Doxycycline (doxycycline 100 mg) Dailymed

Doxycycline Capsules, Usp

Rx only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline capsules, USP and other antibacterial drugs, doxycycline capsules, USP 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 antibacterial synthetically derived from oxytetracycline. Doxycycline capsules, USP 100 mg, 75 mg, and 50 mg contain doxycycline monohydrate, USP equivalent to 100 mg, 75 mg, or 50 mg of doxycycline for oral administration. The chemical designation of the yellow crystalline powder 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 monohydrate.

Structural formula:

•  C₂₂H₂₄N₂O₈ • H₂O M.W. = 462.46

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.

Each capsule for oral administration contains doxycycline monohydrate, USP equivalent to 50 mg, 75 mg or 100 mg of doxycycline. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The capsule shell contains D&C Red No. 28, FD&C Blue No. 1, gelatin, and titanium dioxide. The edible printing ink contains black iron oxide, potassium hydroxide, propylene glycol, and shellac.

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	1.5	2	3	4	8	12	24	48	72
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.

Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 pediatric patients (2 to 18 years of age) showed that allometrically-scaled clearance (CL) of doxycycline in pediatric patients ≥2 to ≤8 years of age (median [range] 3.58 [2.27 to 10.82] L/h/70 kg, N = 11) did not differ significantly from pediatric patients >8 to 18 years of age (3.27 [1.11 to 8.12] L/h/70 kg, N = 33). For pediatric patients weighing ≤45 kg, body weight normalized doxycycline CL in those ≥2 to ≤8 years of age (median [range] 0.071 [0.041 to 0.202] L/kg/h, N = 10) did not differ significantly from those >8 to 18 years of age (0.081 [0.035 to 0.126] L/kg/h, N = 8). In pediatric patients weighing >45 kg, no clinically significant differences in body weight normalized doxycycline CL were observed between those ≥2 to ≤8 years (0.050 L/kg/h, N = 1) and those >8 to 18 years of age (0.044 [0.014 to 0.121] L/kg/h, N = 25). No clinically significant differences in CL between oral and IV dosing was observed in the small cohort of pediatric patients who received the oral (N = 19) or IV (N = 21) formulation alone.

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 (see INDICATIONS AND USAGE).

GramNegative Bacteria

Acinetobacter species

Bartonella bacilliformis

Brucella species

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella granulomatis

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

GramPositive Bacteria

Bacillus anthracis

Listeria monocytogenes

Streptococcus pneumoniae

Anaerobic Bacteria

•   Clostridium species

Fusobacterium fusiforme

Propionibacterium acnes

Other Bacteria

Nocardiae and other Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema pallidum subspecies pertenue

Ureaplasma urealyticum

Parasites

Balantidium coli

Entamoeba species

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 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 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.^1,5 The MIC values obtained should be interpreted according to the criteria provided in Table 1
Doxycycline

Tetracycline

Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline

Bacteria*	Minimal Inhibitory Concentration (mcg per mL)			Zone Diameter (mm)			Agar Dilution (mcg per 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†
Doxycycline	≤ 1	-	-	-	-	-	-	-	-
Tetracycline	≤ 1	-	-	-	-	-	-	-	-
Brucella species†
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†
Doxycycline	≤ 4	-	-	-	-	-	-	-	-
Tetracycline	≤ 4	-	-	-	-	-	-	-	-
Haemophilus influenzae
Tetracycline	≤ 2	4	≥ 8	≥ 29	26 to 28	≤ 25	-	-	-
Mycoplasma pneumoniae†
Tetracycline	-	-	-	-	-	-	≤ 2	-	-
Neisseria gonorrhoeae‡
Tetracycline	-	-	-	≥ 38	31 to 37	≤ 30	≤ 0.25	0.5 to 1	≥ 2
Norcardiae and other aerobic Actinomyces species†
Doxycycline	≤ 1	2 to 4	≥ 8	-	-	-	-	-	-
Streptococcus pneumoniae
< 0.25 ≤ 1	0.5 2	≥ 1 ≥ 4	≥ 28 ≥ 28	25 to 27 25 to 27	< 24 < 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

•  * 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 less than 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 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 or 30 mcg tetracycline disk, the criteria noted in 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	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	-	-	0.125 to 0.5
Bacteroides thetaiotaomicron ATCC 29741
Doxycycline Tetracycline	2 to 8 -	-	8 to 32
Mycoplasma pneumoniae ATCC 29342
Tetracycline	0.06 to 0.5	-	0.06 to 0.5
Ureaplasma urealyticum ATCC 33175
Tetracycline	-	-	≥ 8

ATCC is the American Type Culture Collection