doxycycline (doxycycline 100 mg) Dailymed

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 a broad-spectrum antibiotic synthetically derived from oxytetracycline. Doxycycline film coated tablet contains 50 mg, 75 mg or 100 mg doxycycline monohydrate equivalent to 50 mg, 75 mg or 100 mg of doxycycline for oral administration. Inactive ingredients include colloidal silicon dioxide, FD&C blue #2 aluminum lake, FD&C yellow #6 aluminum lake, magnesium stearate; microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium starch glycolate, talc, and titanium dioxide. The 50 mg and 100 mg tablets also contain FD&C yellow #5 aluminum lake and black iron oxide. The 75 mg tablets contain yellow iron oxide. Its molecular weight is 462.45. The chemical designation of the light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline.

Structural formula:

C₂₂H₂₄N₂O₈ • H₂O

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

Clinical Pharmacology

Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. Doxycycline is virtually completely absorbed after oral administration.

Following a 200 mg dose of doxycycline monohydrate, 24 normal adult volunteers averaged the following serum concentration values:

Time (hr):	0.5	1.0	1.5	2.0	3.0	4.0	8.0	12.0	24.0	48.0	72.0
Conc. (mcg/mL)	1.02	2.26	2.67	3.01	3.16	3.03	2.03	1.62	0.95	0.37	0.15

Average Observed Values

Maximum Concentration	3.61 mcg/mL (± 0.9 sd)
Time of Maximum Concentration	2.60 hr (± 1.10 sd)
Elimination Rate Constant	0.049 per hr (± 0.030 sd)
Half-Life	16.33 hr (± 4.53 sd)

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.

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

Doxycycline 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: Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended:

Bacillus anthracis

Listeria monocytogenes

Staphylococcus aureus*

*Doxycycline is not the drug of choice in the treatment of any type of staphylococcal infection.

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, tetracyclines should not be used to treat streptococcal infections unless the microorganism has been demonstrated to be susceptible.

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 recommended:

Acinetobacter species

Enterobacter aerogenes

Escherichia coli

Klebsiella species

Shigella species

Anaerobic Microorganisms

Actinomyces israelii

Clostridium species

Fusobacterium fusiforme

Other Microorganisms

Borrelia recurrentis

Chlamydia psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema pertenue

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^{1 ,3} (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tetracycline powder. The MIC values should be interpreted according to the following criteria for indicated aerobic microorganisms other than Haemophilus species, Neisseria gonorrhoeae, and Streptococcus pneumoniae :

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

When testing Haemophilus spp.^a

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

When testing Neisseria gonorrhoeae ^b

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

When testing Streptococcus pneumoniae ^c

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

^a Interpretative criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).<sup>1,3

b</sup> Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.<sup>1,3

c</sup> Interpretative criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.^1,3

Reporting Results

Recommended interpretive criteria are based on usual dosage regiment and routes of administration in the U.S. Susceptible, intermediate, or resistant interpretations of zone diameter measurements are reported and defined as follows:

1. Susceptible (S)

The “susceptible” category implies that isolates are inhibited by the usually achievable concentration of antimicrobial agent when the recommended dosage is used for the site of infection.

2. Intermediate (I)

The “intermediate” category includes isolates with antimicrobial agent MICs that approach usually attainable blood and tissue levels and for which response rates may be lower than for susceptible isolates. The intermediate category implies clinical efficacy in body sites where the drugs are physiologically concentrated (e.g., quinolones and β-lactams in urine) or when a higher than normal dosage of a drug can be used (e.g., β-lactams). This category also includes a buffer zone, which should prevent small, uncontrolled, technical factors from causing major disappearances in interpretations, especially for drugs without narrow pharmaceutical margins.

3. Resistant (R)

The “resistant” category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules, and/or that demonstrate zone diameters that fall in the range where specific microbial resistance mechanisms (e.g., beta-lactamases) are likely, and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard tetracycline powder should provide the following MIC values:

Microorganism		MIC (mcg/mL)
Enterococcus faecalis	ATCC 29212	8-32
Escherichia coli	ATCC 25922	0.5-2
Haemophilus influenzae Range applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM).1,3	ATCC 49247	4-32
Neisseria gonorrhoeae Range applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement. 1,3	ATCC 49226	0.25-1
Pseudomonas aeruginosa	ATCC 27853	8-32
Staphylococcus aureus	ATCC 29213	0.12-1
Streptococcus pneumoniae Range applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood. 1,3	ATCC 49619	0.12-0.5

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^{2 ,3} requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg tetracycline or 30 mcg doxycycline to test the susceptibility of microorganisms to doxycycline.

Reports from the laboratory providing results of the standard single-disk susceptibility test with 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should be interpreted according to the following criteria for indicated aerobic microorganisms other than Haemophilus species, Neisseria gonorrhoeae, and Streptococcus pneumoniae :

Zone Diameter (mm)		Interpretation
tetracycline	doxycycline
≥15	≥14	Susceptible (S)
12-14	11-13	Intermediate (I)
≤11	≤10	Resistant (R)

When testing Haemophilus spp.^a

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

When testing Neisseria gonorrhoeae ^b

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

Gonococci with 30 mcg tetracycline disk zone diameters ≤19 mm usually indicate a plasmid-mediated tetracycline-resistant N. gonorrhoeae (TRNG) isolate. These strains should be confirmed by the dilution test (MIC ≥16 mcg/mL).

When testing Streptococcus pneumoniae ^c

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

^a Interpretative criteria applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using Haemophilus Test Medium (HTM) and incubated with 5% CO₂.<sup>2,3

b</sup> Interpretative criteria applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using GC agar base with 1% defined growth supplement and incubated with 5% CO₂.<sup>2,3

c</sup> Interpretative criteria applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO₂.^2,3

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 tetracycline or doxycycline, respectively.

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

Microorganism		Zone Diameter (mm)
		tetracycline	doxycycline
Escherichia coli	ATCC 25922	18-25	18-24
Haemophilus influenzae a	ATCC 49247	14-22	---
Neisseria gonorrhoeae b	ATCC 49226	30-42	---
Staphylococcus aureus	ATCC 25923	24-30	23-29
Streptococcus pneumoniae c	ATCC 49619	27-31	---

^a Range applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using Haemophilus Test Medium (HTM) and incubated with 5% CO₂.<sup>2,3

b</sup> Range applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using GC agar base with 1% defined growth supplement and incubated with 5% CO₂.<sup>2,3

c</sup> Range applicable only to tests performed by disk diffusion method using a 30-mcg tetracycline-class disk and using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO₂.^2,3

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to tetracycline as MICs can be determined by standardized test methods.⁴ The MIC values obtained should be interpreted according to the following criteria:

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

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized tetracycline powder should provide the following MIC values:

Microorganism		MIC (mcg/mL)
Bacteroides fragilis Range applicable only to tests performed by the reference agar dilution method.	ATCC 25285	0.12-0.5
Bacteroides thetaiotaomicron a	ATCC 29741	8-32