Doxycycline Hyclate

DOXYCYCLINE HYCLATE- doxycycline hyclate capsule
NuCare Pharmaceuticals,Inc.

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

DESCRIPTION

Doxycycline hyclate, USP is an antibacterial drug synthetically derived from oxytetracycline for oral administration.

The structural formula of doxycycline monohydrate is

Structural Formula
(click image for full-size original)

with a molecular formula of C 22 H 24 N 2 O 8 •H 2 O and a molecular weight of 462.46. 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 (C 22 H 24 N 2 O 8 •HCl) 2 •C 2 H 6 O•H 2 O and the molecular weight is 1025.89.

Doxycycline, USP is a light-yellow crystalline powder. Doxycycline hyclate, USP is soluble in water.

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

Inert ingredients in the capsule formulations are: magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The hard gelatin capsule shells contains: FD&C Blue 1, gelatin, sodium lauryl sulfate and titanium dioxide. The printing ink contains: black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

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% to 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 to 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 the 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 method 1,2,4 (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 method 1,3,4. This procedure uses paper disks impregnated with 30-mcg 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 method 5. 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

Bacteria a

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 to 12

≤9

Tetracycline

≤4

8

≥16

≥15

12 to 14

≤11

Anaerobes

Tetracycline

≤4

8

≥16

Bacillus anthracis b

Doxycycline

≤1

Tetracycline

≤1

Brucella species b

Doxycycline

≤1

Tetracycline

≤1

Enterobacteriaceae

Doxycycline

≤4

8

≥16

≥14

11 to 13

≤10

Tetracycline

≤4

8

≥16

≥15

12 to 14

≤11

Franciscella tularensis b

Doxycycline

≤4

Tetracycline

≤4

Haemophilus influenzae

Tetracycline

≤2

4

≥8

≥29

26 to 28

≤25

Mycoplasma pneumoniae b

Tetracycline

≤2

Nocardiae and other aerobic Actinomyces species b

Doxycycline

≤1

2 to 4

≥8

Neisseria gonorrhoeae c

Tetracycline

≥38

31 to 37

≤30

≤0.25

0.5 to 1

≥2

Streptococcus pneumoniae

Doxycycline

≤0.25

0.5

≥1

≥28

25 to 27

≤24

Tetracycline

≤1

2

≥4

≥28

25 to 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 30 mcg 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 ≥16 mcg/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 Resistant (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 test 1,2,3,4,5,6,7. 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 to 8

Tetracycline

8 to 32

Escherichia coli ATCC 25922

Doxycycline

0.5 to 2

18 to 24

Tetracycline

0.5 to 2

18 to 25

Eggerthella lenta ATCC 43055

Doxycycline

2 to 16

Haemophilus influenzae ATCC 49247 Tetracycline

4 to 32

14 to 22

Neisseria gonorrhoeae ATCC 49226

Tetracycline

30 to 42

0.25 to 1

Staphylococcus aureus ATCC 25923

Doxycycline

23 to 29

Tetracycline

24 to 30

Staphylococcus aureus ATCC 29213

Doxycycline

0.12 to 0.5

Tetracycline

0.12 to 1

Streptococcus pneumoniae ATCC 49619

Doxycycline

0.015 to 0.12

25 to 34

Tetracycline

0.06 to 0.5

27 to 31

Bacteroides fragilis ATCC 25285

Tetracycline

0.12 to 0.5

Bacteroides thetaiotaomicron ATCC 29741

Doxycycline

2 to 8

Tetracycline

8 to 32

Mycoplasma pneumoniae ATCC 29342

Tetracycline

0.06 to 0.5

Ureaplasma urealyticum ATCC 33175

Tetracycline

≥8

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