Doxycycline Hyclate

DOXYCYCLINE HYCLATE- doxycycline hyclate tablet
Novel Laboratories, Inc.

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

DESCRIPTION

Doxycycline is an antibacterial drug synthetically derived from oxytetracycline, and is available as Doxycycline Hyclate Tablets (doxycycline hydrochloride hemiethanolate hemihydrate) for oral administration.

The structural formula of doxycycline hyclate is:

structure
(click image for full-size original)

The chemical designation for doxycycline is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrate. The molecular formula for doxycycline hydrochloride hemiethanolate hemihydrate is (C22 H24 N2 O8 •HCl)2 •C2 H6 O•H2 O and the molecular weight is 1025.89. Doxycycline is a light-yellow crystalline powder. Doxycycline hyclate is soluble in water.

Doxycycline has a high degree of lipoid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.

Inert ingredients are: colloidal silicon dioxide, corn starch, croscarmellose sodium, docusate sodium, magnesium stearate, microcrystalline cellulose, ethyl alcohol and a coating containing hypromellose, polyethylene glycol, titanium dioxide, FD&C Blue No. 2 and FD&C Yellow No. 6.

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

Mechanism of Action

Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria.

Resistance

Cross resistance with other tetracyclines is common.

Antimicrobial Activity

Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for doxycycline hyclate.

Gram-Negative Bacteria Acinetobacter species

Bartonella bacilliformis

Brucella species

Klebsiella species

Klebsiella granulomatis

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

Gram-Positive Bacteria Bacillus anthracis

Listeria monocytogenes Streptococcus pneumoniae

Anaerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes

Other Bacteria Nocardiae and other aerobic Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema pallidum subspecies pertenue

Ureaplasma urealyticum

Parasites Balantidium coli Entamoeba species 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 Testing Methods:

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

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 test method1,2,4, (broth or agar). The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method1,3,4. This procedure uses paper disks impregnated with 30-μg doxycycline to test the susceptibility of microorganisms to doxycycline. The disk diffusion interpretive criteria are provided in Table 1.

Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method5. The MIC values obtained should be interpreted according to the criteria provided in Table 1.

Table 1 : Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline
Bacteriaa Minimal Inhibitory Concentration ( mcg / mL ) Zone Diameter ( mm ) Agar Dilution ( mcg / mL )
S I R S I R S I R
Acinetobacter spp .
Doxycycline ≤4 8 ≥16 ≥13 10-12 ≤9
Tetracycline ≤4 8 ≥16 ≥15 12-14 ≤11
Anaerobes
Tetracycline ≤4 8 ≥16
Bacillus anthracisb
Doxycycline ≤1
Tetracycline ≤1
Brucella speciesb
Doxycycline ≤1
Tetracycline ≤1
Enterobacteriaceae
Doxycycline ≤4 8 ≥16 ≥14 11-13 ≤10
Tetracycline ≤4 8 ≥16 ≥15 12-14 ≤11
Franciscella tularensisb
Doxycycline ≤4
Tetracycline ≤4
Haemophilus influenzae
Tetracycline ≤2 4 ≥8 ≥29 26-28 ≤25
Mycoplasma pneumoniaeb
Tetracycline ≤2
Norcardiae and other aerobic Actinomyces speciesb
Doxycycline ≤1 2-4 ≥8
Neisseria gonorrhoeaec
Tetracycline ≥38 31-37 ≤30 ≤0.25 0.5-1 ≥2
Streptococcus pneumoniae
Doxycycline ≤0.25 0.5 ≥1 ≥28 25-27 ≤24
Tetracycline ≤1 2 ≥4 ≥28 25-27 ≤24
Vibrio cholerae
Doxycycline ≤4 8 ≥16
Tetracycline ≤4 8 ≥16
Yersinia pestis
Doxycycline ≤4 8 ≥16
Tetracycline ≤4 8 ≥16
Ureaplasma urealyticum
Tetracycline ≤1 ≥2
a Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline.b The current absence of resistance isolates precludes defining any results other than “Susceptible.” If isolates yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. c Gonococci with 30mcg tetracycline disk zone diameters of <19 mm usually indicate a plasmid-mediated tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution test (MIC ≥16mcg per mL).

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) 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 product is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistan t (R) indicates that the antimicrobial drug is not likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3,4,5,6,7. Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline
QC Strain Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm) Agar Dilution (mcg/mL)
Enterococcus faecalis ATCC 29212
Doxycycline 2-8
Tetracycline 8-32
Escherichia coli ATCC 25922
Doxycyline 0.5-2 18-24
Tetracycline 0.5-2 18-25
Eggerthella lenta ATCC 43055
Doxycycline 2-16
Haemophilus influenzae ATCC 49247
Tetracycline 4-32 14-22
Neisseria gonorrhoeae ATCC 49226
Tetracycline 30-42 0.25-1
Staphylococcus aureus ATCC 25923
Doxycyline 23-29
Tetracycline 24-30
Staphylococcus aureus ATCC 29213
Doxycyline 0.12-0.5
Tetracycline 0.12-1
Streptococcus pneumoniae ATCC 49619
Doxycycline 0.015-0.12 25-34
Tetracycline 0.06-0.5 27-31
Bacteroides fragilis ATCC 25285
Tetracycline 0.12-0.5
Bacteroides thetaiotaomicron ATCC 29741
Doxycycline 2-8
Tetracycline 8-32
Mycoplasma pneumoniae ATCC 29342
Tetracycline 0.06-0.5 0.06-0.5
Ureaplasma urealyticum ATCC 33175
Tetracycline ≥8
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