To describe challenges in the management of prophylaxis against infections for patients receiving medicinal leech therapy given changes in antimicrobial resistance patterns in the normal flora of leeches. This article presents a patient case of reconstructive surgery complicated by infection associated with the use of medicinal leeches, as well as a discussion of prophylaxis in medicinal leech therapy, focusing on considerations for choosing a prophylactic agent. Our case report highlights resistance changes in Aeromonas isolates associated with medicinal leeches and the potential for complications if isolates resistant to chosen prophylactic agents arise. When administering antimicrobial prophylaxis in patients receiving medicinal leech therapy, clinicians should be familiar with the susceptibilities of Aeromonas species but also conscious of evolving antimicrobial resistance given the extent of the consequences of infected surgical grafts.