Doxycycline (doxycycline 100 mg) Dailymed

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

Description

Doxycycline Capsules USP is a broad-spectrum antibiotic synthetically derived from oxytetracycline. Doxycycline 150 mg, 100 mg and 50 mg capsules contain Doxycycline monohydrate equivalent to 150 mg, 100 mg or 50 mg of doxycycline for oral administration. Inactive ingredients include colloidal silicon dioxide, gelatin, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and titanium dioxide. In addition, the 50 mg strength contains FD&C Yellow #6 and D&C Yellow #10. The 100 mg strength also contains black iron oxide, red iron oxide and yellow iron oxide. The 150 mg strength includes FD&C Red #40 and FD&C Yellow #6. Its molecular weight is 462.46. The chemical designation of the light-yellow crystalline powder is alpha-6-deoxy-5-oxytetracycline.

Structural formula:

C 22H 24N 2O 8•H 20

Doxycycline Capsules USP 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

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.

Gram-Negative Bacteria:

Acinetobacter species

Bartonella bacilliformis

Brucella species

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella granulomatis

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Vibrio fetus

Yersinia pestis

Gram-Positive Bacteria:

Bacillus anthracis

Streptococcus pneumonia

Anaerobes:

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 a 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 antimircrobial 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 method (broth and/or agar). ^1,2,4,6,7 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 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. Doxycyline Tetracycline	≤4 ≤4	8 8	≥16 ≥16	≥13 ≥15	10-12 12-14	≤9 ≤11	- -	- -	- -
Anaerobes Tetracycline	-	-	-	-	-	-	≤4	8	≥16
Bacillus anthracis b Doxycycline Tetracycline	≤1 ≤1	- -	- -	- -	- -	- -	- -	- -	- -
Brucell species b Doxycycline Tetracycline	≤1 ≤1	- -	- -	- -	- -	- -	- -	- - -	- -
Enterobacteriaceae Doxycycline Tetracycline	≤4 ≤4	8 8	≥16 ≥16	≥14 ≥15	11-13 12-14	≤10 ≤11	- -	- -	- -
Franciscella tularensis b Doxycyline Tetracycline	≤4 ≤4	--	- -	- -	- -	- -	- -	- -	- -
Haemophilus influenzae Tetracycline	≤2	4	≥8	- ≥29	- 26-28	- ≤25	-	-	-
Mycoplasma pneumoniae b Tetracycline	-	-	-	-	-	-	≤2	-	-
Neisseria gonorrhoeae b Tetracycline	-	-	-	≥38	31-37	≤30	≤0.25	0.5-1	≥2
Norcardiae and other aerobic Actinomyces species Doxycycline	≤1	2-4	≥8	-	-	-	-	-	-
Streptococcus pneumonia Doxycycline Tetracycline	≤0.25 <1	0.5 2	>1 >4	>28 >28	25-27 25-27	<24 <24	-	-	-
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 -

^aOrganisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms that are intermediate or resistant to tetracycline may be susceptible to doxycycline.

^bThe 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.

^cGonococci 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 per 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 Resistant (R) indicates that the pathogen 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 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 per mL)	Zone Diameter (mm)	Agar Dilution (mcg per mL)
Enterococcus faecalis ATCC 29212 Doxycycline Tetracycline	2 - 8 8 - 32	- -	- -
Escherichia coli ATCC 25922 Doxycycline Tetracycline	0.5 - 2 0.5 - 2	18 - 24 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 Doxycycline Tetracycline	- -	23 - 29 24 - 30	- -
Staphylococcus aureus ATCC 29213 Doxycycline Tetracycline	0.12 - 0.5 0.12 - 1	- -	- -
Streptococcus pneumoniae ATCC 49619 Doxycycline Tetracycline	0.015 - 0.12 0.06 - 0.5	25 - 34 27 - 31	- -
Bacteroides fragilis ATCC 25285 Tetracycline	-	-	0.12 - 0.5
Bacteroides thetaiotaomicron ATCC 29741 Tetracycline	2-8	-	8 - 32
Mycoplasma pneumoniae ATCC 29342 Tetracycline	0.06 - 0.5	-	0.06 - 0.5
Ureaplasma urealyticum ATCC 33175 Tetracycline	-	-	≥8