Summary Of Exposure |
A) USES: VETERINARY USE ONLY: These agents are antibiotics of the macrolide class. Their therapeutic spectrum includes both gram positive and gram negative bacteria. TILMICOSIN: Tilmicosin phosphate is indicated for the treatment of bovine respiratory disease associated with Pasteurella haemolytica and given by the parenteral route. TYLOSIN: Tylosin is the parent compound of tilmicosin and is commonly used in veterinary medicine in various species. It can be given by the parenteral route, capsules or orally mixed in feed or water.
B) PHARMACOLOGY: These agents are made by the bacterium Streptomyces fradiae and act to inhibit bacterial protein synthesis by inhibiting the 50S ribosome.
C) TOXICOLOGY: In vitro studies of human cardiac myocytes shows that tilmicosin has calcium channel antagonist activity.
D) EPIDEMIOLOGY: Human exposure is not common TILMICOSIN: Parenteral exposure in humans (deliberate and inadvertent) can cause severe toxicity and may be rapidly fatal. TYLOSIN: Limited reports of human exposure, severe toxicity has not been reported.
E) WITH POISONING/EXPOSURE
1) HUMAN EXPOSURE: TILMICOSIN: There been several large case series describing adverse events reported following inadvertent human exposure to tilmicosin during veterinary care, as well as reports of intentional exposure. TYLOSIN: Limited reports of human exposure.
2) MILD TO MODERATE TOXICITY: TILMICOSIN: Inadvertent exposure can result in nausea, vomiting, abnormal taste, headache, dizziness, and paresthesia. Generalized weakness and inability to speak lasting several hours were reported after inadvertent injection of 0.5 to 1 mL. INJECTION SITE: Small quantities of tilmicosin accidentally injected into animal workers during bovine treatment have resulted in minimal localized skin reactions including pain, swelling and inflammation at the site. TYLOSIN: Contact dermatitis has occurred following occupational exposure (dermal and airborne) to tylosin.
3) SEVERE TOXICITY: TILMICOSIN: Fatalities have been reported following both inadvertent (injection into a caregiver while trying to administer to a struggling animal ) and intentional parenteral exposure to tilmicosin. Collapse and cardiac arrest have been observed in some of these patients. Other signs and symptoms observed prior to death included: chest pain, dysrhythmias, tachycardia, and cyanosis. TYLOSIN: Limited data. There have been no reports of severe toxicity following inadvertent human exposure.
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Heent |
3.4.3) EYES
A) WITH POISONING/EXPOSURE 1) CONJUNCTIVITIS/ANIMAL DATA: Moderate conjunctivitis occurred in rabbits exposed to Micotil(R) with symptoms resolving within 48 hours (Jordan et al, 1993).
2) Tilmicosin is considered an eye irritant (S Sweetman , 2000).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) ELECTROCARDIOGRAM ABNORMAL 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) CASE REPORT: A 34-year-old man with a previous history of incomplete RBBB with normal T waves had peaked T waves approximately 30 minutes after inadvertent parenteral exposure to tilmicosin. The patient refused cardiac monitoring and was lost to follow-up (McGuigan, 1994).
B) CARDIAC ARREST 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) CASE SERIES: In a retrospective study of 3168 human exposures to tilmicosin, 13 deaths were reported and in 2 cases collapse and cardiac arrest were the only clinical signs observed prior to death. In 2 other cases, chest pain, dysrhythmias, tachycardia, cyanosis, agonal heart rhythm with cardiac and respiratory arrest occurred prior to death (Veenhuizen et al, 2006). 2) CASE REPORT: A 25-year-old man was found dead following an intravenous injection of an unknown quantity of tilmicosin. Postmortem blood levels for tilmicosin (30 ppm) were markedly elevated. Although the mechanism for tilmicosin toxicity remains unclear, the authors suggested that toxicity may have been a combination of tilmicosin and/or propylene glycol (tilmicosin is solubilized in 25% propylene glycol), with its known cardiac toxicity (Kuffner & Dart, 1996). 3) CASE REPORT: A 17-year-old suicidal female was found in cardiopulmonary arrest following coingestion of alcohol (blood alcohol 170 mg/dL), acetaminophen with hydrocodone (unknown amount), and an empty 3 cc syringe believed to contain tilmicosin was found near the patient (a wound consistent with a needle mark was found on the patient's arm). A urine drug screen for drugs of abuse was negative. Despite resuscitation efforts the patient died from cardiopulmonary arrest (Personal Communication, 1997). 4) PROPYLENE GLYCOL a) SUMMARY: Rapid injection of propylene glycol may be associated with hypotension, circulatory collapse, and dysrhythmia.
