What are recommendations for antibiotic prophylaxis in medicinal leech therapy?

Comment by InpharmD Researcher

There are no consensus recommendations or guidance regarding the use of antimicrobial prophylaxis for hirudotherapy (medicinal leech therapy). Common prophylactic agents include fluoroquinolones, sulfamethoxazole/trimethoprim, and third-generation cephalosporins; however, there have been growing reports of antimicrobial-resistant Aeromonas species (particularly, growing fluoroquinolone resistance) causing infection after hirudotherapy. Some authors have proposed culturing the water leeches reside in to determine appropriate prophylactic agents, but this is not always feasible. Another proposed solution is to use dual antimicrobial prophylaxis; however, this may interfere with antimicrobial stewardship standards and still result in infection.

Background

A 2022 case report (Table 1) and systematic review addressed the growing concern of antibiotic-resistant infections arising from medicinal leech therapy. Historical susceptibility profiles of Aeromonas species have resulted in fluoroquinolones (ciprofloxacin or levofloxacin) being used as the most common antimicrobial prophylactic agents for medicinal leech therapy. However, a number of case reports have raised concern over changing antimicrobial susceptibility in the normal flora of the leech. The reason for the rise of drug-resistant Aeromonas species isolated from medicinal leeches is unclear. One hypothesis suggests the blood used to feed these leeches may contain antibiotics that induce resistance in the leech's normal flora. Similar pathways of antimicrobial resistance have been seen in humans stemming from the agricultural industry (antibiotic use in livestock). Additionally, studies have found that resistant normal flora can be transmitted between leeches, as evidenced by the presence of resistant isolates in the water in which leeches are stored. The development of antimicrobial-resistant Aeromonas species can complicate postoperative recovery in patients receiving medicinal leech therapy. While culturing leeches or the water they are stored in may provide insight into ideal antibiotic prophylaxis regimens, this may not be feasible for all locations, and the susceptibilities may vary among institutions. Double coverage with two prophylactic agents may decrease the risk of infection when using leeches, but the risk must also be balanced with the public health implications of increased use of broad-spectrum agents. Currently, there are no consensus recommendations on ideal prophylactic agents, the timing of administration, or the duration of prophylaxis. [1]

A 2018 qualitative study surveyed 23 French centers regarding their use of medicinal leeches. While there are no guidelines or consensus thoughts on antimicrobial prophylaxis with medicinal leech therapy, most authors suggest starting antimicrobial prophylaxis before or when starting leech application to the patient. Some authors suggest continuing antimicrobial prophylaxis until leech therapy is completed, while others suggest continuing prophylaxis until cicatrization has occurred. The most common prophylactic medications are fluoroquinolones, sulfamethoxazole/trimethoprim, and third-generation cephalosporins; however, there has been growing concern regarding the appropriate selection of agent due to the emergence of drug-resistant Aeromonas species. Amoxicillin/clavulanic acid should be avoided because aeromonads are virtually all resistant to this antimicrobial agent because oxacillinase and/or cephalosporinase are expressed by the vast majority of aeromonads. Other approaches to infection control with medicinal leeches include attempting to sterilize the leech gut by immersing the leeches in an antibiotic solution or eliminating Aeromonas species from the leech by administering an arginine/ciprofloxacin solution; these methods have been unsuccessful and could potentially increase the risk of drug-resistant infections. Another proposed method of infection control involves external decontamination by treating the leeches with chlorhexidine 0.02% for 15 seconds followed by sterile water rinses. [2]

A 2020 case report (Table 2) of multidrug-resistant Aeromonas infection following medical leech therapy prompted an interdisciplinary investigation and subsequent development of infection prevention protocol to proactively monitor for antimicrobial resistance among the institution’s leech supply. One leech from each batch of 50 is sacrificed and 0.5 to 1 mL of leech water collected, both being cultured upon delivery and every 30 days thereafter. The Microbiology lab performs culture and susceptibility testing on Aeromonas hydrophila from leech water and leech gut contents. Upon receiving susceptibility results, antimicrobial stewardship pharmacists will then select the prophylactic antibiotics accordingly. In the absence of ceftriaxone, ciprofloxacin, or meropenem resistance, patients will receive standard antibiotic prophylaxis with ceftriaxone or TMP-SMX if allergic to penicillin. If resistant patterns are detected, the leech batch is quarantined and the leeches ordered will be replaced. If emergent leech therapy is required, pharmacists will recommend antibiotic prophylaxis based on susceptibilities. In case of patients receiving leeches that harbor resistant Aeromonas, infection prevention closely follows up with these patients for any risks of complications. After successful implementation of this protocol, the institution reports no further cases of leech-associated infections. It is worth noting, this proactive monitoring protocol for resistance may not readily apply to all institutions. [3]

