Vibramycin (Doxycycline Monohydrate) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

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.

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 organisms. Cross-resistance of these organisms to tetracyclines is common.

Gram-Negative Bacteria

• Neisseria gonorrhoeae
• Calymmatobacterium granulomatis
• Haemophilus ducreyi
• Haemophilus influenzae
• Yersinia pestis (formerly Pasteurella pestis)
• Francisella tularensis (formerly Pasteurella tularensis)
• Vibrio cholerae (formerly Vibrio comma)
• Bartonella bacilliformis
• Brucella species

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:

• Escherichia coli
• Klebsiella species
• Enterobacter aerogenes
• Shigella species
• Acinetobacter species (formerly Mima species and Herellea species)
• Bacteroides species

Gram-Positive Bacteria

Because many strains of the following groups of 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 Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracycline should not be used for streptococcal disease unless the organism has been demonstrated to be susceptible.

• Streptococcus pyogenes
• Streptococcus pneumoniae
• Enterococcus group (Streptococcus faecalis and Streptococcus faecium)
• Alpha-hemolytic streptococci (viridans group)

Other Microorganisms

• Rickettsiae
• Chlamydia psittaci
• Chlamydia trachomatis
• Mycoplasma pneumoniae
• Ureaplasma urealyticum
• Borrelia recurrentis
• Treponema pallidum
• Treponema pertenue
• Clostridium species
• Fusobacterium fusiforme
• Actinomyces species
• Bacillus anthracis
• Propionibacterium acnes
• Entamoeba species
• Balantidium coli
• Plasmodium falciparum

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 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 which has been recommended for use with disks to test susceptibility of organisms to doxycycline uses the 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for tetracycline or doxycycline, respectively.

Reports from the laboratory giving 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:

Zone Diameter (mm)		Interpretation
tetracycline	doxycycline
≥19	≥16	Susceptible
15–18	13–15	Intermediate
≤14	≤12	Resistant

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of "Intermediate" suggests that the organism would be susceptible if a high dosage is used or if the infection is confined to tissues and fluids in which high 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 class disk or the 30-mcg doxycycline disk should give the following zone diameters:

Organism	Zone Diameter (mm)
	tetracycline	doxycycline
E. coli ATCC 25922	18–25	18–24
S. aureus ATCC 25923	19–28	23–29

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	Susceptible
8	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	MIC (mcg/mL)
E. coli ATCC 25922	1.0–4.0
S. aureus ATCC 29213	0.25–1.0
E. faecalis ATCC 29212	8–32
P. aeruginosa ATCC 27853	8–32

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.