A 54-year-old employee of a cattle farm argued with a coworker and hinted that she wanted to harm herself. Shortly thereafter, she was found unresponsive near a used syringe and a tourniquet with a puncture wound in her antecubital fossa. CPR was started, and she was transported to the hospital, but resuscitation efforts were unsuccessful.
A 38-year-old cattle rancher was holding a 12 cc syringe as he prepared to inject a cow with a subcutaneous medication. When an agitated animal in the next pen struck the fence, the rancher fell to the ground and accidentally injected himself with some of the medication. He was taken by ambulance to a nearby hospital but died within several hours of arrival.
The toxic agent in both of these publicly reported cases was tilmicosin (Micotil 300), a veterinary antibiotic commonly used to treat and prevent bovine respiratory disease.
You haven't heard of tilmicosin? Don't worry—you're not alone. Many emergency practitioners and even some medical toxicologists are not aware of the drug. A number of deaths have been attributed to tilmicosin over the past decade or so from intentional and inadvertent parenteral exposure, and it is not even mentioned in some standard textbooks such as Goldfrank's Toxicologic Emergencies. Tilmicosin is a drug you should know, especially if you practice in rural or farming areas.
How is tilmicosin used? Tilmicosin is a veterinary macrolide antibiotic used in sheep and cattle, and the “300” in the commercial name refers to its concentration—300 mg/mL. The recommended veterinary dose is 1.5-3.0 mL/100 pounds subcutaneously.
Tilmicosin has been used in the United States and Canada for three decades. A rancher typically restrains multiple animals in squeeze chutes and goes down the line injecting each from a single syringe. This method can be extremely dangerous, and has resulted in morbidity and mortality from accidental human injection.
Why is tilmicosin so dangerous? Like some other macrolide antibiotics such as erythromycin and clarithromycin, tilmicosin has calcium channel blocking activity. The veterinary preparation is formulated to treat large farm animals, so it is exceptionally potent and even a small amount inadvertently injected can be lethal in humans. Fatalities have been reported after exposure to as little as 5-6 mL, and significant toxicity can occur from injections of less than 0.5 mL. Any parenteral exposure to tilmicosin should be considered a medical emergency requiring immediate evaluation at a health care facility.
How does tilmicosin toxicity present clinically? Signs and symptoms typically begin immediately after accidental or deliberate parenteral exposure, but in some reports, onset was delayed for several hours. Local manifestations at the site of injection include pain, bleeding, and swelling. Victims have experienced nausea, dizziness, headache, chest pain or tightness, dyspnea, diaphoresis, blurred vision, tinnitus, and ataxia. Typically, patients will be tachycardic and hypotensive. As is evident in the two cases above, death can come on rapidly even if the patient receives prompt medical attention.
What does science tell us about tilmicosin poisoning? A study in dogs showed that toxic but sublethal doses of intravenous tilmicosin impair myocardial contractility and increase heart rate, both of which were dose-dependent. (J Vet Pharmacol Ther. 1996;19:225.) Administering propranolol after tilmicosin further decreased cardiac function without ameliorating the tachycardia. The authors of this study found that dobutamine improved cardiac contractility and systolic blood pressure, at least in a canine model. Another study in dogs from the same lab showed that intravenous calcium reversed tilmicosin's negative inotropic effects. (Clin Toxicol. 2005 North American Congress of Clinical Toxicology Annual Meeting [abstract]. 2005;43:695.)
How do we treat tilmicosin toxicity? Apply ice locally to the site of injection, and arrange for immediate transport to a health care facility. Advanced supportive care begins with the usual attention to airway, breathing, and circulation. Treat hypotension with calcium. Fluids can be administered cautiously, bearing in mind that tilmicosin causes myocardial depression. Avoid beta-blockers and epinephrine, which may exacerbate tachycardia.
An interesting letter described a 36-year-old man who presented to the hospital after unintentionally injecting himself in the left forearm with tilmicosin. (Clin Toxicol [Phila]. 2016;54:812.) Several hours after arrival, he complained of shortness of breath and was tachycardic (137 bpm) and hypotensive (67/32 mm Hg). Bedside ultrasound showed global hypokinesis. Because of persistent hypotension, the patient was treated with calcium gluconate infusion and high-dose insulin. He was also given intravenous lipid emulsion therapy. (The authors pointed out that tilmicosin is approximately as lipophilic as bupivacaine.)
The patient did well and was discharged after four days in the hospital. Unfortunately, the brief letter did not provide many details regarding the course of treatment and response, so it is not clear which interventions were actually beneficial. The authors sensibly concluded: “While we are unable to definitively ascribe therapeutic success to a single agent in this case, calcium would appear to be the best candidate.”
Dr. Gussowis a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Read his blog atwww.thepoisonreview.com, follow him on Twitter@poisonreview, and read his past columns athttp://bit.ly/EMN-ToxRounds.