Vibramycin is a broad-spectrum antibiotic synthetically derived from oxytetracycline, and is available as Vibramycin Monohydrate (doxycycline monohydrate); Vibramycin Hyclate and Vibra-Tabs (doxycycline hydrochloride hemiethanolate hemihydrate); and Vibramycin Calcium (doxycycline calcium) for oral administration.

The structural formula of doxycycline monohydrate is

images/16/29514901.jpg

with a molecular formula of C 22 H 24 N 2 O 8 ·H 2 O and a molecular weight of 462.46. The chemical designation for doxycycline is 4-(Dimethylamino)-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydro-3, 5, 10, 12, 12a-pentahydroxy-6-methyl-1, 11-dioxo-2-naphthacenecarboxamide monohydrate. The molecular formula for doxycycline hydrochloride hemiethanolate hemihydrate is (C 22 H 24 N 2 O 8 ·HCl) 2 ·C 2 H 6 O·H 2 O and the molecular weight is 1025.89. Doxycycline is a light-yellow crystalline powder. Doxycycline hyclate is soluble in water, while doxycycline monohydrate is very slightly soluble in water.

Doxycycline has a high degree of lipoid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.

Inert ingredients in the syrup formulation are: apple flavor; butylparaben; calcium chloride; carmine; glycerin; hydrochloric acid; magnesium aluminum silicate; povidone; propylene glycol; propylparaben; raspberry flavor; simethicone emulsion; sodium hydroxide; sodium metabisulfite; sorbitol solution; water.

Inert ingredients in the capsule formulations are: hard gelatin capsules (which may contain Blue 1 and other inert ingredients); magnesium stearate; microcrystalline cellulose; sodium lauryl sulfate.

Inert ingredients for the oral suspension formulation are: carboxymethylcellulose sodium; Blue 1; methylparaben; microcrystalline cellulose; propylparaben; raspberry flavor; Red 28; simethicone emulsion; sucrose.

Inert ingredients for the tablet formulation are: ethylcellulose; hydroxypropyl methylcellulose; magnesium stearate; microcrystalline cellulose; propylene glycol; sodium lauryl sulfate; talc; titanium dioxide; Yellow 6 Lake.

Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form. Doxycycline is virtually completely absorbed after oral administration.

Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours decreasing to 1.45 mcg/mL at 24 hours. 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 function.

Hemodialysis does not alter serum half-life.

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

Microbiology

The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including doxycycline, have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance of these organisms to tetracyclines is common.

Gram-Negative Bacteria

Neisseria gonorrhoeae

Calymmatobacterium granulomatis

Haemophilus ducreyi

Haemophilus influenzae

Yersinia pestis (formerly Pasteurella pestis )

Francisella tularensis (formerly Pasteurella tularensis )

Vibrio cholera (formerly Vibrio comma )

Bartonella bacilliformis

Brucella species

Because many strains of the following groups of gram-negative microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended:

Escherichia coli

Klebsiella species

Enterobacter aerogenes

Shigella species

Acinetobacter species (formerly Mima species and Herellea species

Bacteroides species

Gram-Positive Bacteria

Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracycline, culture and susceptibility testing are recommended. Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracycline should not be used for streptococcal disease unless the organism has been demonstrated to be susceptible.

Streptococcus pyogenes

Streptococcus pneumoniae

Enterococcus group (Streptococcus faecalis and Streptococcus faecium )

Alpha-hemolytic streptococci (viridans group)

Other Microorganisms

Rickettsiae

Chlamydia psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Ureaplasma urealyticum

Borrelia recurrentis

Treponema pallidum

Treponema pertenue

Clostridium species

Fusobacterium fusiforme

Actinomyces species

Bacillus anthracis

Propionbacterium acnes

Entamoeba species

Balantidium coli

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 tests: Diffusion techniques: Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedure 1 which has been recommended for use with disks to test susceptibility of organisms to doxycycline uses the 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for tetracycline or doxycycline, respectively.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk should be interpreted according to the following criteria:

Zone Diameter (mm) Interpretation
tetracycline doxycycline  
>/=19 >/=16 Susceptible
15-18 13-15 Intermediate
</=14 </=12 Resistant

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of "Intermediate" suggests that the organism would be susceptible if a high dosage is used or if the infection is confined to tissues and fluids in which high antimicrobial levels are attained. A report of "Resistant" indicates that achievable concentrations are unlikely to be inhibitory, and other therapy should be selected.

