Successful Management of Refractory Pulmonary Mucormycosis Using Intracavitary Amphotericin B: A Case Report and Literature Review

Introduction

Mucormycosis is an infectious disease caused by Mucor fungus. The human body is infected by inhaling fungal spores through the respiratory tract. This disease predominantly occurs in immunocompromised patients with underlying conditions such as diabetes mellitus, neutropenia, malnutrition, or trauma, progresses rapidly, and has a high mortality rate [1]. Mucormycosis can cause nasal-orbital-cerebral, pulmonary, gastrointestinal, skin, and disseminated infections, among which the lungs are the second most commonly infected organ [2]. The clinical manifestations of pulmonary mucormycosis are nonspecific respiratory symptoms (fever, cough, hemoptysis). Early-stage presentation may resemble bronchitis-like changes, while late-stage progression can lead to necrotizing pneumonia [3]. Imaging features include nodules, wedge-shaped consolidations, and halo signs. Definitive diagnosis requires a combination of imaging, metagenomic next-generation sequencing of bronchoalveolar lavage fluid (BALF-tNGS), fungal culture, or pathological examination [4]. Active treatment of underlying diseases, early surgical treatment, and the use of systemic antifungal drugs are the principles of treatment for mucormycosis [5]. In patients with diffuse pulmonary lesions, systemic intravenous amphotericin B therapy often yields suboptimal outcomes due to fungal hyphae obstructing blood vessels, which impedes drug penetration into infected lung tissues and results in insufficient local drug concentrations [6]. Surgical intervention has inherent limitations and is primarily indicated for patients with adequate functional status, preserved pulmonary function, persistent symptoms despite medical therapy, and disease localized to a single lobe [7]. The management of pulmonary mucormycosis poses several challenges, such as poor systemic drug penetration into necrotic lung tissues and the limitations of surgical intervention in unstable patients. Therefore, identifying effective treatments for pulmonary mucormycosis is critical. In this report, we present the case of a diabetic woman with cavitary pulmonary mucormycosis refractory to systemic antifungal therapy due to poor drug penetration. CT-guided intracavitary amphotericin B injection was successfully employed as salvage therapy, delivering a high local drug concentration that resulted in marked clinical and radiological improvement.

Case Report

A 51-year-old female patient was admitted to Taihe Hospital on June 12, 2023, due to “chest pain for more than 10 days”. The patient had experienced chest pain without an obvious trigger more than 10 days prior; the pain was accompanied by fever and chills, with a maximum temperature of 38.6°C. She presented with diffuse chest pain, cough, and expectoration and denied any other discomfort. The patient’s fever disappeared after anti-infection treatment at a local hospital, but her cough, expectoration, and chest pain remained. She had a history of diabetes. Physical examination revealed that there was no deformity of the bilateral thorax, the breath sounds were low in both lungs, mainly on the left side, and no obvious crackles or wheezing were found upon pulmonary auscultation. The patient’s pre-admission outpatient chest CT scan demonstrated multiple inflammatory lesions in both lungs (Figure 1A). Physical examination revealed that there was no deformity of the bilateral thorax, the breath sounds were low in both lungs, mainly on the left side, and no obvious crackles or wheezing were found upon pulmonary auscultation. On admission, peripheral blood analysis revealed that the whole-blood leukocyte count was 22.02×109/L [neutrophils, 92.4% (normal range, 50–70%); lymphocytes, 4.1% (normal range, 20–50%); monocytes, 3.5% (normal range, 3–10%); eosinophils, 0% (normal range, 0.4–8%); and basophils, 0% (normal range, 0–1%)]. Other laboratory results were as follows: high-sensitivity C-reactive protein: 55.16 mg/L; erythrocyte sedimentation rate: 103 mm/h; interleukin-6: 94.45 pg/ml; and normal liver and kidney function. Brain natriuretic peptide, cardiac troponin, tuberculosis antibody, and serum galactomannan test results were negative, as were IgM antibodies for respiratory syncytial virus, adenovirus, and influenza virus A and B. Given the extensive pulmonary involvement and markedly elevated inflammatory markers, following hospital admission, empirical antimicrobial therapy with linezolid plus meropenem was initiated. After 2 days of treatment, bronchoscopy revealed purulent inflammation in the left upper-lobe bronchus (Figure 2A). Concurrent bronchoalveolar lavage fluid (BALF) analysis was obtained for microbiological and cytological examinations. A follow-up chest CT obtained after 4 days of empirical antibiotic therapy revealed multiple inflammatory lesions in both lungs, some cavities, and a small effusion in the left thoracic cavity (Figure 1B). Microbiological and cytological tests of the BALF, including Gram staining/acid-fast bacillus staining and bacterial and fungal smears and cultures, revealed negative results. In addition, the GM test and X-pert MTB/RIF test results for the BALF were negative. However, tNGS analysis of BALF revealed Rhizopus microsporus and Klebsiella pneumoniae. Based on the tNGS results, the diagnosis of mucormycosis coexisting with Klebsiella pneumoniae was confirmed.

