Cardiotoxicity Secondary to Accidental Tilmicosin (Micotil^®300) Ingestion in a Young Shepherd: A Case Report

Introduction

Tilmicosin (Micotil®300) is a veterinary macrolide antibiotic primarily used to treat cattle and sheep for pathogens associated with bovine respiratory diseases [1,2]. Agricultural workers are at significant risk for occupational injuries, particularly needle-stick injuries, which are common among those handling large animals [3]. A survey of veterinary technicians revealed that 93% reported experiencing at least 1 needle-stick injury in their careers [4]. Tilmicosin is typically administered via subcutaneous injection, making parenteral exposure the most frequent form in humans, along with potential ingestion and dermal contact [1].

Tilmicosin has been shown to exhibit significant human toxicity at the doses used in animals [5]. Exposure to Tilmicosin has been associated with several fatalities, both intentional and accidental, due to its potential cardiotoxic properties [1]. Clinical manifestations of Tilmicosin toxicity are primarily linked to its positive chronotropic and negative inotropic effects on the cardiovascular system [6]. Additionally, Tilmicosin can lead to neurological symptoms, including dizziness, headache, blurred vision, ataxia, and limb weakness [1].

This report describes the case of a 29-year-old male shepherd who presented with syncope and severe chest pain following accidental ingestion of Tilmicosin, and we discuss proposed treatments in the literature shown to improve outcomes in severe Tilmicosin-associated cardiac toxicity.

Case Report

A 29-year-old man known to have bronchial asthma was brought to our Emergency Department (ED) after loss of consciousness. The patient worked as a shepherd, predominantly handling sheep. Three days prior to presentation, his sheep started to have flu-like symptoms. He was told by other shepherds that an antibiotic, Tilmicosin, was a good treatment. A veterinarian prescribed the antibiotic, and instructed the shepherd to give the sheep 1 ml subcutaneously. On the day of presentation to the ED, while attempting to open the syringe cap using his mouth, he accidentally spilled (not injected) the medication into his mouth (1 ml), and unintentionally swallowed it. He tried to wash his mouth afterwards, but had already tasted the medication going down his throat. He felt fine at that time and did not seek medical attention. Of note, he gave the sheep the medication subcutaneously with the same dose, one of which had immediately collapsed and died after the Tilmicosin injection.

Approximately 3 hours after exposure, he developed dizziness, described as a room-spinning sensation, accompanied by severe fatigue, generalized body aches, and nausea. He called for help and lay down, after which he lost consciousness. He was found unconscious by his relatives and was brought to the emergency department within 30 minutes from the onset of his symptoms. No seizure activity was observed. He regained consciousness in the emergency department, with no recollection of how he was brought there. On awakening, he reported severe stabbing pain in the left side of his chest radiating to his neck. On examination, he reacted immediately to painful stimuli, was vitally stable with a blood pressure of 122/75 mmHg, a heart rate of 84 beats per minute, a respiratory rate of 18 breaths per minute, was afebrile, and maintaining oxygen saturation at 98% on room air. Cardiac auscultation revealed normal first and second heart sounds, without added sounds or murmurs. The rest of the examination was unremarkable. He had an immediate electrocardiogram (ECG) done (Figure 1), which showed non-specific ST segment changes in the anterolateral leads, with sinus arrythmia. Laboratory studies revealed a mild elevation in creatinine kinase of 307 (ref 24–204 IU/L). Serum troponin measurements were normal (troponin I <0.010 ng/ml, ref <0.010 ng/ml). An echocardiogram revealed no abnormalities, with an ejection fraction of 55–60% and no regional wall motion abnormality. We consulted with our local toxicology center, which recommended admission for observation and supportive care for 24 hours. The patient had an uneventful hospital stay, with gradual resolution of chest pain, which coincided with normalization of ECG changes, and continued to have normal cardiac enzymes upon serial measurements. No arrythmias were noted during hospitalization. He was discharged in good conditions and was lost to follow-up thereafter.