Standardized procedures require the use of laboratory control organisms. The 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk should give the following zone diameters:

   Organism
Zone Diameter (mm)
 
tetracycline doxycycline
   E. coli ATCC 25922
18-25 18-24
   S. aureus ATCC 25923
19-28 23-29

Dilution techniques: Use a standardized dilution method 2 (broth, agar, microdilution) or equivalent with tetracycline powder. The MIC values obtained should be interpreted according to the following criteria:

MIC (mcg/mL) Interpretation
 </=4 Susceptible
  8 Intermediate
>/=16 Resistant

As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard tetracycline powder should provide the following MIC values:

   Organism
MIC (mcg/mL)
E. coli ATCC 25922
1.0-4.0
S. aureus ATCC 29213
0.25-1.0
E. faecalis ATCC 29212
8-32
P. aeruginosa ATCC 27853
8-32

Treatment:

Doxycycline is indicated for the treatment of the following infections:

Rocky mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.

Respiratory tract infections caused by Mycoplasma pneumoniae.

Lymphogranuloma venereum caused by Chlamydia trachomatis.

Psittacosis (ornithosis) caused by Chlamydia psittaci.

Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence.

Inclusion conjunctivitis caused by Chlamydia trachomatis.

Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis.

Nongonococcal urethritis caused by Ureaplasma urealyticum.

Relapsing fever due to Borrelia recurrentis.

Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms:

Chancroid caused by Haemophilus ducreyi.

Plague due to Yersinia pestis (formerly Pasteurella pestis ).

Tuleremia due to Francisella tulerensis (formerly Pasteurella tulerensis ).

Cholera caused by Vibrio cholerae (formerly Vibrio comma ).

Campylobacter fetus infections caused by Campylobacter fetus (formerly Vibrio fetus ).

Brucellosis due to Brucella species (in conjunction with streptomycin).

Bartonellosis due to Bartonella bacilliformis.

Granuloma inguinale caused by Calymmatobacterium granulomatis.

Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.

Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug:

Escherichia coli.

Enterobacter aerogenes (formerly Aerobacter aerogenes ).

Shigella species

Acinetobacter species (formerly Mima species and Herellea species

Respiratory tract infections caused by Haemophilus influenzae.

Respiratory tract and urinary tract infections caused by Klebsiella species

Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug:

Upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae ).

When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections:

Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.

Syphilis caused by Treponema pallidum.

Yaws caused by Treponema pertenue.

Listeriosis due to Listeria monocytogenes.

Anthrax due to Bacillus anthracis.

Vincent' infection caused by Fusobacterium fusiforme.

Actinomycosis caused by Actinomyces israelii.

Infections caused by Clostridium species

In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides.

In severe acne, doxycycline may be useful adjunctive therapy.

Prophylaxis:

Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (<4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. See DOSAGE AND ADMINISTRATION section and Information for Patients subsection of the PRECAUTIONS section.

CONTRAINDICATIONS

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN). This adverse reaction is more common during long-term use of the drugs, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.

All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

Vibramycin Syrup contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The over-all prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

PRECAUTIONS

General

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued.

Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy, when indicated.

Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains

Doxycycline does not suppress P. falciparum's sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.

Information for Patients

Patients taking doxycycline for malaria prophylaxis should be advised:

--that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria.

--to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (e.g., staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent.)

--that doxycycline prophylaxis:

 --should begin 1-2 days before travel to the malarious area,

 --should be continued daily while in the malarious area and after leaving the malarious area,

 --should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area,

 --should not exceed 4 months.

All patients taking doxycycline should be advised:

--to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered. (See .)

--to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS .)

--that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. (See DRUG INTERACTIONS .)

--that the absorption of tetracyclines is reduced when taking bismuth subsalicylate. (See DRUG INTERACTIONS .)

--that the use of doxycycline might increase the incidence of vaginal candidiasis.

Laboratory Tests

In venereal disease, when co-existent syphilis is suspected, dark field examinations should be done before treatment is started and the blood serology repeated monthly for at least 4 months.

In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies, should be performed.

Drug Interactions

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations.

Absorption of tetracyclines is impaired by bismuth subsalicylate.

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

The concurrent use of tetracycline and Penthrane (methoxyflurane) has been reported to result in fatal renal toxicity.