b) Rapid administration of Dilantin(R) in a 40% propylene glycol diluent was associated with cardiac arrest and death in 6 reported cases of elderly patients treated for dysrhythmias; most also had digitalis toxicity (Gellerman & Martinez, 1967) (Goldschlager & Karliner, 1967) (Russell & Bousvaros, 1968) (Unger & Sklaroff 1967) (Voigt, 1968) (Zoneraich et al, 1976).
c) Death has occurred at excessively high infusion concentrations. 17.5 mg/mL was associated with cardiac arrest and death in two patients, aged 44 and 68 years during seizure treatment, only one of whom had known cardiac disease (York & Coleridge, 1988).
d) NOTE: See specific management for PROPYLENE GLYCOL when appropriate.
C) HYPOTENSIVE EPISODE 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) CASE REPORT: A 36-year-old man inadvertently injected tilmicosin into his left distal forearm and his wife immediately applied a tourniquet (about 1 hour of tourniquet time). Initially, he was anxious and his vital signs were within normal limits. Serial ECGs showed sinus tachycardia. Two hours after admission, he developed dyspnea, chest tightness and hypotension (BP 89/67 mmHg). IV fluids were given but hypotension (BP 67/32 mmHg) continued and calcium gluconate, phenylephrine and a dopamine infusion were begun. Additional therapy included calcium chloride (3 g), dextrose (25 g), an insulin infusion (100 units bolus then 100 units/hr) and dopamine at 2.5 mcg/kg/min. His systolic blood pressure improved to greater than 90 mmHg. A lipid infusion (500 mL bolus followed by an infusion of 20% lipids) was given over 30 minutes. Dopamine was stopped and dobutamine was added (started at 2.5 mcg/kg/min) and was continued until the patient's systolic blood pressure stabilized at greater than 120 mmHg. Other infusions (insulin and calcium) were gradually weaned off over 16 hours. A repeat chest x-ray revealed pulmonary edema. The patient was discharged to home on day 4 with only arm pain and swelling that was treated with outpatient therapy (Besserer et al, 2015).
2) CASE REPORT: A 46-year-old man presented with nausea, diaphoresis, hypotension (79/53 mmHg) and tachycardia (112 beats/min) 1.5 hours after intentionally injecting 3.6 g (12 mL) tilmicosin. He was treated with norepinephrine and dobutamine (for 1 and 3 days, respectively). Echocardiogram 24 hours after presentation revealed global left ventricular hypokinesis and an ejection fraction of 45%. He recovered and was discharged 6 days after admission (DeWitt et al, 2005).
D) CHEST PAIN 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) CASE SERIES: In a retrospective study of 3168 human exposures to tilmicosin, 1404 (44%) cases developed one or more clinical symptoms. Of those cases, chest pain developed in 4% (Veenhuizen et al, 2006).
2) CASE REPORT: A 29-year-old male farmer inadvertently injected himself with 0.5 to 1 cc of tilmicosin and developed neurological symptoms along with a sudden onset of crushing chest pain which occurred approximately 2 hours after exposure. The patient was given nitroglycerin and morphine with resolution of intermittent chest pain over the next 3.5 hours. ECG and cardiac enzymes were within normal limits. It was uncertain if the symptoms exhibited by the patient were related to tilmicosin or anxiety secondary to exposure (Crown & Smith, 1999).
E) TACHYARRHYTHMIA 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) SUMMARY: Tachycardia may develop following exposure to tilmicosin (Besserer et al, 2015; Forrester, 2005; Veenhuizen et al, 2006).
2) CASE SERIES: In a retrospective study of 3168 exposures to tilmicosin, 1404 (44%) cases developed one or more clinical symptoms. Of those cases, tachycardia occurred in 5% (Veenhuizen et al, 2006).