References:

[1] McCracken JA, Koehler SM, Sharma R. Rethinking antimicrobial prophylaxis in patients receiving medicinal leech therapy. Am J Health Syst Pharm. 2022;79(1):e14-e19. doi:10.1093/ajhp/zxab330
[2] Grau D, Masson R, Villiet M, Lamy B; French Hospitals Group. Leech management before application on patient: a nationwide survey of practices in French university hospitals. Antimicrob Resist Infect Control. 2018;7:19. Published 2018 Feb 5. doi:10.1186/s13756-018-0311-7
[3] Masters MC, Gupta AR, Rhodes NJ, et al. Multidrug resistant Aeromonas infection following medical leech therapy: A case report and development of a joint antimicrobial stewardship and infection prevention protocol. J Glob Antimicrob Resist. 2020;23:349-351. doi:10.1016/j.jgar.2020.10.010

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What is the role of antibiotic prophylaxis in medicinal leech therapy?

Level of evidence

D - Case reports or unreliable data  Read more→



Please see Tables 1-4 for your response.


 

Rethinking Antimicrobial Prophylaxis in Patients Receiving Medicinal Leech Therapy

Design

Case report

Case Presentation

A 47-year-old female with a history of traumatic damage to the brachial plexus nerves presented for elective reconstructive surgical reanimation of a flail right arm, a procedure intended to restore mobility to the arm. Free functional muscle reanimation of the patient’s elbow was performed utilizing the patient’s left gracilis muscle. Despite initial flap viability, the patient presented with late venous congestion of her flap on postoperative day 8, exhibiting flap swelling and skin color changes.

A portion of the suture line of the inset flap was opened to alleviate pressure. Leech therapy was initiated in an attempt to change neorevascularization. Per institutional protocol, the patient was given levofloxacin 500 mg IV q24h for antimicrobial prophylaxis against Aeromonas at the time of leech placement. The leech therapy continued for 10 days (until postoperative day 17). After leech therapy, the patient returned to the operating room for closure of native skin that had been exposed around the flap. Levofloxacin was continued following the cessation of leech therapy.

On postoperative day 21, purulent drainage was observed from the surgical incision on the upper arm. This prompted levofloxacin to be changed to piperacillin/tazobactam. Upon return to the operating room, complete necrosis of the gracilis muscle flap was found, requiring immediate removal of the entire flap and radical debridement of the surgical site.

Drainage cultures identified the pathogen as A. caviae that was resistant to levofloxacin. A full culture susceptibility report is listed below. Due to susceptibility to ceftriaxone, empiric antibiotics were discontinued, and the patient was discharged to complete a total of 6 weeks of ceftriaxone.

Culture and Susceptibility Report Antibiotic Aeromonas caviae Susceptibility Result
Amikacin Susceptible
Ampicillin/sulbactam Intermediate
Aztreonam Susceptible
Cefazolin Resistant
Cefepime Susceptible
Ceftriaxone Susceptible
Ciprofloxacin Resistant
Gentamicin Susceptible
Levofloxacin Resistant
Meropenem Susceptible
Piperacillin/tazobactam Susceptible
Tetracycline Resistant
Trimethoprim/sulfamethoxazole Resistant

Study Author Conclusions

This 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.

Historical susceptibility profiles of Aeromonas species have resulted in fluoroquinolones (ciprofloxacin or levofloxacin) being used as the most common antimicrobial prophylactic agents for medicinal leech therapy. However, a number of case reports have raised concern over changing antimicrobial susceptibility in the normal flora of the leech. While the overall rate of infection reported in the literature ranges from 7% to 20%, and results for an infected flap may vary based on many factors aside from antibiotic resistance, flaps that do become infected have an estimated survival rate of 30% or less.

The reason for the rise of drug-resistant Aeromonas species isolated from medicinal leeches is unclear. One hypothesis suggests the blood used to feed these leeches may contain antibiotics that induce resistance to the leech's normal flora. Similar pathways of antimicrobial resistance have been seen in humans stemming from the agricultural industry (antibiotic use in livestock). Additionally, studies have found that resistant normal flora can be transmitted between leeches, as evidenced by the presence of resistant isolates in the water in which leeches are stored.

