FARAD Digest

1 FARAD DigestExtralabel use of oxytetracyclineTomas Martin-jimenez, DVM; Arthur L. Craigmill, PhD; jim E. Riviere, DVM. PhDThe tetracyclines most commonly used in animalsare chlortetracycline, tetracycline, oxytetracycline,doxycycline, and minocycline, with oxytetracyclinebeing the most used. Despite its popularity inthe United States, this antibiotic is not officially ap-proved for use in all domestic species or in all possibleclinical situations. Thus, extralabel use of oxytetracy-cline in food animals is common, and appropriate with-drawal times may not correspond with the ones estab-lished for label .nd PharmacokinetlcPropertiesOxytetracycline can be administered IV or 1M, butthe oral route is often preferred for treating populationsof food animals. Absorption of oxyte~cycline frommuscular tissue and the gasttointestinal tract is generallygood.

2 Metabolism of oxytetracycline is negligible (Table 1).Approximately 60% of the dose is eliminated in urine viaglomerular filtration, and the other 40% is eliminated infeces. Enterohepatic circulation has been described forpractically every species ~ted, with up to 20 times theplasma concentration of oxyte~cycline in the bile. Thisprocess tends to prolong drug residues in ~~ may affect the disposition of oxytet-racycline. In pneumonic pigs ~ted orally with oxytet-racycline, a great intertndividual variation in the plasmaconcen~tion was found. The ultimate consequence ofthese differences may be increased variability in tissueresidue depletion and, consequently, the need to increasewithdrawal times to avoid violative U. of OxytetracyclineWhen using oxytetracycline in an extralabel man-ner, all requirements of the recently enacted AMDUCA legislation must be followed.

3 According to this legisla-tion, extralabel use of oxytetracycline, or any otherdrug. in animal feed is use of injectable oxytetracycline prod-ucts in cattle-label withdrawal times range between15 and 22 days for short-acting. and 28 days for long-From * Food Animal Residue AvotdaDCe Detabank ( FARAD ).Cutaneous PbanDacology aDd Toxicology Cenler, Collese of Vet-erinary Medicine, Nom Carolina State University, Raleigh, NC27606 (Martin-jimenez. Riviere). and the Environmental Toxicol-oar Ext DSion. College of AgricultUral and Environmental ScI-ences, University of California. Davis, CA 9561"6-8588 (CrailJnill).Referencu to ltudiu mentioned In this repon and referencufor FARAD determinations are available on written 1-Ph8rmacokinetic variables of oxytetracyclinein horses.

4 Swine, and cattle-- w ~ -- ..H-. IV 13 PIgs IV .PIgs PO IA .PlgsIF~cI PO 15 IV .CIIV8 II M) IV 11 14CM8n2M) U IV .CM8 (14 M) 17:1 IV ,.I 11'T 0 ~ d-. - .. -, "'~acting, formulations a\ dosages of to ms'kg ofbody weight/d (3 to 5 mg/lhld) administered IV or tolerance for oxytetracycline in edible tissues ofcattle is ~g/g of tissue (100 ppb). Recently, thefDA/Center for Veterinary Medicine established a "safelevel" of 30 ppb of oxytetracycline in milk. This "safelevel" does not represent an official tolerance level,but rather is a guide to assess whether a potential pub-lic health hazard may arise. At the present time, noinjectable products have been approved for use in lac-tating dairy a recent study, a short-acting preparation ofoxytetracycline was administered once by 1 of 3 routes:IV, 1M, or IU (intrauterine).

5 When oxytetracycline wasadministered as a single dose, ms'kg ( mg/lb),IV; or 11 ms'kg (5 mg/ib), 1M, milk from most cowswas cleared of oxytetracycline 30 ppb) by 120 hoursafter ad!!1 Jnistration and 156 hours were required forall animals to have residue concentrations < 30 to this information and label withdrawaltimes in foreign countries, parenteral administration(IV, 1M) of a short-acting preparation of oxytetracy-cline at 10 to 20 ms'kg ( to mg/ib) would re-quire a minimum 144-hour mUk-discard interval. Test-ing of milk from treated cows is also recommended,because the variability in residue depletion is hightespecially when clinical conditions are another study in which a long-acting prepara-tion of oxytetracycline (25 mg/kg [ mg/ibl, q 24 h)was administered 1M twice to postparturient cows withretained fetal membranes, milk residue levels of 400ppb were detected for> 144 hours.]