Following definitive diagnosis, on hospital day 4, ultrasound-guided right subclavian deep-vein puncture + catheterization was performed to assist in pumping 200 mg of amphotericin B cholesterol for antifungal therapy. Concomitant antibiotic regimen was optimized to: Cefoperazone-sulbactam and Moxifloxacin. Radiological findings on hospital day 14 included chest CT scans revealing multiple nodules and cavities (mucors) in both lungs, and the lesions in the posterior part of the left lower lobe were larger than those in the previous lobe (Figure 1C). The patient had a large abscess cavity in her left upper lung and diffuse lesions in both lungs, rendering surgical intervention unsuitable. The lesions were considered to be caused by Rhizopus microsporus; therefore, antifungal treatment was continued. The treatment regimen was adjusted to amphotericin B pumped into the central vein, with discontinuation of all antibiotic therapy. At the same time, the patient was given 150 ml of 0.9% sodium chloride plus 300 mg of posaconazole for intravenous infusion combined with amphotericin B nebulization for local treatment. Repeat electronic bronchoscopy suggested chronic inflammation of the bronchus (Figure 2B). Follow-up (hospital day 25) enhanced chest CT revealed that the multiple nodules and cavities in both lungs were the same as before, with little change compared with before treatment (Figure 1D). On hospital day 38, due to suboptimal therapeutic response, CT-guided percutaneous lung puncture was conducted to inject 25 mg of amphotericin B diluted with 10 ml of 0.9% glucose into the cavity (Figure 2C). After intrapulmonary drug administration, the patient exhibited no fever, nausea, vomiting, skin itching, pain at the injection site, or other adverse reactions. Antifungal therapy was continued with intravenous amphotericin B and posaconazole, supplemented by local amphotericin B nebulization. Chest CT performed at day 50 revealed that the multiple nodules and cavities in both lungs (mucor fungi) were significantly smaller than before (Figure 1E). Moreover, the white blood cell count (4.24×109/L), interleukin-6 levels (21.47 pg/ml), and high-sensitivity C-reactive protein (13.5 mg/L) were significantly improved compared with those at admission. On hospital day 51, a repeat CT-guided percutaneous lung puncture and intracavitary injection of amphotericin B were performed. Throughout the intracavitary amphotericin B injection and post-procedure recovery, clinicians continuously monitored the patient’s electrocardiogram, vital signs, and blood oxygen saturation.

With resolution of chest pain, cough, and sputum production plus radiographic improvement on follow-up CT, the patient requested to be discharged on hospital day 52, and she was advised to continue oral posaconazole antifungal treatment outside the hospital. At the 15-day post-discharge follow-up, the patient returned to our hospital for a follow-up chest CT scan. At this time, the patient’s lung lesions were better absorbed than before, and there was no pleural effusion (Figure 1F). In addition, her condition was stable, with no fever, chest pain, or other symptoms of discomfort. A repeat chest CT at the local hospital at the 14-month post-discharge follow-up showed complete resolution of pulmonary inflammation (Figure 2D). The patient’s condition is currently stable, and she is being followed up regularly.