 

References:

McCracken JA, Koehler SM, Sharma R. Rethinking antimicrobial prophylaxis in patients receiving medicinal leech therapy. Am J Health Syst Pharm. 2022;79(1):e14-e19. doi:10.1093/ajhp/zxab330

 

Multidrug resistant Aeromonas infection following medical leech therapy: A case report and development of a joint antimicrobial stewardship and infection prevention protocol

Design

Case report 

Case presentation

A 50-year-old woman underwent a left-sided mastectomy for ductal carcinoma in situ followed by immediate reconstruction with a superficial inferior epigastric artery flap and right-sided breast reduction for symmetry. As the mastectomy flap developed signs of congestion on postoperative day 1, 3 days of medical leech therapy (MLT) was initiated, leading to improved perfusion to the flap. The patient received prophylactic intravenous (IV) ceftriaxone during the MLT and was then discharged on oral cephalexin and trimethoprim-sulfamethoxazole (TMP-SMX).

Unfortunately, patients developed swelling of the left breast and experienced fevers despite change of antibiotics to amoxicillin/clavulanate and levofloxacin. As her condition continued to decline with erythema of her abdominal wound and a 15 cm area of necrosis of the mastectomy flap and ongoing fever, she was started on empiric IV vancomycin and piperacillin/tazobactam before being taken back to the operating room for debridement of her left breast and abdominal wounds.

Without clinical improvement, antibiotic coverage was broadened to meropenem. Subsequent cultures from the operating room grew a multidrug-resistant (MDR) Aeromonas species notably resistant to ciprofloxacin, ceftriaxone, and TMP-SMX. With the additional debridement and carbapenem therapy, the patient began to demonstrate clinical improvement. She was discharged on meropenem for a total of 21 days of antibiotic therapy following the second debridement. The patient was doing well without recurrent infection at a 12-month follow-up.

Antibiotic susceptibility testing
Antibiotic MIC  MIC Interpretation
Amikacin 32 Intermediate 
Ampicillin ≥32 Resistant
Ampicillin/sulbactam ≥32 Resistant
Aztreonam ≤1 Susceptible
Cefazolin ≥64 Resistant
Ceftriaxone ≥64 Resistant
Ciprofloxacin ≥4 Resistant
Gentamicin ≥16 Resistant
Meropenem ≤0.25 Susceptible
Piperacillin/tazobactam Susceptible
Tobramycin ≥16 Resistant
Trimethoprim/sulfamethoxazole ≥16/304 Resistant 

Study Author Conclusions

Although antibiotic prophylaxis can reduce the risk of Aeromonas infection following MLT, reports of emerging resistance are increasing. This report is the first case of an MLT-associated Aeromonas infection with resistance to all three first-line prophylactic antibiotic classes (fluoroquinolones, TMP-SMX, and third-generation cephalosporins).

In response to this sentinel event, the institution reviewed its MLT practices and developed a protocol to monitor for emerging resistance and guide appropriate antibiotic prophylaxis during MLT. In light of increasing antimicrobial resistance and the potentially devastating consequences of MLT-associated infections, institutions offering MLT should be aware of these risks and ensure that protocols are in place to minimize infection risks for patients.

 

References:

Masters MC, Gupta AR, Rhodes NJ, et al. Multidrug resistant Aeromonas infection following medical leech therapy: A case report and development of a joint antimicrobial stewardship and infection prevention protocol. J Glob Antimicrob Resist. 2020;23:349-351. doi:10.1016/j.jgar.2020.10.010

 

Implementation of a Leeches + Antimicrobial Prophylaxis Order Panel to Optimize Medicinal Leech Use at a Tertiary Care Academic Medical Center

Design

Retrospective, observational, pre-post study

N= 50

Objective

To assess the effectiveness of the implemented panel in promoting appropriate antimicrobial prophylaxis use when leech therapy is administered

Study Groups

Leech therapy before antimicrobial order panel implementation (2010-2017) (n= 40)

Leech therapy after antimicrobial order panel implementation (2018-2019) (n= 10)

Inclusion Criteria

Adult patients with orders for medicinal leech (Hirudo medicinalis) therapy

Exclusion Criteria

N/A

Methods

A retrospective electronic medical record review was conducted for all orders of medicinal leech therapy before and after an antimicrobial order panel was implemented to improve agent selection.

Storage of leeches: (per Leeches USA, LTD. recommendations) in Hirudosalt solution in the medication refrigerators both in pharmacy and on the patient units until applied for patient use

Optimal prophylaxis was defined as antibiotic active against Aeromonas species administration ≥30-60 minutes (≥60 minutes for ciprofloxacin, ≥30 minutes for other agents) before applying the first medicinal leech, and continued for the duration of the medicinal leech therapy.