6 A study of 10 cowsthat received a single dose (20 ms'kg [9 mg/ibl, 1M) ofa long-acting preparation of oxytetracycline reporteda withdrawal interval of 156 hours. According to thisinformation, the FARAD recommends a milk withdrawalint~ of 168 hours after parenteral administrationof a long-acting preparation .of oxytetracycline at 20mg/kg. A milk withdrawal interval of 192 hours couldbe conservatively extrapolated for use of oxytetracy-cline at 20 to 30 mg/kg ( to mg/ib).A minimum meat withdrawal time of 35 days shouldbe observed when short-acting formulations of oxytet-racycline are administered by injection (IV; 1M) at dos-ages> 20 mg/kg (9 mg/lb). This recommendation isbased on results of a study in which violative concen-trations of oxytetracycline persisted in the kidneys andmuscle at the injection site for> 19 days after the finaldose of a short-acting preparation of oxytetracycline(20 mg/kg) that was administered for 3 consecutivedays.]

7 The label withdrawal time of 15 to 22 days fordosages of to mg/kg (3 t~.5 mg/ib), every Mhours, should be increased to 28 to 30 days in animalstreated at shortened dosing intervals (as happens whencows are treated for pneumonia). Detectable residuelevels of oxytetracycline were found at the injectionsite for 35 days after administration mg of oxytet-racycline/kg ( mg/ib), 1M (combined with anotherantibiotic), every 12 hours, for 6 days. For long-actingformulations, results of some studies in which singledoses (20 to 40 mg/kg [9 to 18 mg/lb) were adminis-tered 1M to cattle suggest an extended meat withdrawaltime of 50 days. However, different formulations wouldbe expected to result in various tissue depletion pro-m es .ExtraIabel intrauterine use of oxytetracycline incattle-Results of a study conducted in healthy cowsrevealed that a single lU dose of 2 g of oxytetracyclinein 500 ml of saline solution/cow yielded milk residues< 30 ppb by 6 days after treatment (in 1/6 cows).]

8 Theresidue levels in the milk of the other 5 cows were lessthan the FDA safe level of 30 ppb by 96 hours. Accord-ing to these data and label withdrawal times for ox-ytetracycline formulations approved in foreign coun-tries, the FARAD recommends a milk discard time of168 hours for doses up to 2 g. If the dose is increasedto 4 to 6 g, the milk discard time should be extendedto 192 hours. These milk withdrawal intervals applyonly to oxytetracycline administered as an aqueoussolution. As always, FARAD recommends testing milk,because individual variation is excessive. On the basisof label withdrawal times in foreign countries, FARAD recommends meat withdrawal intervals of 18 days fora single 1- to 2-g dose, 28 days for a single 3-g dose,and 35 days for a single 4- to 6-g intramammary use of oxytetracyclinein cattle-The only oxytetracycline formulation ap-proved for intramammary treatment for mastitis is nolonger marketed Studies have shown that followingintramammary infusion into 1 quarter, oxytetracyclineresidues are in milk from untreated quarters.

9 Afteradministration at the label dose (1 to 3 infusions, 12 orM hours apart) of the approved preparation that con-tained 426 mg of oxytetracycline, the labd milk dis-card and meat withdrawal times were 96 extralabel use of a different parenteraloxytetracycline formulation at the same dose wouldrequire a minimum 96-hour milk-discard interval, fol-lowed by milk residue testing. If the dose is doubled,milk should be withheld for a minimum of 120 hours,followed by residue testing. The effects of differentformulations have not been studied; thus, this milkdiscard estimate may not apply to all drugs are readily absorbed from mastitic glands,an extended meat withdrawal interval of 19 days shouldbe oral use of oxytetracycline in cattle(in water only)-According to label information forthis use of oxytetracycline in other countries and theavailable literature, a withdrawal time of 14 days formeat and 7 days for milk should be allowed after ad-ministration of oxytetracycline hydrochloride in waterat a dosage of 20 to 40 mg/kg (9 to 18 mg/lb), every 12hours, for 3 to + days in adult animals.

10 In preruminantcalves, a meat withdrawal time of 21 days after admin-istration at the rate of 30 mg/kg/d ( mg/ibld) for 4days should be application of oxytetracycline productsin cattle-Topical ~pplication of oxytetracycline solu-tion (25 mgtml) in footba~ or sprays to treat hairyfoot warts requires no withdrawal time. To avoid milkresidues, it is recommended that someone other thanthe milker do the use of oxytebWcycline products in smallruminants-Phamlacokinetic studies of oxytetracyclinedone through the USDA's Minor Use Animal Drug Pr0-gram indicate that sheep and goats eliminate oxytetracy-cline faster than cattle after IV and 1M ; an interspecies analysis of all FARAD phanna-cokinetic data selected oxytetracycline as a "well-behaved"drug amenable to interspecies extrapolation.