Demeclocycline (Demeclocycline Hydrochloride) - Description and Clinical Pharmacology

1007010102
Rx only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of demeclocycline and other antibacterial drugs, demeclocycline should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Description:

Demeclocycline hydrochloride is an antibiotic isolated from a mutant strain of Streptomyces aureofaciens. Chemically it is 7-Chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12, 12a-pentahydroxy-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride. The structural formula is as follows:

C₂₁H₂₁CIN₂O_8● Hcl Molecular Weight: 501.32

Each film coated tablet, for oral administration contains 150 mg or 300 mg of demeclocycline hydrochloride, and contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, FD&C red no. 40, FD&C yellow no. 6, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, sodium stearyl fumarate, and titanium dioxide.

Clinical Pharmacology:

Pharmacokinetics:

The absorption of demeclocycline is slower than that of tetracycline. The time to reach the peak concentration is about 4 hours. After a 150 mg oral dose of demeclocycline tablet, the mean concentrations at 1 hour and 3 hours are 0.46 and 1.22 mcg/mL (n = 6), respectively. The serum half-life ranges between 10 and 16 hours.

When demeclocycline hydrochloride is given concomitantly with some dairy products, or antacids containing aluminum, calcium, or magnesium, the extent of absorption is reduced by more than 50%.

Demeclocycline hydrochloride penetrates well into various body fluids and tissues. The percent of demeclocycline hydrochloride bound to plasma protein is about 40% using a dialysis equilibrium method and 90% using an ultra-filtration method. Demeclocycline hydrochloride, like other tetracyclines, is concentrated in the liver and excreted into the bile where it is found in much higher concentrations than in the blood. The rate of demeclocycline hydrochloride renal clearance (35 mL/min/1.73 m²) is less than half that of tetracycline. Following a single 150 mg dose of demeclocycline hydrochloride in normal volunteers, 44% (n = 8) was excreted in urine and 13% and 46%, respectively, were excreted in feces in two patients within 96 hours as active drug.

Microbiology:

The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including demeclocycline, have a similar antimicrobial spectrum of activity against a wide range of gram-negative and gram-positive organisms. Cross-resistance of these organisms to tetracyclines is common.

Demeclocycline 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:

Bacillus anthracis

Listeria monocytogenes

Staphylococcus aureus

Streptococcus pneumoniae

AEROBIC GRAM-NEGATIVE MICROORGANISMS:

Bartonella bacilliformis

Brucella species

Calymmatobacterium granulomatis

Campylobacter fetus

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

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

Enterobacter aerogenes

Escherichia coli

Klebsiella species

Shigella species

OTHER MICROORGANISMS:

Actinomyces israelii

Borrelia recurrentis

Chlamydia psittaci

Chlamydia trachomatis

Clostridium species

Entamoeba species

Fusobacterium fusiforme

Mycoplasma pneumoniae

Propionibacterium acnes

Rickettsiae

Treponema pallidum subspecies pallidum

Treponema pallidum subspecies pertenue

Ureaplasma urealyticum

Susceptibility Tests:

Dilution Techniques: 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 procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of demeclocycline hydrochloride or tetracycline powder.¹ The MIC values should be interpreted according to the following criteria:

For organisms other than Haemophilus species, Neisseria gonorrhoeae and Streptococcus species:²

MIC mcg/mL)	Interpretation
≤ 4	Susceptible (S)
8	Intermediate (I)
≥ 16	Resistant (R)

For Haemophilus and Streptococcus species:²

MIC mcg/mL)	Interpretation
≤ 2	Susceptible (S)
4	Intermediate (I)
≥ 8	Resistant (R)

 For Neisseria gonorrhoeae:²

MIC mcg/mL)	Interpretation
≤ 0.25	Susceptible (S)
0.5 to 1	Intermediate (I)
≥ 2	Resistant (R)

A report of “Susceptible” indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. 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 usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that 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 demeclocycline or tetracycline powder should provide the following MIC values:²

Microorganism	MIC (mcg/mL)
E. coli, ATCC 25922	1 to 4
E. faecalis, ATCC 29212	8 to 32
H. influenzae, ATCC 49247	4 to 32
N. gonorrhoeae, ATCC 49226	0.25 to 1
S. aureus, ATCC 29213	0.25 to 1
S. pneumoniae, ATCC 49619	0.12 to 0.5

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 procedure requires the use of standardized inoculum concentrations.² This procedure uses paper disks impregnated with 30-mcg tetracycline (as a class disk) or a 30-mcg demeclocycline hydrochloride disk to test the susceptibility of microorganisms to demeclocycline.

Reports from the laboratory providing results of the standard single-disk susceptibility test with either a 30-mcg tetracycline-class disk or a 30-mcg demeclocycline disk should be interpreted according to the following criteria:

For organisms other than Haemophilus species, Neisseria gonorrhoeae and Streptococcus species:² 

Zone Diameter (mm)	Interpretation
≥ 19	Susceptible (S)
15 to 18	Intermediate (I)
≤ 14	Resistant (R)

 For Haemophilus species:²

Zone Diameter (mm)	Interpretation
≥ 29	Susceptible (S)
26 to 28	Intermediate (I)
≤ 25	Resistant (R)

 For N. gonorrhoeae:²

Zone Diameter (mm)	Interpretation
≥ 38	Susceptible (S)
31 to 37	Intermediate (I)
≤ 30	Resistant (R)

 For Streptococcus species:²

Zone Diameter (mm)	Interpretation
≥ 23	Susceptible (S)
19 to 22	Intermediate (I)
≤ 18	Resistant (R)

  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 demeclocycline hydrochloride or tetracycline.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-mcg demeclocycline hydrochloride disk or the 30-mcg tetracycline-class disk should provide the following zone diameters in these laboratory test quality control strains:²

Microorganism	Zone Diameter (mm)
E. coli, ATCC 25922	18 to 25
H. influenzae, ATCC 49247	14 to 22
N. gonorrhoeae, ATCC 49226	30 to 42
S. aureus, ATCC 25923	24 to 30
S. pneumoniae, ATCC 49619	27 to 31

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.