Prescription Drug Information: Doxycycline Hyclate

DOXYCYCLINE HYCLATE- doxycycline hyclate tablet
C.O. Truxton, Inc.

Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline tablets and other antibacterial drugs, doxycycline 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 for oral administration.

The chemical designation of 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-naphthacene-carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate.

The structural formula of doxycycline hyclate is

structure
(click image for full-size original)

with a molecular formula of (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.

Active Ingredient: Doxycycline hyclate USP equivalent to 100 mg of doxycycline USP.

Inactive Ingredient: Microcrystalline cellulose and magnesium stearate.

Tablet coating contains hypromellose, titanium dioxide, polyethylene glycol, FD&C yellow #6, polysorbate 80 and FD&C blue #2.

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 1to 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

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. Cross resistance with other tetracyclines is common.

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 tablets.

Gram-Negative Bacteria

Acinetobacter species

Bartonella bacilliformis

Brucella species

Calymmatobacterium granulomatis

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

Gram-Positive Bacteria

Bacillus anthracis

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 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 results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals 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 provides an estimate 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-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 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

Bacteria*

Minimal Inhibitory Concentration (mcg/mL)

Zone Diameter (mm)

Agar Dilution (mcg/mL)

S

I

R

S

I

R

S

I

R

Acinetobacter spp.

Doxycycline

Tetracycline

≤4

≤4

8

8

≥16

≥16

≥13

≥15

10 to 12

12 to 14

≤9

≤11

Anaerobes

Tetracycline

≤4

8

≥16

Bacillus anthracis

Doxycycline

Tetracycline

≤1

≤1

Brucella species†

Doxycycline

Tetracycline

≤1

≤1

Enterobacteriaceae

Doxycycline

Tetracycline

≤4

≤4

8

8

≥16

≥16

≥14

≥15

11 to 13

12 to 14

≤10

≤11

Franciscella tularensis

Doxycycline

Tetracycline

≤ 4

≤ 4

Haemophilus influenzae

Tetracycline

≤2

4

≥8

≥29

26 to 28

≤25

Mycoplasma pneumoniae

Tetracycline

≤2

Nocardiae and other aerobic

Actinomyces species†

Doxycycline

≤1

2 to 4

≥8

Neisseria gonorrhoeae

Tetracycline

≥38

31 to 37

≤30

≤0.25

0.5 to 1

≥2

Streptococcus pneumoniae

Tetracycline

≤2

4

≥8

≥ 23

19 to 22

≤ 18

Vibrio cholerae

Doxycycline

Tetracycline

≤4

≤4

8

8

≥16

≥16

Yersinia pestis

Doxycycline

Tetracycline

≤4

≤4

8

8

≥16

≥16

Ureaplasma urealyticum

Tetracycline

≤1

≥2

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

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.

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 is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria 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 is not likely to inhibit growth of the pathogen if the antimicrobial compound 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

Tetracycline

2 to 8

8 to 32

Escherichia coli ATCC 25922

Doxycycline

Tetracycline

0.5 to 2

0.5 to 2

18 to 24

18 to 25

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

Tetracycline

23 to 29

24 to 30

Staphylococcus aureus ATCC 29213

Doxycycline

Tetracycline

0.12 to 0.5

0.12 to 1

Streptococcus pneumoniae ATCC 49619

Doxycycline

Tetracycline

0.015 to 0.12

0.06 to 0.5

25 to 34

27 to 31

Bacteroides fragilis ATCC 25285

Tetracycline

0.12 to 0.5

Bacteroides thetaiotaomicron ATCC 29741

Tetracycline

8 to 32

Mycoplasma pneumoniae ATCC 29342

Tetracycline

0.06 to 0.5

0.06 to 0.5

Ureaplasma urealyticum ATCC 33175

Tetracycline

≥8

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