Concurrent use of tetracycline may render oral contraceptives less effective.

Drug/Laboratory Test Interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors).

Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibiotics (tetracycline, oxytetracycline).

Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied.

Pregnancy Category

Teratogenic effects: Category "D" -- (See ).

Nonteratogenic effects: (See ).

Labor and Delivery

The effect of tetracyclines on labor and delivery is unknown.

Nursing Mothers

Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See ).

Pediatric Use

See and DOSAGE AND ADMINISTRATION .

ADVERSE REACTIONS

Due to oral doxycycline' virtually complete absorption, side effects of the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines:

Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of the drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION .)

Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See .)

Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See .)

Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus.

Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.

Other: bulging fontanels in infants and intracranial hypertension in adults. (See PRECAUTIONS -- General .)

When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function studies are known to occur.

OVERDOSAGE

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

DOSAGE AND ADMINISTRATION

THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE DIFFERS FROM THAT OF THE OTHER TETRACYCLINES. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS. Adults: The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg/day. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours.

In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended.

For children above eight years of age: The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight divided into two doses on the first day of treatment, followed by 1 mg/lb of body weight given as a single daily dose or divided into two doses, on subsequent days. For more severe infections up to 2 mg/lb of body weight may be used. For children over 100 lb the usual adult dose should be used.

The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

When used in streptococcal infections, therapy should be continued for 10 days.

Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS .)

If gastric irritation occurs, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk.

Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.

Uncomplicated gonococcal infections in adults (except anorectal infections in men): 100 mg, by mouth, twice a day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose. The dose may be administered with food, including milk or carbonated beverage, as required.

Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis: 100 mg by mouth twice a day for 7 days.

Nongonococcal urethritis (NGU) caused by C. trachomatis or U. urealyticum: 100 mg by mouth twice a day for 7 days.

Syphilis--early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice a day for 2 weeks.

Syphilis of more than one year's duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice a day for 4 weeks.

Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg, by mouth, twice a day for at least 10 days.

Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice a day for at least 10 days.

For prophylaxis of malaria: For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1-2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area.

HOW SUPPLIED

Vibramycin Hyclate (doxycycline hyclate) is available in capsules containing doxycycline hyclate equivalent to:

50 mg doxycycline

bottles of 50 (NDC 0069-0940-50),

unit-dose pack of 100 (10 × 10's) (NDC 0069-0940-41).

The capsules are white and light blue and are imprinted with "VIBRA" on one half and "PFIZER 094" on the other half.

100 mg doxycycline

bottles of 50 (NDC 0069-0950-50) and 500 (NDC 0069-0950-73),

unit-dose pack of 100 (10 × 10's) (NDC 0069-0950-41).

The capsules are light blue and are imprinted with "VIBRA" on one half and "PFIZER 095" on the other half.

Vibra-Tabs (doxycycline hyclate) is available in salmon colored film-coated tablets containing doxycycline hyclate equivalent to:

100 mg doxycycline

bottles of 50 (NDC 0069-0990-50) and 500 (NDC 0069-0990-73),

The tablets are imprinted on one side with "VIBRA-TABS" and "PFIZER 099" on the other side.

Vibramycin Calcium Syrup (doxycycline calcium oral suspension) is available as a raspberry-apple flavored oral suspension. Each teaspoonful (5 mL) contains doxycycline calcium equivalent to 50 mg of doxycycline: bottles of 1 oz (30 mL) (NDC 0069-0971-51), and 1 pint (473 mL) (NDC 0069-0971-93).

Vibramycin Monohydrate (doxycycline monohydrate) for Oral Suspension is available as a raspberry-flavored, dry powder for oral suspension. When reconstituted, each teaspoonful (5 mL) contains doxycycline monohydrate equivalent to 25 mg of doxycycline: 2 oz (60 mL) bottles (NDC 0069-0970-65).

All products are to be stored below 86°F (30°C) and dispensed in tight, light-resistant containers (USP). The unit dose packs should also be stored in a dry place.

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 PO 4 , and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4 , and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO 4 , 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. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests, Fourth Edition. Approved Standard NCCLS Document M2-A4, Vol. 10, No. 7 NCCLS, Villanova, PA, April 1990.
  2. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Second Edition. Approved Standard NCCLS Document M7-A2, Vol. 10, No. 8 NCCLS, Villanova, PA, April 1990.

69-1680-00-5                        Revised April 1993