CLINICAL PHARMACOLOGY
Tetracyclines are adequately but incompletely absorbed from the gastrointestinal tract. Approximately 65 percent of a short-acting tetracycline is bound to plasma proteins; the plasma protein binding for intermediate- and long-acting analogues is usually greater.
Penetration of the tetracyclines into most body fluids and tissues is excellent. Tetracyclines are distributed in varying degrees into bile, liver, lung, kidney, prostate, urine, cerebrospinal fluid, synovial fluid, mucosa of the maxillary sinus, brain, sputum, and bone. Tetracyclines cross the placenta and enter the fetal circulation and amniotic fluid.
Following a single oral dose, peak plasma concentrations are achieved in two to four hours.
Tetracyclines are concentrated by the liver in the bile. They are excreted in both the urine and feces at high concentrations in a biologically active form. Since renal clearance of tetracyclines is by glomerular filtration, excretion is significantly affected by the state of renal function. (See WARNINGS.)
Microbiology
The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance of these organisms to tetracyclines is common. In addition, gram-negative bacilli made tetracycline-resistant, may also show cross-resistance to chloramphenicol.
GRAM-NEGATIVE BACTERIA
Bartonella bacilliformis
Brucella species
Calymmatobacterium granulomatis
Campylobacter fetus
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae
Listeria monocytogenes
Neisseria gonorrhoeae
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 testing are especially recommended:
Acinetobacter species
Bacteroides species
Enterobacter aerogenes
Escherichia coli
Klebsiella species
Shigella species
GRAM-POSITIVE BACTERIA
Enterococcus group [ Enterococcus faecalis (formerly Streptococcus faecalis) and Enterococcus
faecium (formerly Streptococcus faecium)]
Streptococci viridans group
Streptococcus pneumoniae
Streptococcus pyogenes
Because many strains of these gram-positive microorganisms have been shown to be resistant to tetracycline, culture and susceptibility testing are recommended. Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Enterococcus faecalis (formerly Streptococcus faecalis) have been found to be resistant to tetracycline drugs. Therefore, tetracyclines should not be used for treatment of streptococcal disease unless the organism is known to be susceptible.
OTHER MICROORGANISMS
Actinomyces species
Bacillus anthracis
Balantidium coli
Borrelia recurrentis
Chlamydia psittaci
Chlamydia trachomatis
Clostridium species
Entamoeba species
Fusobacterium fusiforme
Mycoplasma pneumoniae
Rickettsiae
Propionibacterium acnes
Treponema pallidum
Treponema pertenue
Ureaplasma urealyticum
Susceptibility Tests
DIFFUSION TECHNIQUES:
Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedure1 that has been recommended for use with disks to test susceptibility of microorganisms to tetracycline uses the 30-mcg tetracycline disk. Interpretation involves the correlation of the zone diameters obtained in the disk test with the minimum inhibitory concentration (MIC) for tetracycline.
Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30-mcg tetracycline disk should be interpreted according to the following criteria:
| Zone diameter (mm) | Interpretation |
| ≥ 19 | Susceptible |
| 15 – 18 | Intermediate |
| ≤ 14 | Resistant |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited by generally achievableblood levels. A report of “Intermediate” suggests that the organism would be susceptible if high dosage isused or if the infection is confined to tissues or fluids in which high antibiotic (or antimicrobial) levels are attained. A report of “Resistant” indicates that achievable concentrations are unlikely to be inhibitory and other therapy should be selected.
Standardized procedures require the use of laboratory control organisms. The 30-mcg tetracycline disk should give the following zone diameters:
| Organism | - | Zone Diameter (mm) |
| E. coli | ATCC25922 | 18 – 25 |
| S. aureus | ATCC25923 | 19 - 18 |
DILUTION TECHNIQUES:
Use a standardized dilution method2 (broth, agar, microdilution) or equivalent with tetracycline powder. The MIC values obtained should be interpreted according to the following criteria:
| MIC (mcg/mL) | Interpretation |
| ≤ 4.0 | Susceptible |
| > 4.0 < 16 | Intermediate |
| ≥ 16 | Resistant |
As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard tetracycline powder should provide the following MIC values:
| Organism | - | Zone Diameter (mm) |
| E. coli | ATCC25922 | 1 – 4 |
| S. aureus | ATCC29213 | 0.25 – 1 |
| E. faecalis | ATCC29212 | 8 – 32 |
| P. aeruginosa | ATCC27853 | 8 - 32 |
ANIMAL PHARMACOLOGY AND/OR 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.
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