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Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form. Doxycycline is virtually completely absorbed after oral administration.
Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours, decreasing to 1.45 mcg/mL at 24 hours. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min.). This percentage excretion may fall as low as 1–5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min.). Studies have shown no significant difference in serum half-life of doxycycline (range 18–22 hours) in individuals with normal and severely impaired renal function.
Hemodialysis does not alter serum half-life.
Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.
Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Cross resistance with other tetracyclines is common.
Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for VIBRAMYCIN.
Nocardiae and other aerobic Actinomyces species
1Doxycycline 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 Testing Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals 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 test method1,2,4 (broth or agar). The MIC values should be interpreted according to criteria provided in Table 1.
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method1,3,4. This procedure uses paper disks impregnated with 30-μg doxycycline to test the susceptibility of microorganisms to doxycycline. The disk diffusion interpretive criteria are provided in Table 1.
For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method5. The MIC values obtained should be interpreted according to the criteria provided in Table 1.
Table 1: Susceptibility Test Interpretive Criteria for
Doxycycline and Tetracycline
|Bacteria*||Minimal Inhibitory Concentration (mcg/mL)||Zone Diameter (mm)||Agar Dilution (mcg/mL)|
|Doxycycline||≤ 4||8||≥ 16||≥ 13||10- 12||≤ 9||-||-||-|
|Tetracycline Anaerobes||≤ 4||8||≥ 16||≥ 15||12- 14||≤ 11||-||-||-|
|Tetracycline||-||-||-||-||-||-||< 4||8||> 16|
|Doxycycline||≤ 4||8||≥ 16||≥ 14||11- 13||≤ 10||-||-||-|
|Tetracycline||≤ 4||8||≥ 16||≥ 15||12 -14||≤ 11||-||-||-|
|Tetracycline||≤ 2||4||≥ 8||≥ 29||26- 28||≤ 25||-||-||-|
|Nocardiae and other aerobic Actinomyces species†|
|Doxycycline||≤ 1||2-4||≥ 8|
|Neisseria gonorrhoeae ‡|
|Tetracycline||-||-||-||≥ 38||31- 37||≤ 30||< 0.25||0.5- 1||> 2|
|Doxycycline||≤ 0.25||0.5||≥ 1||≥ 28||25- 27||≤ 24||-||-||-|
|Tetracycline||≤ 1||2||≥ 4||≥ 28||25- 27||≤ 24|
|Doxycycline||≤ 4||8||≥ 16|
|Tetracycline||≤ 4||8||≥ 16|
|Doxycycline||≤ 4||8||≥ 16|
|Tetracycline||≤ 4||8||≥ 16|
|Tetracycline||-||-||-||-||-||-||≤ 1||-||≥ 2|
|* Organisms susceptible to tetracycline are also
considered susceptible to doxycycline. However, some organisms that are
intermediate or resistant to tetracycline may be susceptible to doxycycline
† The current absence of resistance isolates precludes defining any results other than “Susceptible”. If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
‡ Gonococci with 30 mcg tetracycline disk zone diameters of < 19 mm usually indicate a plasmid-mediated tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC ≥ 16 mcg/mL)
A report of “Susceptible” (S) indicates that the antimicrobial drug is likely to inhibit growth of the microorgamism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria 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 product 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 (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; 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 test1,2,3,4,5,6,7. Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 should be achieved.
Table 2: Acceptable Quality Control Ranges for
Susceptibility Testing for Doxycycline and Tetracycline
|QC Strain||Minimal Inhibitory Concentration (mcg/mL)||Zone Diameter (mm)||Agar Dilution (mcg/mL)|
|Enterococcus faecalis ATCC 29212|
|Doxycycline||2 - 8||-||-|
|Tetracycline||8 - 32||-||-|
|Escherichia coli ATCC 25922|
|Doxycycline||0.5 - 2||18 - 24||-|
|Tetracycline||0.5 - 2||18 - 25||-|
|Eubacteria lentum ATCC 43055|
|Doxycycline||2 - 16|
|Haemophilus influenzae ATCC 49247|
|Tetracycline||4 - 32||14 - 22||-|
|Neisseria gonorrhoeae ATCC 49226|
|Tetracycline||-||30 - 42||0.25 - 1|
|Staphylococcus aureus ATCC 25923|
|Doxycycline||-||23 - 29||-|
|Staphylococcus aureus ATCC 29213|
|Tetracycline||0.12 - 1||-||-|
|Streptococcus pneumoniae ATCC 49619|
|Doxycycline||0.015 - 0.12||25 - 34||-|
|Tetracycline||0.06 - 0.5||27 - 31||-|
|Bacteroides fragilis ATCC 25285|
|Tetracycline||-||-||0.12 - 0.5|
|Bacteroides thetaiotaomicron ATCC 29741|
|Doxycycline||2 - 16|
|Tetracycline||-||-||8 - 32|
|Mycoplasma pneumoniae ATCC 29342|
|Ureaplasma urealyticum ATCC 33175|
Animal Pharmacology And Animal Toxicology
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 HCl, and tetracycline HCl 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.
1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fourth Informational Supplement, CLSI document M100-S24. CLSI document M100-S24, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2014.
2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Second Edition CLSI document M45-A2, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2010.
5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
6. Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard—Second Edition. CLSI document M24-A2. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2011.
7. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2011.
Last reviewed on RxList: 5/18/2015
This monograph has been modified to include the generic and brand name in many instances.
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