetracyclines in animal that was once used in the manufac- bophlebitis when administered feeds and in treatment of infectious turing process. Treatment of tetra- intravenous1y.l diseases through the years has re-

226 Prim Care Update Ob/Gyns TETRACYCLINE/DOXYCYCLINE

sulted in increasing bacterial resis- a day, would cost $15 and $9, re- eds. Drug evaluation monograph: tance to these drugs. Although tet- spectively. If a dose is missed, the doxycycline and tetracycline. Den- ver (CO): Micromedex Inc., 1985: racyclines are considered to have patient should immediately take the VoI. 85. the broadest antibacterial spectrum missed dose and then the next dose 3. Neuvonen PJ. Interaction with the of any class of antibiotics, many as previously scheduled, unless the absorption of tetracyclines. Drugs pathogenic organisms such as subsequent dose is due within the 1976;11:45-54. group-B and group-D streptococci, next 2 hours. In that case, the 4. Barza M, Scheife R. Antimicrobial Staphylococcus aureus, Pseudomo- missed dose should not be taken to spectrum, pharmacology, and ther- nas aeruginosa, Neisseria gonor- avoid double dosing, which in- apeutic use of antibiotics. J ME Med rhoeae, and Bacteroides fragilis are creases the risk of toxic side effects, Assoc 1977;68:194-212. 5. Neely NL, Abate M, Swinker M, resistant to the drug. This resis- especially to the gastrointestinal D’Angio R. The effect of doxycy- tance, along with the availability of tract.6 cline on the serum levels of ethinyl superior antimicrobial agents, has estradiol, norethindrone, and en- limited the number of indications dogenous progesterone. Obstet Gy- for the use of tetracyclines. Never- Conclusion necol 1991;77:416-20. theless, these agents are still of 6. Parke Davis. Product information: value in many infectious diseases When used appropriately, tetracy- doryx, doxycycline. Ann Arbor cline and doxycycline continue to (MI): Parke Davis, 1987. that are of particular interest to the 7. Winckler K. Tetracycline ulcers of obstetrician/gynecologist.‘.* Table be effective antimicrobials in the the oesophagus. Endoscopy 1981; 1 summarizes the clinical applica- treatment of a number of infectious 13:225-8. tion of tetracycline and doxycycline diseases. Although the two medica- 8. Sanford JP. Guide to antimicrobial in clinical practice.*.“.‘” tions are similar, doxycycline may therapy, 1993. Bethesda (MD]: San- be taken with food, is better toler- ford, 1993. ated, and need only be administered 9. Centersfor DiseaseControl and Pre- twice daily. If these differences im- vention. Recommended treatment Cost and schedules,1993. Atlanta (GA): CDC, Dispensing Information prove patient compliance, then it 1993. justifies the slightly higher cost of 10. Levallois P, Rioux JE. Prophylactic Tetracycline is supplied in 250- and doxycycline and favors its use over antibiotics for suction curettage 500-mg capsules and doxycycline tetracycline in most situations. abortion: results of a clinical con- in 50- and 100-mg tablets and cap- trolled trial. Am J Obstet Gynecol sules. A typical i’-day course of 1988:158:100-5. generic tetracycline and doxycy- References cline costs approximately $5 and 1. Goodman L, Gilman A. The phar- macologic basis of therapeutics. Address correspondence and reprint re- $9, respectively. As a comparison, a Macmillan Publishing Co., 1985: quests to Sean F. Lynn, MD, Dept. of i’-day course of generic cephalexin 1170-8. Ob/Gyn, University of Florida, P.O. Box or erythromycin, 500 mg four times 2. Gelman CR, Rumack BH, Hoff AJ, 100294, GainesvilJe, FL 3261 O-0294.

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