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Mechanism of Action
Doxycycline is virtually completely absorbed after oral administration. Following administration of a single 200 mg dose to adult volunteers, average peak serum doxycycline levels were 2.6 mcg/mL at 2 hours, decreasing to 1.45 mcg/mL at 24 hours. The mean Cmax and AUC0-∞ of doxycycline are 24 percent and 13 percent lower, respectively, following single dose administration of DORYX Tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean Cmax of doxycycline is 19 percent lower and the AUC0-∞ is unchanged following single dose administration of DORYX Tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown. When DORYX Tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly. Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40 percent/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1 to 5 percent/72 hours in individuals with a creatinine clearance below 10 mL/min.
Studies have shown no significant difference in the 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.
The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including doxycycline, have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance between tetracyclines is common.
Because isolates of the following gram-negative, gram-positive, anaerobic and other microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing, when possible, is recommended prior to initiating therapy.
Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure based on dilution methods (broth, agar, or microdilution),5,7 or equivalent using standardized inoculum and concentrations of doxycycline. The MIC values should be interpreted according to the criteria provided in Table 1.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standard procedure6,7 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 meg doxycycline to test the susceptibility of microorganisms to doxycycline. Interpretation involves the correlation of the diameter obtained in the disk test with the MIC for doxycycline. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 meg doxycycline disk should be interpreted according to the criteria in Table 1:
Table 1: Susceptibility Test Interpretive Criteria for Doxycycline
|Pathogen|| Susceptibility Interpretive Criteria
| Disk Diffusion Zone
Diameter(mm) - 30 mcg disk
|Acinetobacter spp.||≤4||8||≥16||≤9||10 to 12||≥13|
|Enterobacteriaceae||≤4||8||≥16||≤10||11 to 13||≥14|
|nterococcus faecalis and faecium||<4||8||≥16||≤12||13 to 15||≥16|
|aThe current absence of resistance isolates precludes defining any results other than "Susceptible". Isolates yielding results other than susceptible should be subjected to additional testing.|
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.5,6,7 Standard doxycycline powder should provide the MIC values provided in Table 2. For the diffusion technique using the 30 mcg tigecycline disk the criteria provided in Table 2 should be achieved.
Table 2: Acceptable Quality Control Ranges for Doxycycline
to be Used for Validation of Susceptibility Test Results
|Pathogen|| Acceptable Quality Control Ranges
Minimal Inhibitory Concentration (mcg/mL)
| Disk Diffusion Zone
Diameter (mm) - 30 mcg disk
|Enterococcus faecalis ATCC 29212||2 to 8||NONE|
|Escherichia coli ATCC 25922||0.5 to 2||18 to 24|
|Staphylococcus aureus ATCC 25923 for Enterococcus spp.||Not Applicable||23 to 29|
|Staphylococcus aureus ATCC 29213 for Enterococcus spp., B. anthracis and F. tularensis||0.1 2 to 0.5||Not Applicable|
|Streptococcus pneumoniae ATCC 49619 for Brucella spp.||0.015 to 0.12||Not Applicable|
Animal Toxicology and/or Pharmacology
Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.
Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HC1, and tetracycline HC1, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.
Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.
Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.
1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195.
2. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528.
3. Home HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317.
4. Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing 2000; 225-226.
5. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - 7th ed. Approved Standard, CLSI document M7-A7, Vol. 26. CLSI, Wayne, PA. January 2006.
6. CLSI. Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests -9th ed. Approved Standard, CLSI document M2-A9, Vol. 26. CLSI, Wayne, PA. January 2006.
7. CLSI. Performance Standards for Antimicrobial Susceptibility Testing - 18th Informational Supplement. Approved Standard, CLSI document M100-S18, Vol. 28. CLSI, Wayne, PA. January 2008.
Last reviewed on RxList: 4/17/2012
This monograph has been modified to include the generic and brand name in many instances.
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