CLINICAL PHARMACOLOGY
Minocycline hydrochloride tablets are rapidly absorbed from the gastrointestinal tract following oral administration. Following a single dose of one 100 mg tablet of minocycline hydrochloride administered to 28 normal fasting adult volunteers, maximum serum concentrations were attained in 1 to 3 hours (average 1.71 hours) and ranged from 491.71 to 1292.70 ng/mL (average 758.29 ng/mL). The serum half-life in the normal volunteers ranged from 11.38 to 24.31 hours (average 17.03 hours).
When minocycline hydrochloride tablets were given concomitantly with a meal, which included dairy products, the extent of absorption of minocycline hydrochloride tablets was slightly decreased (6%). The peak plasma concentrations were slightly decreased (12%) and delayed by 1.09 hours when administered with food, compared to dosing under fasting conditions.
In previous studies with other minocycline dosage forms, the minocycline serum half-life ranged from 11 to 16 hours in 7 patients with hepatic dysfunction, and from 18 to 69 hours in 5 patients with renal dysfunction. The urinary and fecal recovery of minocycline when administered to 12 normal volunteers is one-half to one-third that of other tetracyclines.
Microbiology
The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including minocycline, have similar antimicrobial spectra of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance of these organisms to tetracyclines is common.
Minocycline 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 gram-positive microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are especially recommended. Tetracycline antibiotics should not be used for streptococcal diseases unless the organism has been demonstrated to be susceptible. Tetracyclines are not the drug of choice in the treatment of any type of staphylococcal infection.
Bacillus anthracis †
Listeria monocytogenes †
Staphylococcus aureus
Streptococcus pneumoniae
AEROBIC GRAM-NEGATIVE MICROORGANISMS
Bartonella bacilliformis
Brucella species
Calymmatobacterium granulomatis
Campylobacter fetus
Francisella tularensis
Haemophilus ducreyi
Vibrio cholerae
Yersinia pestis
Because many strains of the following groups of gram-negative microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility tests are especially recommended.
Acinetobacter species
Enterobacter aerogenes
Escherichia coli
Haemophilus influenzae
Klebsiella species
Neisseria gonorrhoeae †
Neisseria meningitidis †
Shigella species
“OTHER” MICROORGANISMS
Actinomyces species†
Borrelia recurrentis
Chlamydia psittaci
Chlamydia trachomatis
Clostridium species†
Entamoeba species
Fusobacterium nucleatum ssp. fusiforme †
Mycobacterium marinum
Mycoplasma pneumoniae
Propionibacterium acnes
Rickettsiae
Treponema pallidum subspecies pallidum †
Treponema pallidum subspecies pertenue †
Ureaplasma urealyticum
†When penicillin is contraindicated, tetracyclines are alternative drugs in the treatment of infections caused by the cited microorganisms.
Susceptibility Tests
Susceptibility testing should be performed with tetracycline since it predicts susceptibility to minocycline. However, certain organisms (e.g., some staphylococci, and Acinetobacter ssp.) may be more susceptible to minocycline and doxycycline than tetracycline.
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs 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 testing aerobic gram-negative microorganisms (Enterobacteriaceae), Acinetobacter ssp. and Staphylococcus aureus.
| MIC (mcg/mL) | Interpretation |
| ≤ 4 | Susceptible (S) |
| 8 | Intermediate (I) |
| ≥ 16 | Resistant (R) |
For testing Haemophilus influenzae a and Streptococcus pneumoniae b:
| MIC (mcg/mL) | Interpretation |
| ≤ 2 | Susceptible (S) |
| 4 | Intermediate (I) |
| ≥ 8 | Resistant (R) |
a. These interpretative standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae using Haemophilus Test Medium.1
b. These interpretative standards are applicable only to broth microdilution susceptibility testing using cation-adjusted Muller-Hinton broth with 2 - 5% lysed horse blood.1
For testing Neisseria gonorrhoeae c:
| MIC (mcg/mL) | Interpretation |
| ≤ 0.25 | Susceptible (S) |
| 0.5-1 | Intermediate (I) |
| ≥ 2 | Resistant (R) |
c. These interpretative standards are applicable only to agar dilution susceptibility testing using GC agar base and 1% defined growth supplements.1
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) |
Escherichia coli
Enterococcus faecalis
Staphylococcus aureus
Haemophilus influenzae
Streptococcus pneumoniae
Neisseria gonorrhoeae | ATCC 25922 0.5-2
ATCC 29212 8-32
ATCC 29213 0.25-1
ATCC 49247 4-32
ATCC 49619 0.12-0.5
ATCC 49226 0.25-1
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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 (class disk) or 30 mcg minocycline to test the susceptibility of microorganisms to minocycline. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg tetracycline or minocycline disk should be interpreted according to the following criteria:
For testing aerobic gram-negative microorganisms (Enterobacteriaceae).
Acinetobacter ssp. and Staphylococcus aureu:
| Zone Diameter (mm) | Interpretation |
| ≥ 19 | Susceptible (S) |
| 15-18 | Intermediate (I) |
| ≤ 14 | Resistant (R) |
For testing Haemophilus influenzae d:
| Zone Diameter (mm) | Interpretation |
| ≥ 29 | Susceptible (S) |
| 26-28 | Intermediate (I) |
| ≤ 25 | Resistant (R) |
d. These zone diameter standards are applicable only to susceptibility testing with Haemophilus influenzae using Haemophilus Test Medium and a 30 mcg tetracycline disk.2
For testing Neisseria gonorrhoeae e:
| Zone Diameter (mm) | Interpretation |
| ≥ 38 | Susceptible (S) |
| 31-37 | Intermediate (I) |
| ≤ 30 | Resistant (R) |
e. These interpretative standards are applicable only to disk diffusion testing using GC agar and 1% growth supplements, and a 30 mcg tetracycline disk.2
For testing Streptococcus pneumoniae f:
| Zone Diameter (mm) | Interpretation |
| ≥ 23 | Susceptible (S) |
| 19-22 | Intermediate (I) |
| ≤ 18 | Resistant (R) |
f. These interpretative standards are applicable only to disk diffusion testing using Muller-Hinton agar adjusted with 5% sheep blood and a 30 mcg tetracycline-class disk.2
For testing Vibrio cholerae g:
| Zone Diameter (mm) | Interpretation |
| ≥ 19 | Susceptible (S) |
| 15-18 | Intermediate (I) |
| ≤ 14 | Resistant (R) |
g. These interpretative standards are applicable only to disk diffusion testing performed with a 30 mcg tetracycline-class disk.2
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.
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 or minocycline disk should provide the following zone diameters in these laboratory test quality control strains:
| Microorganism | | Zone Diameter Range (mm) |
| Tetracycline | Minocycline |
Escherichia coli
Staphylococcus aureus
Haemophilus influenzae
Neisseria gonorrhoeae
Streptococcus pneumoniae | ATCC 25922
ATCC 25923
ATCC 49247
ATCC 49226
ATCC 49619 | 18-25
24-30
14-22
30-42
27-31 | 19-25
25-30
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ANIMAL PHARMACOLOGY AND TOXICOLOGY
Minocycline hydrochloride has been observed to cause a dark discoloration of the thyroid in experimental animals (rats, minipigs, dogs and monkeys). In the rat, chronic treatment with minocycline hydrochloride has resulted in goiter accompanied by elevated radioactive iodine uptake and evidence of thyroid tumor production. Minocycline hydrochloride has also been found to produce thyroid hyperplasia in rats and dogs.
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