Discussion

Tilmicosin (Micotil®300) is an antibiotic used in the treatment and prevention of bovine respiratory tract diseases, approved for veterinary use in 1992 [7]. It is a macrolide antibiotic used as a subcutaneous injection [7]. Since its approval, a boxed warning has been issued regarding its toxic effects on humans. Even in animals, dose-dependent toxicities and deaths have been documented [7]. The main toxicity associated with Tilmicosin is related to its calcium channel antagonistic properties, which causes reduction in left ventricle’s ability to contract, by affecting calcium movement across cell membranes as well as decreasing intracellular calcium levels [5].

Human exposure to Tilmicosin can occur through different routes, including parenteral, dermal, oral, and ocular [5]. Studies have reported that most clinical symptoms and signs from Tilmicosin toxicity appeared after parenteral exposure compared to other routes of exposure, as demonstrated in Oakes et al’s review [5]. Those symptoms include, but are not limited to, headache, dizziness, lightheadedness, weakness, numbness, tachycardia or bradycardia, chest pain, nausea, and vomiting [5]. Veenhuizen et al reported in their review that the onset of these systemic effects takes place within the first hour after being exposed to Tilmicosin [7]. However, our patient presented with systemic symptoms of toxicity (dizziness, severe fatigability, generalized body ache, chest pain, and nausea) 3 hours after unintentional oral ingestion of a small dose of Tilmicosin.

To date, there is no known antidote for Tilmicosin toxicity [2]. As it is a veterinary antibiotic, there is a lack of human studies on potential management of toxicity [7]. The Tilmicosin label indicates that since calcium channel blockade can cause cardiotoxicity, and that, as shown in dogs, intravenous (IV) calcium administration can reverse the tachycardia and negative inotropy induced by Tilmicosin [7]. The only report found in the literature with specific experimental therapies on humans is by Besserer et al [6], who reported a case of a severe cardiotoxicity in a 36-year-old man following accidental subcutaneous injection of Tilmicosin [6]. He developed resistant hypotension despite fluid boluses and phenylephrine administration [6], and an echocardiogram showed global cardiac hypokinesia [6]. As their patient was in a negative ionotropic state similar to calcium channel blocker toxicity, they administered IV calcium chloride and high-dose IV insulin [6]. They also postulated that Tilmicosin was lipid-bound, and administered IV lipid emulsion [6]. The patient’s blood pressure improved, he made full recovery, and was discharged after 4 days of hospitalization [6]. Other management strategies have been proposed in animal studies [8]. Er et al explored the role of amiodarone in the prevention of Tilmicosin-induced cardiotoxicity [8]. In their experimental rat trial, the experimental group was injected with amiodarone at minute 8 post Tilmicosin exposure [8]. The survival rate was significantly higher in the amiodarone group (40% vs 0% in the control group) [8]. The mechanism by which amiodarone prevented deaths is not well understood [8], but it has been proposed to exert cardio-protection through its anti-arrhythmogenic and potassium channel-blocking activities [8]. In a recent report by Coscun et al, amiodarone and amiodarone + dobutamine prevented troponin rise in a group of goats injected with Tilmicosin [9], but this was not associated with improved survival [9].

In patients without severe cardiac toxicities, most of the current management recommendations suggest that hospital admission and observation for a minimum of 8 hours after parenteral exposure to Tilmicosin is sufficient [5]. Our case shows that other routes of exposure can lead to severe toxicities, and patients accidentally exposed to Tilmicosin through any route should be evaluated carefully.

Conclusions

Tilmicosin, a common veterinary macrolide antibiotic used in the management of bovine respiratory tract diseases, can lead to significant human toxicities at doses used in animals. Most moderate and severe toxicities are secondary to parenteral exposure, but as demonstrated in this report, severe toxicity can also occur following enteral administration and at a low dose of only 1 ml. We emphasize the need for agricultural workers to be careful when handling Tilmicosin, and the importance of seeking immediate medical attention to avoid fatalities. More human studies are needed to evaluate the role of amiodarone and dobutamine in the management of Tilmicosin-induced toxicity.