3) CASE SERIES: In a series of 22 accidental parenteral exposures to tilmicosin reported to the Texas poison centers, one patient (7%) developed tachycardia (Forrester, 2005).
F) HYPERTENSIVE EPISODE 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) In a series of 22 inadvertent parenteral exposures to tilmicosin reported to the Texas poison centers, one patient (7%) developed hypertension (Forrester, 2005).
3.5.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) TILMICOSIN a) SUMMARY: The cardiovascular system appears to be the primary organ system affected by tilmicosin. Cardiac toxicity (tachycardia and decreased contractility) is the primary adverse event seen in domestic and laboratory animals given tilmicosin by oral or parenteral routes (Jordan et al, 1993). b) TACHYCARDIA 1) DOGS: Dose-dependent increases in heart rate occurred in dogs, as well as left ventricular end-diastolic pressure at 2.5 and 5 mg/kg dose levels. Negative inotrope effects of tilmicosin were reported (Main et al, 1996).
2) Following sublethal doses, left ventricular function, systemic arterial pressure and heart rate were evaluated with dobutamine and propranolol. Treatment with propranolol exacerbated the negative inotropic effect and the decrease in left ventricular systolic pressure; tachycardia was unaffected. Dobutamine (a positive inotrope) reversed the ventricular inotropic state and was able to restore left ventricular systolic pressure at doses of 3 or 10 mcg/min/kg (Main et al, 1996).
3) DOGS: Sinus tachycardia, myocardial depression (negative inotropy) and a reduction in arterial pulse pressure have been reported with intravenous administration of tilmicosin. Propranolol was able to block some of the tachycardic effects of tilmicosin, but appeared to potentiate micotil-induced negative inotropy (Jordan et al, 1993).
4) BEAGLE DOGS: An increase in tachycardia was the only observable effect seen at oral doses of 20 mg/kg twice daily. Persistent severe tachycardia was observed in dogs given high doses (70 mg/kg) of tilmicosin (Jordan et al, 1993).
5) CHRONIC EXPOSURE: Beagle dogs given twice daily high doses (total daily dose 36 mg/kg) of tilmicosin for 1 year had an increased incidence of tachycardia; at necropsy most dogs exposed to the high dose had slight to moderate heart enlargement (Jordan et al, 1993).
c) ECG ABNORMAL 1) DOGS: A slightly shortened PR interval and prolonged QRS duration were noted in dogs given intravenous doses of 5 mg/kg of tilmicosin (Jordan et al, 1993).
2) BEAGLE DOGS: Treatment-related effects of high doses of tilmicosin resulted in persistent severe tachycardia and ST segment depression in all 8 dogs studied (Jordan et al, 1993).
d) HYPOTENSION 1) DOGS: Marked hypotension (mean arterial pressure less than 20 mm Hg) was observed in 2 of 3 dogs given intravenous doses (5 mg/kg) of tilmicosin (Jordan et al, 1993).
e) CARDIAC FAILURE 1) DOGS developed decreased cardiac output and stroke volume, increased wedge pressure, and peripheral vasoconstriction following IV doses of 5 mg/kg (Jordan et al, 1993). Dizziness, lightheadedness, generalized weakness and inability to speak developed in one patient after injection of 0.5 to 1 mL.
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) CENTRAL NERVOUS SYSTEM FINDING 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) CASE SERIES: In a retrospective study of 3168 exposures to tilmicosin, 1404 (44%) cases developed one or more clinical symptoms. Of those cases, common neurological events following exposure included: dizziness (5%), headache (5%), anxiety (4%), paresthesia (4%), and numbness (3%) (Veenhuizen et al, 2006).
2) CASE REPORT: A 29-year-old male farmer inadvertently injected himself with 0.5 to 1 cc of tilmicosin and developed dizziness, lightheadedness and weakness within 15 minutes of exposure. The patient had a past medical history of allergy to penicillin and codeine. Over the next 20 minutes, the patient had difficulty moving his extremities or speaking, but remained alert and responded appropriately (by moving his head). Neurological exam was unremarkable and the patient gradually regained movement and speech during the next hour. The patient was discharged the following day with no long term neurological sequelae reported (Crown & Smith, 1999).
