Case Report: Amphotericin B and Mefloquine as a Salvage Treatment of Alveolar Echinococcosis

ABSTRACT.

Alveolar echinococcosis is an emerging zoonotic disease caused by the parasite Echinococcus multilocularis. Most patients are diagnosed at a late stage, when lifelong treatment with benzimidazoles is required to stop disease progression. However, for patients who do not tolerate benzimidazole therapy, there are no alternatives. Here, we present a patient with advanced alveolar echinococcosis who was successfully treated with amphotericin B deoxycholate and mefloquine as a rescue therapy after he developed albendazole intolerance.

INTRODUCTION

Alveolar echinococcosis (AE) is an emerging, neglected zoonotic infection caused by Echinococcus multilocularis. Humans contract the disease by ingesting food contaminated with parasite eggs that hatch into oncospheres in the intestines, penetrate the mucosa, enter the circulation, and infiltrate visceral organs where they mature into alveolar cysts that exert tumor-like behavior.¹ Diagnosis is made by imaging and serologic testing.² A cancer-like staging of the disease was developed on the basis of location of liver lesions, adjacent organ involvement, and metastatic spread.² The treatment approach varies depending on disease stage: 1) radical curative resection with 2 years of albendazole (ABZ) treatment in the early stages; 2) lifelong parasitostatic ABZ treatment in all nonresectable cases; and 3) procedures aimed at alleviating local complications such as percutaneous or endoscopic drainage or palliative surgery in rare selected cases when the former are not possible.^2,3 Because most cases are diagnosed in advanced stages, fewer than one-third of patients may benefit from radical resection; thus, lifelong benzimidazole therapy remains the only option to control disease progression.⁴ However, for patients who experience severe side effects, there are no alternatives. When the infection is untreated, the 10-year mortality rate may reach 90%.⁵ New or repurposed drugs have not been tested in clinical trials, and only limited data on in vitro activity and several case reports are available.⁶

CASE REPORT

A 63-year-old male patient was diagnosed with AE in September 2017. A cystic lesion in the liver was initially detected as an incidental finding during routine ultrasonography in November 2014. Computed tomography (CT) revealed a heterogenous zone measuring 11 × 8 cm, with irregular postcontrast enhancement and an enlarged right adrenal gland (6.7 × 4.8 cm). Histopathological examination of the lesion excluded malignant disease. In November 2015, nodular lesions in both lungs were noticed. Although a repeated liver biopsy suggested echinococcosis in 2016, it was September 2017 when he was finally referred to an infectious diseases specialist and the diagnosis of AE was established. At that time, the disease was in stage IV (P4N1M1); the liver lesion had increased in size to 13 × 12 × 12 cm and had infiltrated adjacent vasculature (vena cava inferior, v. portae, v. hepatis), whereas lung nodules and pleural effusion had increased in size. Echinococcus multilocularis was retrospectively confirmed by polymerase chain reaction from 2016 liver biopsy samples and serology (ELISA and Western blot were positive for E. multilocularis). This was the first reported case of AE in Croatia.⁷ At that time, positron emission tomography CT (PET-CT) was not performed to evaluate disease activity.

Owing to the extent of pleural effusion and the need for repeated thoracic drainage as well as multiple episodes of bacteremia of suspected origin in the biliary tract, surgery was offered to the patient to alleviate symptoms and prevent further complications. The patient refused surgery, and treatment with ABZ 400 mg two times per day was initiated. However, because of the worsening of symptoms and lesion growth, in June 2018 right-sided hepatectomy, diaphragm resection, adrenalectomy, and hepaticojejunal anastomosis were performed (nonradical resection). In the following months, the patient developed alopecia and a mild toxic hepatic lesion. However, ABZ treatment was continued until February 2019, when he developed an episode of febrile agranulocytosis. Computed tomography showed multiple partial thromboses of the vena cava inferior, the remaining cystic collection within the falciform ligament, and the remaining part of the left liver lobe (6 × 2 cm) without growth in size. Afterward, ABZ or mebendazole was reintroduced in reduced dosages, again with the development of pancytopenia, and benzimidazole intolerance was diagnosed.

In May 2019, salvage treatment with amphotericin B deoxycholate (AmBD) was initiated: induction phase with 50 mg/day for 14 days, followed by 50 mg three times per week for the next 4 weeks, and then 50 mg once per week for the next 2 years. The patient tolerated therapy well without any significant side effects. In May 2021, after 2 years of treatment, there were no active lesions on PET-CT (Figure 1). However, a slight elevation of serum creatinine (110 μmol/L) and gamma-glutamyl transferase (231 IU/L) levels was observed, and the patient expressed a desire for different treatment options. AmBD was discontinued, and oral mefloquine 250 mg once per week was started. One year later, the patient had not experienced any adverse effects, and there were no clinical or radiological signs of disease progression on PET-CT performed in May 2022.

