CLINICAL PHARMACOLOGY
Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. Doxycycline is virtually completely absorbed after oral administration.
Following a 200 mg dose of doxycycline monohydrate, 24 normal adult volunteers averaged the following serum concentration values:
| Time (hr): | 0.5 | 1.0 | 1.5 | 2.0 | 3.0 | 4.0 | 8.0 | 12.0 | 24.0 | 48.0 | 72.0 |
| Conc. | 1.02 | 2.26 | 2.67 | 3.01 | 3.16 | 3.03 | 2.03 | 1.62 | 0.95 | 0.37 | 0.15 (mcg/mL) |
Average Observed Values | Maximum Concentration | 3.61 mcg/mL (± 0.9 sd) |
| Time of Maximum Concentration | 2.60 hr (± 1.10 sd) |
| Elimination Rate Constant | 0.049 per hr (± 0.030 sd) |
| Half-Life | 16.33 hr (± 4.53 sd) |
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.
Microbiology: 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 microorganisms. Cross-resistance of these microorganisms to tetracyclines is common.
Doxycycline has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic Gram-Positive Microorganisms:
Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended.
Bacillus anthracis
Listeria monocytogenes
Staphylococcus aureus*
*Doxycycline is not the drug of choice in the treatment of any type of staphylococcal infection.
Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracyclines should not be used to treat streptococcal infections unless the microorganism has been demonstrated to be susceptible.
Streptococcus pneumoniae
Aerobic Gram-Negative Microorganisms:
| Bartonella bacilliformis | Haemophilus ducreyi |
| Brucella species | Haemophilus influenzae |
| Calymmatobacterium granulomatis | Neisseria gonorrhoeae |
| Campylobacter fetus | Vibrio cholerae |
| Francisella tularensis | Yersinia pestis |
Because many strains of the following groups of gram-negative microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended:
| Acinetobacter species | Klebsiella species |
| Enterobacter aerogenes | Shigella species |
| Escherichia coli | |
Anaerobic Microorganisms:
| Actinomyces israelii | Fusobacterium fusiforme |
| Clostridium species | |
Other Microorganisms:
| Borrelia recurrentis | Rickettsiae |
| Chlamydia psittaci | Treponema pallidum |
| Chlamydia trachomatis | Treponema pertenue |
| Mycoplasma pneumoniae | |
Susceptibility Tests:
Dilution Techniques:
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC’s). These MIC’s provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC’s should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tetracycline powder. The MIC values should be interpreted according to the following criteria for indicated aerobic microorganisms other than Haemophilus species, Neisseria gonorrhoeae, and Streptococcus pneumoniae:
| MIC (mcg/mL) | Interpretation |
| ≤ 4 | Susceptible (S) |
| 8 | Intermediate (I) |
| ≥ 16 | Resistant (R) |
| When testing Haemophilus spp.a | |
| MIC (mcg/mL) | Interpretation |
| ≤ 2 | Susceptible (S) |
| 4 | Intermediate (I) |
| ≥ 8 | Resistant (R) |
| When testing Neisseria gonorrhoeae b | |
| MIC (mcg/mL) | Interpretation |
| ≤ 0.25 | Susceptible (S) |
| 0.5-1 | Intermediate (I) |
| ≥ 2 | Resistant (R) |
| When testing Streptococcus pneumoniae c | |
| MIC (mcg/mL) | Interpretation |
| ≤ 2 | Susceptible (S) |
| 4 | Intermediate (I) |
| ≥ 8 | Resistant (R) |
| a. Interpretative criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1,3 |
| b. Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.1,3 |
| c. Interpretative criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1,3 |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood 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 which 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 in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard tetracycline powder should provide the following MIC values:
| Microorganism | | MIC (mcg/mL) |
| Enterococcus faecalis | ATCC 29212 | 8-32 |
| Escherichia coli | ATCC 25922 | 0.5-2 |