B) HEADACHE 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) In a series of 22 inadvertent parenteral exposures to tilmicosin reported to the Texas poison centers, two patients (14%) developed headache (Forrester, 2005).
2) CASE SERIES: In a retrospective study of 3168 exposures to tilmicosin, 1404 (44%) cases developed one or more clinical symptoms. Of those cases, headache developed in 5% (Veenhuizen et al, 2006).
3.7.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) TILMICOSIN a) MICE: No significant CNS effects occurred after mice were exposed to oral doses of 10 or 100 mg tilmicosin/kg; death was reported following doses of 500 and 1000 mg/kg (Jordan et al, 1993).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) CASE SERIES: In a retrospective study of 3168 human exposures to tilmicosin, 1404 (44%) cases developed one or more clinical symptoms. Of those cases the following gastrointestinal symptoms developed: abnormal taste (20%), nausea (6%), and vomiting (3%) (Veenhuizen et al, 2006).
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Hepatic |
3.9.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) HEPATIC ENZYMES INCREASED a) TILMICOSIN 1) RATS: Doses of 50, 175, and 600 mg/kg tilmicosin were given to Fischer rats daily for 2 weeks. Only doses of 600 mg/kg resulted in an increased serum alanine transaminase (ALT), although no evidence of hepatotoxicity was present (Jordan et al, 1993).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) CONTACT DERMATITIS 1) WITH POISONING/EXPOSURE a) TYLOSIN 1) CASE SERIES: Occupational contact dermatitis has been reported in several animal workers. Facial redness and lesions appear attributable to airborne contact during administration of the antibiotic and exposure to animal feed dust (Caraffini et al, 1994). Several cases of direct skin contact with tylosin resulted in eczema to the hands (Danese et al, 1994; Tuomi & Rasanen, 1995). Symptoms resolved in all cases when the individuals were removed from the occupational environment (Caraffini et al, 1994; Danese et al, 1994; Tuomi & Rasanen, 1995).
B) LACK OF EFFECT 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) CASE SERIES: McGuigan (1994) reviewed 36 inadvertent human exposures with tilmicosin which occurred predominantly as a parenteral exposure (n=26); the remaining cases involved splashes onto the skin, or into the eyes and mouth (McGuigan, 1994).
2) Most cases resulted in minimal exposures of less than 1 mL of tilmicosin while 4 were between 5 to 15 mL. In the majority of cases, no effect was reported; no unexpected local tissue reaction or evidence of systemic toxicity occurred (McGuigan, 1994).
3.14.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) IRRITATION a) TILMICOSIN 1) RABBITS: Slight skin irritation occurred in rabbits exposed to Micotil(R) with symptoms resolving within 48 hours (Jordan et al, 1993).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ACUTE ALLERGIC REACTION 1) WITH POISONING/EXPOSURE a) TILMICOSIN 1) Exposure to tilmicosin can result in an allergic reaction (S Sweetman , 2000).
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Reproductive |
3.20.1) SUMMARY
A) No adverse effects of pregnancy or teratogenicity were seen in rat studies.
3.20.2) TERATOGENICITY
A) LACK OF EFFECT 1) TILMICOSIN - a) RATS - Fetal viability, weight, and morphology were not adversely affected by tilmicosin. Limited clinical toxicity included: an increase in salivation at 70 mg/kg/d, and alopecia in rats given 500 mg/kg/d (Jordan et al, 1993).
3.20.3) EFFECTS IN PREGNANCY
A) LACK OF EFFECT 1) TILMICOSIN - a) RATS - Perinatal mortality or the reproductive process were not adversely affected by the administration of tilmicosin to male or female CD rats (Jordan et al, 1993).
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Carcinogenicity |
3.21.3) HUMAN STUDIES
A) LACK OF INFORMATION 1) TILMICOSIN - a) Although no studies have been conducted on tilmicosin, a review of the literature indicated that compounds similar in structure (tylosin) have shown no evidence of carcinogenicity (Jordan et al, 1993).
2) TYLOSIN - a) No evidence of carcinogenicity was observed in Wistar rats fed dietary concentrations of tylosin as high as 1% for 2 years (Jordan et al, 1993).
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