Figure 1.

Whole-body positron emission tomography/computed tomography images obtained in May 2021. (A) Images did not show increased uptake of 18F-fluorodeoxyglucose (18F-FDG) in a pulmonary nodule in the right lower lobe. (B) A small area of 18F-FDG accumulation was seen at the place of liver resection near metallic surgical clips.

DISCUSSION

Although benzimidazoles exert suppressive parasitostatic effects on the progression of AE, they can also cause serious adverse effects, including central nervous system disturbances, nephrotoxicity, hepatotoxicity and cytopenias, which limit their use.⁸ In lieu of any official alternatives for treatment of AE, numerous drugs and compounds have been investigated.^6,8,9

In 2003, Reuter et al.¹⁰ reported three patients treated with AmBD 0.5 mg/kg body weight through intravenous ports three times per week as a salvage therapy. One patient had a partial response, with decreased metabolic activity around parasitic lesions (including liver, subcutaneous tissue, and ribs) but with progression in the heart tissue. In the other two patients, treatment had to be stopped, with further dosage reduction after reintroduction because of a significant rise in serum creatinine. During temporary AmBD discontinuation, the disease progressed, confirming the primary parasitostatic effect.¹⁰ In 2009, Tappe et al.¹¹ reported a patient treated with AmBD and nitazoxanide combination, although without clinical success. The AmBD was administered in a dosage of 0.5 mg/kg/day for 3 consecutive days every 4 weeks.

Here, we chose a simpler treatment protocol: After 2-week induction therapy, AmBD was administered three times per week for 4 weeks and after that once per week for 2 years. This regimen was chosen owing to in vitro kinetics studies that showed the cycling effect and possible prolonged suppressive effect on parasite growth.¹²

Recently, Burkert et al.¹³ reported the largest series yet, comprising 11 patients treated with different AmBD formulations and dosing regimens. Of these, three had stable disease, three had clear progression, and six developed nephrotoxicity requiring treatment cessation or reduction of dosage. Interestingly, the authors suggested possible differences in treatment outcomes with liposomal and non-liposomal formulations; 43% of patients treated with liposomal formulations had treatment failure.¹³

Because of its parasitostatic effect, AmBD treatment should be lifelong, requires intravenous application, and can be inconvenient for some patients. In addition, long-term use can cause adverse effects such as nephrotoxicity and hepatotoxicity.

Several antimalarial drugs have shown good antiparasitical activity against E. multilocularis.⁹ Mefloquine has shown parasitostatic activity in vitro and in infected mice.⁹ Mefloquine was used in our patient as an alternative owing to its availability, safety, and simplicity of use. The patient has been using the medication for 14 months and has not shown signs of disease progression or medication toxicity. Because mefloquine was started after PET-CT showed no active lesions, its parasitostatic effect may be partially attributed to previous AmBD treatment. Only one patient treated with mefloquine in combination with ABZ and AmBD has been reported, with no treatment response after 7 months.¹³

Although avoidance of palliative surgery is advised whenever possible,³ in the case of our patient, it was performed to alleviate symptoms, need for repeated hospitals admissions (pleural effusions and recurring bacteremia episodes), and deterioration of the patient’s condition despite pharmacological therapy. However, because palliative surgery can result in a worse outcome than pharmacological therapy alone, it is important to carefully choose patients who can benefit from the procedure.

It is unclear if treatment can be safely stopped, despite PET-CT showing no metabolic activity. Although ABZ discontinuation resulted in new activity on follow-up PET-CT scans in most cases, a certain number of patients did not have disease relapse, leaving an option for temporary treatment discontinuation.^14,15 However, there is no clear correlation of prior treatment duration and lesion size prompting safe medication discontinuation, and no official guidelines recommend such an approach. The same can be assumed for AmBD and mefloquine, given their parasitostatic in vitro effect.

In conclusion, we demonstrated the potential for salvage therapy of AmBD and mefloquine in patients with late-stage AE. Both drugs were well tolerated and controlled disease progression. Alveolar echinococcosis is a disease with high morbidity and mortality, and current conservative treatment options are severely limited as a result of potential adverse effects. Thus, it is of high importance to continue searching for alternatives.