Duration

Pre-panel implementation: 2010-2017

Post-panel implementation: 2018-2019

Outcome Measures

Primary: incidence of optimal antimicrobial prophylaxis pre- and post-panel implementation

Secondary: incidence of failure due to timing or due to antibiotic agent selection, antibiotic agent selection, duration of therapies, rates of Aeromonas infection, and resistance patterns of Aeromonas cultures to recommended prophylaxis agents

Baseline Characteristics

 

Pre-panel (n=40)

Post-panel (n=10)

p-value

Optimal Aeromonas Prophylaxis

 40%  70%  0.089

Optimal prophylaxis timing

 40%  60%  0.216

Optimal antimicrobial prophylaxis (not mutually exclusive)

Sulfamethoxazole-trimethoprim

Ciprofloxacin

Other (piperacillin-tazobactam, meropenem, ampicillin-sulbactam, ceftriaxone)

 92.5%

 2.5%

 65%

 30%

 100%

 50%

 20%

 60%

 0.504

 0.001

 0.013

 0.261

Results

 

Pre-panel (n=40)

Post-panel (n=10)

p-value

Development of Aeromonas infection

 5%*  10%*  0.496

Time to Aeromonas infection, days

 7.26  6.78  0.2207

Aeromonas spp. sensitivity profiles

Ciprofloxacin Resistance

Sulfamethoxazole-trimethoprim Resistance

 

 100%

 0%

 

 0%

 100%

 

 N/A

 N/A

*All patients who developed Aeromonas spp infections did not have optimized antimicrobial prophylaxis.

Study Author Conclusions

In conclusion, the implementation of an order panel in the EMR which prompts initiation of antimicrobial prophylaxis when medicinal leeches are ordered was effective in improving adherence to institutional recommendations for Aeromonas prophylaxis.

InpharmD Researcher Critique

The study was underpowered to demonstrate a significant difference in infection incidence, and the much smaller post-panel group may compound this effect. Notably, the order panel listed sulfamethoxazole-trimethoprim at the top of the list, potentially contributing the dramatic change in resistance patterns via easier ordering compared to finding ciprofloxacin further down the list.



References:

Palm NM, Wesolowski JC, Wu JY, Srinivas P. Implementation of a Leeches + Antimicrobial Prophylaxis Order Panel to Optimize Medicinal Leech Use at a Tertiary Care Academic Medical Center. J Pharm Pract. 2022;35(3):427-430. doi:10.1177/0897190021993683

 

A Case of Leech-associated Infection Involving an Extended-spectrum β-lactamase-producing and Extensively Drug-resistant Aeromonas hydrophila

Design

Case report

Case presentation

A 58-year-old woman underwent unilateral breast reconstruction following mastectomy with a deep inferior epigastric artery perforator flap and silicone implant. A total of 25 leeches were applied to the flap. The patient received dual antimicrobial prophylaxis with oral trimethoprim/sulfamethoxazole 80 mg/400 mg and ofloxacin 200 mg, started on the first postoperative day and continued for five days. Hirudotherapy was effective and the appearance of the flap rapidly improved.

One month later, the patient presented with partial flap necrosis associated with non-union of the mastectomy scar, prompting surgical revision with removal of the implant and flap, and reconstruction using an extended latissimus dorsi flap. Surgical debridement was performed and 3 intraoperative bacteriological specimens (peri-prosthetic collection, wound, drainage fluid) were sent to the clinical bacteriology for examination.

Aerobic cultures grew Aeromonas hydrophila that was found to be resistant to ciprofloxacin, trimethoprim/sulfamethoxazole, ticarcillin, ticarcillin/clavulanate, piperacillin, piperacillin/tazobactam, cefotaxime, cefepime, and aztreonam. The isolate was susceptible to ceftazidime, imipenem, and meropenem. The patient received IV ceftazidime 2 g and gentamicin 80 mg daily, which resulted in clinical improvement. 

Study Author Conclusions

In the era of increasing antibiotic resistance, leeches can be vectors of bacteria harboring genes of resistance to major antibiotics. Such infections may require revision of prophylactic protocols, such as microbiological assessment of the safety of leeches and detection of bacterial resistance to major antibiotics.

In this case, the water containing the leeches was cultured and resulted positive for the A. hydrophila species identified in the patient. Additionally, these isolates also produced acquired β-lactamases (TEM-1 and CTX-M-3). 

Aeromonas species are responsible for hirudotherapy-associated infections in 2.4–20% of treated patients, especially those with poorly vascularized flaps. The benefit-risk balance should therefore be assessed before considering leech therapy, as infections are associated with prolonged hospital stay and failure of reconstruction.

 

References:

Floug Q, Sinna R, Fillatre A, Plésiat P, Hamdad F. A case of leech-associated infection involving an extended-spectrum β-lactamase-producing and extensively drug-resistant Aeromonas hydrophila. Clin Microbiol Infect. 2019;25(3):394-395. doi:10.1016/j.cmi.2018.11.006