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Doryx

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Doryx




CLINICAL PHARMACOLOGY

Mechanism Of Action

Doxycycline is an antibacterial drug [see Microbiology].

Pharmacokinetics

Doxycycline is virtually completely absorbed after oral administration. Following single and multiple-dose administration of DORYX Tablets, 200 mg to adult volunteers, average peak plasma doxycycline concentration (Cmax) was 4.6 mcg/mL and 6.3 mcg/mL, respectively with median tmax of 3 hours; the corresponding mean plasma concentration values 24 hours after single and multiple doses were 1.5 mcg/mL and 2.3 mcg/mL, respectively. The mean Cmax and AUC 0-∞ of doxycycline are 24% and 13% lower, respectively, following single dose administration of DORYX Tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean Cmax of doxycycline is 19% lower and the AUC 0-∞ is unchanged following single dose administration of DORYX Tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown. Doxycycline bioavailability from DORYX Tablets, 200 mg was not affected by food, but the incidence of nausea was higher in fasted subjects. The 200 mg tablets may be administered without regard to meals.

When DORYX Tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly.

Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min.

Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life.

Microbiology

Mechanism of Action

Doxycycline inhibits bacterial protein systhesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Cross-resistance between tetracyclines is common.

Doxycycline has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for DORYX Tablets [see INDICATIONS AND USAGE].

Gram-Negative 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

Gram-Positive Bacteria

Bacillus anthracis
Streptococcus pneumoniae

Anerobic Bacteria

Clostridium species
Fusobacterium fusiforme

Propionibacterium acnes

Other Bacteria

Borrelia recurrentis
Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Norcardiae and other aerobic

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 Test 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 method (broth and/or agar)5,6,8. The MIC values should be interpreted according to the criteria provided in Table 2.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. Zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method5,7,8. This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 2.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method9. The MIC values obtained should be interpreted according to the criteria provided in Table 2.

Table 2: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline

Bacteriaa 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- 12 ≤ 9 - - -
  Tetracycline ≤ 4 8 ≥ 16 ≥ 15 12-14 ≤ 11 - - -
Anaerobes
  Tetracycline - - - - - - ≤ 4 8 ≥ 16
b
  Doxycycline ≤ 1 - - - - - - - -
  Tetracycline ≤ 1 - - - - - - - -
Brucella speciesab
  Doxycycline ≤ 1 - - - - - - - -
  Tetracycline ≤ 1 - - - - - - - -
Enterobacteriac eae
  Doxycycline ≤ 4 8 ≥ 16 ≥ 14 11-13 ≤ 10 - - -
  Tetracycline ≤ 4 8 ≥ 16 ≥ 15 12-14 ≤ 11 - - -
Francisella tularensisab
  Doxycycline ≤ 4 - - - - - - - -
  Tetracycline ≤ 4 - - - - - - - -
Haemophilus influenzae
  Tetracycline ≤ 2 4 ≥ 8 ≥ 29 26-28 ≤ 25 - - -
Mycoplasma pneumoniae
  Tetracycline - - - - - - ≤ 2 - -
Nocardiae and other aerobic Actinomyces speciesab
  Doxycycline ≤ 1 2-4 ≥ 8 - - - - - -
Neisseria gonorrhoeaec
  Tetracycline - - - ≥ 38 31-37 ≤ 30 ≤ 0. 25 0.5-1 ≥ 2
Streptococcus pneumoniae
  Doxycycline ≤ 0. 25 0.5 ≥ 1 ≥ 28 25-27 ≤ 24 - - -
  Tetracycline ≤ 1 2 ≥ 4 ≥ 28 25-27 ≤ 24 - - -
Vibrio cholerae
  Doxycycline ≤ 4 8 ≥ 16 - - - - - -
  Tetracycline ≤ 4 8 ≥ 16 - - - - - -
Yersinia pestis
  Doxycycline ≤ 4 8 ≥ 16 - - - - - -
  Tetracycline ≤ 4 8 ≥ 16 - - - - - -
UreapIasma 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 ūrecludes 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 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 greater than or equal to 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 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 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.5,6,7,8,9,10,11 Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 3. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 3 should be achieved.

Table 3: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline

QC Strain Minimal Inhibitory Concentr ation (mcg/mL ) Zone Diameter (mm) Agar Dilution (mcg/mL )
Enterococcus faecalis ATCC 29212
  Doxycycline 2-8 - -
  Tetracycline 8-32 - -
Escherichia coli ATCC 25922
  Doxycycline 0.5-2 18-24 -
  Tetracycline 0.5-2 18-25 -
Eubacteria lentum 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 - 23-29 -
  Tetracycline - 24-30 -
Staphylococcus aureus ATCC 29213
  Doxycycline 0.12-0.5 -
  Tetracycline 0.12-1 -
StaphyIococcus pneumoniae ATCC 49619
  Doxycycline 0.015-0.12 25-34 -
  Tetracycline 0.06-0.5 27-31 -
Bacteroides fragiIis ATCC 25285
  Tetracycline - - 0.125-0.5
Bacteroides thetaiotaomicron ATCC 29741
  Doxycycline 2-8 - -
  Tetracycline - - 8-32
Mycoplasma pneumoniae ATCC 29342
  Tetracycline 0.06-0.5 - 0.06-0.5
Ureaplasma urealyticum ATCC 33175
  Tetracycline - - ≥ 8

Animal Toxicology And/Or Pharmacology

Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.

Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.

Clinical Studies

This was a randomized, double-blind, active-controlled, multicenter trial which enrolled 495 subjects, between 19 to 45 years of age with a confirmed diagnosis of urogenital C. trachomatis infection < 14 days prior to enrollment, or partner(s) of a subject with a known positive test for urogenital C. trachomatis infection. The primary purpose of this study was to evaluate the efficacy and safety of DORYX Tablets, 200 mg once daily versus doxycycline hyclate capsules, 100 mg twice daily for seven days for the treatment of uncomplicated urogenital C. trachomatis infection. The primary efficacy objective was to demonstrate non-inferiority of the DORYX Tablets, 200 mg once daily treatment regimen versus the doxycycline 100 mg twice daily treatment regimen for the indication using a negative nucleic acid amplification test (NAAT) at the test of cure visit (day 28) in the mITT population (subjects who were positive at baseline and took at least one day of study drug). Microbiological cure rates are provided in Table 4.

Table 4: Primary Efficacy Outcome - Microbiological Cure of C. trachomatis at Day 28

mITT Population DORYX Tablets, 200 mg once daily Cure Rate (%) Doxycycline hyclate capsules, 100 mg twice daily Cure Rate (%) Difference (%)
N 188 190  
Microbiological Cure, n (%) 163 (86.7) 171 (90.0) -3.3%
95% Confidence Interval for Cure Rate     -10.0, 3.7

REFERENCES

5. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-forth Informational Supplement, CLSI document M100-S24. Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2014.

6. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Ninth Edition. CLSI document M07-A9, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012.

7. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012.

8. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Second Edition CLSI document M45-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2010.

9. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eighth Edition. CLSI document M11-A8, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012.

10. Clinical and Laboratory Standards Institute (CLSI). Methods for Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard – Second Edition. CLSI document M24-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011.

11. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011.

Last reviewed on RxList: 6/18/2015
This monograph has been modified to include the generic and brand name in many instances.

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