Actions of Coup O.e. in details
Doxycycline inhibits bacterial protein synthesis by binding 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 Coup O.e. Tablets.
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 pneumoniae
Anaerobes
Clostridium species
Fusobacterium fusiforme
Propionibacterium acnes
Other Bacteria
Norcardiae 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 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 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 bacteria 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.
| 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 Tetracycline |
≤4 ≤4 |
8 8 |
≥16 ≥16 |
≥13 ≥15 |
10-12 12-14 |
≤9 ≤11 |
- - |
- - |
- - |
| Anaerobes Tetracycline |
- |
- |
- |
- |
- |
- |
≤4 |
8 |
≥16 |
| Bacillus anthracisb Doxycycline Tetracycline |
≤1 ≤1 |
- - |
- - |
- - |
- - |
- - |
- - |
- - |
- - |
| Brucella speciesb Doxycycline Tetracycline |
≤1 ≤1 |
- - |
- - |
- - |
- - |
- - |
- - |
- - |
- - |
| Enterobacteriaceae Doxycycline Tetracycline |
≤4 ≤4 |
8 8 |
≥16 ≥16 |
≥14 ≥15 |
11-13 12-14 |
≤10 ≤11 |
- - |
- - |
- - |
| Franciscella tularensisb Doxycycline Tetracycline |
≤4 ≤4 |
- - |
- - |
- - |
- - |
- - |
- - |
- - |
- - |
| Haemophilus influenzae Tetracycline |
≤2 |
4 |
≥8 |
≥29 |
26-28 |
≤25 |
- |
- |
- |
| Mycoplasma pneumoniaeb Tetracycline |
- |
- |
- |
- |
- |
- |
≤2 |
- |
- |
| Neisseria gonorrhoeaec Tetracycline |
- |
- |
- |
≥38 |
31-37 |
≤30 |
≤0.25 |
0.5-1 |
≥2 |
| Norcardiae and other aerobic Actinomyces species Doxycycline |
≤1 |
2-4 |
≥8 |
- |
- |
- |
- |
- |
- |
| Streptococcus pneumoniae 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 |
| a 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. b The current absence of resistant 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. c 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 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 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 in Table 2 should be achieved.
| QC Strain | Minimal Inhibitory Contentration (mcg/mL) | Zone Diameter (mm) | Agar Dilution (mcg/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 Doxycycline Tetracycline | 2-8 - | - - | - 8-32 |
| Mycoplasma pneumoniae ATCC 29342 Tetraycline | 0.06-0.5 | - | 0.06-0.5 |
| Ureaplasma urealyticum ATCC 33175 Tetracycline | - | - | ≥8 |
Indications and Usage for Coup O.e. Tablets
To reduce the development of drug-resistant bacteria and maintain effectiveness of Coup O.e. Tablets, USP and other antibacterial drugs, Coup O.e. Tablets, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Coup O.e. pharmacology
Mechanism Of Action
Doxycycline is an antibacterial drug.
Pharmacokinetics
Doxycycline is virtually completely absorbed after oral administration. Following single and multiple-dose administration of Coup O.e. Delayed-Release 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 Coup O.e. Delayed-Release 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 Coup O.e. Delayed-Release 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 Coup O.e. Delayed-Release 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 Coup O.e. Delayed-Release 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 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 between 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 Coup O.e. Delayed-Release Tablets.
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
Actinomyces species
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 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). 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 Susceptiblity Testing for Doxycycline and Tetracycline
| QC Strain | Minimal Inhibitory Concentration (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 | - | |
| Staphylococcus pneumoniae ATCC 49619 | |||
| Doxycycline | 0.015 -0.12 | 25 -34 | - |
| Tetracycline | 0.06 -0.5 | 27 -31 | - |
| Bacteroides fragilis 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 less than 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 Coup O.e. Delayed-Release Tablets, 200 mg once daily versus Coup O.e. 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 Coup O.e. Delayed-Release 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).
Table 4: Primary Efficacy Outcome – Microbiological Cure of C. trachomatis at Day 28
| mITT Population | Coup O.e. Delayed-Release Tablets, 200 mg once daily Cure Rate (%) | Coup O.e. 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 | -10.3, 3.7 |
REFERENCES
5. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth 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.
References
- NCIt. "Procarbazine: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Procarbazine: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
- NCI Cancer Drugs. "procarbazinehydrochloride". https://www.cancer.gov/about-cancer/... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