| Haemophilus influenzae a | ATCC 49247 | 4-32 |
| Neisseria gonorrhoeae b | ATCC 49226 | 0.25-1 |
| Pseudomonas aeruginosa | ATCC 27853 | 8-32 |
| Staphylococcus aureus | ATCC 29213 | 0.12-1 |
| Streptococcus pneumoniae c | ATCC 49619 | 0.12-0.5 |
| a. Range applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1,3 |
| b. Range applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.1,3 |
| c. Range applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.1,3 |
Diffusion Techniques:
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-mcg tetracycline or 30-mcg doxycycline to test the susceptibility of microorganisms to doxycycline.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk should be interpreted according to the following criteria for indicated aerobic microorganisms other than Haemophilus species, Neisseria gonorrhoeae, and Streptococcus pneumoniae:
| Zone Diameter (mm) | Interpretation |
| tetracycline | doxycycline | |
| ≥ 19 | ≥ 16 | Susceptible (S) |
| 15-18 | 13-15 | Intermediate (I) |
| ≤ 14 | ≤ 12 | Resistant (R) |
| When testing Haemophilus spp. a |
| Zone Diameter (mm) | Interpretation |
| tetracycline | |
| ≥ 29 | Susceptible (S) |
| 26-28 | Intermediate (I) |
| ≤ 25 | Resistant (R) |
| When testing Neisseria gonorrhoeae b | |
| Zone Diameter (mm) | Interpretation |
| tetracycline | |
| ≥ 38 | Susceptible (S) |
| 31-37 | Intermediate (I) |
| ≤ 30 | Resistant (R) |
| Zone diameters ≤ 19 mm may indicate a plasmid-mediated tetracycline-resistant Neisseria gonorrhoeae (TRNG) isolate. These TRNG strains should be confirmed by the dilution test (MIC ≥ 16 mcg/mL). When testing Streptococcus pneumoniae c |
| Zone Diameter (mm) | Interpretation |
| tetracycline | |
| ≥ 23 | Susceptible (S) |
| 19-22 | Intermediate (I) |
| ≤ 18 | Resistant (R) |
| a. Interpretative criteria applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using Haemophilus Test Medium (HTM).2,3 |
| b. Interpretative criteria applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using GC agar base with 1% defined growth supplement. 2,3 |
| c. Interpretative criteria applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO2.2,3 |
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tetracycline or doxycycline, respectively.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk should provide the following zone diameters in these laboratory test quality control strains:
| Microorganism | | Zone Diameter (mm) |
| | tetracycline | doxycycline |
| Escherichia coli | ATCC 25922 | 18-25 | 18-24 |
| Haemophilus influenzae a | ATCC 49247 | 14-22 | _ |
| Neisseria gonorrhoeae b | ATCC 49226 | 30-42 | _ |
| Staphylococcus aureus | ATCC 25923 | 24-30 | 23-29 |
| Streptococcus pneumoniae c | ATCC 49619 | 27-31 | _ |
| a. Range applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using Haemophilus Test Medium (HTM).2,3 |
| b. Range applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using GC agar base with 1% defined growth supplement.2,3 |
| c. Range applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO2.2,3 |
Anaerobic Techniques:
For anaerobic bacteria, the susceptibility to tetracycline as MIC’s can be determined by standardized test methods.4 The MIC values obtained should be interpreted according to the following criteria:
| MIC (mcg/mL) | Interpretation |
| ≤ 4 | Susceptible (S) |
| 8 | Intermediate (I) |
| ≥ 16 | Resistant (R) |
Interpretation is identical to that stated above for results using dilution techniques.
As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized tetracycline powder should provide the following MIC values:
| Microorganism | | MIC (mcg/mL) |
| Bacteroides fragilis a | ATCC 25285 | 0.12-0.5 |
| Bacteroides thetaiotaomicron a | ATCC 29741 | 8-32 |
| a. Range applicable only to tests performed by the reference agar dilution method. |
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