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Monodox

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Monodox

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. 1.02 2.26 2.67 3.01 3.16 3.03 2.03 1.62 0.95 0.37 0.15 (μg/mL)

Average Observed Values

Maximum Concentration 3.61 μg/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 1-5%/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 18-22 hours) in individuals with normal and severely impaired renal functioHemodialysis does not alter 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 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 MONODOX.

Gram-Negative Bacteria

Acinetobacter species
Bartonella bacilliformis

Brucella
species
Calymmatobacterium granulomatis

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella
species
Neisseria gonorrhoeae

Shigella
species
Vibrio cholerae

Yersinia pestis

Gram-Positive Bacteria

Bacillus anthracis
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 pertenue

Ureaplasma urealyticum

Parasites

Balantidium coli
Entamoeba
species

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 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* 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 10-12 ≤ 9 - - -
  Tetracycline ≤ 4 8 ≥ 16 ≥ 15 12-14 ≤ 11 - - -
Anaerobes
  Tetracycline - - - - - - ≤ 4 8 ≤ 16
Bacillus anthracis†
  Doxycycline ≤ 1 - - - - - - - -
  Tetracycline ≤ 1 - - - - - - - -
Brucella species†
  Doxycycline ≤ 1 - - - - - - - -
  Tetracycline ≤ 1 - - - - - - - -
Enterobacteriaceae
  Doxycycline ≤ 4 8 ≥ 16 ≥ 14 11-13 ≤ 10 - - -
  Tetracycline ≤ 4 8 ≥ 16 ≥ 15 12-14 ≤ 11 - - -
Franciscella tularensis†
  Doxycycline ≤ 4 - - - - - - - -
  Tetracycline ≤ 4 - - - - - - - -
Haemophilus influenzae
  Tetracycline ≤ 2 4 ≥ 8 ≥ 29 -54 - ≤ 25 - - -
Mycoplasma pneumoniae†
  Tetracycline - - - - - - ≤ 2 - -
Neisseria gonorrhoeae‡
  Tetracycline - - - ≥ 38 31-37 ≤ 30 ≤ 0.25 0.5-1 ≥ 2
Norcardiae and other aerobic Actinomyces species†
  Doxycycline ≤ 1 2-4 ≥ 8 - - - - - -
Streptococcus pneumoniae
  Tetracycline ≤ 2 4 ≥ 8 ≥ 23 19-22 ≤ 18 - - -
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 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 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.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 2 -8 - -
  Tetracycline 8 -32 - -
Escherichia coli ATCC 25922
  Doxycycline 0.5 -2 18 -24 -
  Tetracycline 0.5 -2 18 -25 -
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 - -
Streptococcus 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
  Tetracycline - - 8-32
Mycoplasma pneumoniae ATCC 29342
  Tetracycline 0.06 -0.5 - 0.06 -0.5
Ureaplasma urealyticum ATCC 33175
  Tetracycline - - ≥ 8

Animal Pharmacology And Animal Toxicology

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.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100S23, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2013.

2. 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.

3. 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.

4. 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 M45A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2010.

5. 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.

6. 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.

7. 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: 10/25/2013
This monograph has been modified to include the generic and brand name in many instances.

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