Discussion

Mucormycosis is a rare and invasive infection that mainly occurs in the lungs or the rhinorbital and cerebral compartments. It is more likely to occur in patients with immunodeficiency or diabetes. A hyperglycemic environment is a risk factor for the development of mucormycosis. In recent years, the prevalence of Mucor has gradually increased, showing rapid clinical progression and often proving fatal. Therefore, early diagnosis and timely treatment and intervention are extremely important to prevent progressive tissue invasion of Mucorales and its destructive sequelae, significantly reduce the impact of deformity correction surgery and improve outcomes and survival [8]. Currently, there are few reported treatment options for pulmonary mucormycosis, and their effects are not significant. Treatment of pulmonary mucormycosis relies on the reversal of underlying risk factors, the administration of antifungal drugs, surgical intervention, and various adjuvant therapies. Currently, antifungal treatment is the most commonly used clinical treatment technology, and early antifungal treatment is crucial. Studies have shown that delayed antifungal treatment with amphotericin B significantly increases mortality [9]. The intravenous infusion of amphotericin B yields limited therapeutic effects and severe adverse reactions, whereas the local injection of amphotericin B can increase the local drug concentration and reduce systemic adverse effects [10]. Intracavitary amphotericin B can treat certain fungal infections but requires cautious use due to risks of local irritation, systemic toxicity, poor penetration, and limited indications, as well as complications such as pneumothorax and subcutaneous hematoma [11,12].

Our patient had a history of diabetes and poorly controlled glucose levels. Clinical manifestations included chest pain, fever, and cough. Min Peng et al reported that fever, cough, and sputum production are the most common clinical manifestations of pulmonary mucormycosis, and consolidation, nodules, cavities, and reverse halo signs are more common in imaging [13]. In addition, pleural effusion is relatively common [2]. However, none of the above signs and symptoms are specific manifestations of pulmonary mucormycosis. The clinical symptoms and imaging findings of pulmonary mucormycosis are not specific for the diagnosis of pulmonary mucormycosis, and a clear diagnosis is challenging. However, the reverse halo sign can be observed on lung CT in some patients with mucormycosis. Among infectious diseases, the reverse halo sign is more common in pulmonary sarcoidosis, tuberculosis, and invasive fungal diseases, which greatly limits diagnosis [14]. The above are the clinical manifestations of pulmonary mucormycosis, which indicate the possible presence of Mucorales, and direct microscopy, histopathology, culture, and molecular biology are the diagnostic modalities employed [15]. Direct microscopic examination requires microscopic examination of fungi through specimen staining, smears, and immunofluorescence, and culturing of Mucorales takes 3–5 days. This method is less expensive and involves simple sampling and inspection methods, but traditional microbiological testing is time-consuming and has poor specificity, making it difficult to identify rare genera [16]. The detection of Mucorales by mNGS in BALF is a common method for diagnosing pulmonary mucormycosis. mNGS is a rapid and noninvasive diagnostic method. In immunocompromised patients, such as patients with diabetes, where infection by a specific pathogen is suspected, initiating mNGS testing as soon as possible can enable rapid and accurate diagnosis of the infection. Moreover, intensive treatment should be performed as early as possible [17]. Pulmonary mucormycosis is diagnosed on the basis of host factors combined with clinical manifestations and microbiological evidence. Our patient had signs of infection: chest pain, cough, sputum, and fever. Chest CT revealed reverse halo signs and pleural effusion, showing that ordinary anti-infective treatment had little effect. Consequently, we performed bronchoscopy and collected the lavage fluid. The mNGS test confirmed the diagnosis of pulmonary mucormycosis.

The keys to the treatment of pulmonary mucormycosis are early diagnosis, control of underlying diseases, application of high-dose amphotericin B, and timely surgery [18]. Liposomal amphotericin B is the recommended first-line treatment for pulmonary mucormycosis, and isavuconazole or posaconazole can also be administered orally or intravenously [9]. Species of the Mucorales order exhibit angioinvasive growth, resulting in occlusion of pulmonary vasculature and bronchial obstruction, which frequently culminates in ischemic tissue damage. It is difficult for conventional oral antifungal drugs and intravenously administered amphotericin B to achieve the ideal concentration in local lung tissue, and the therapeutic effect is not significant [19]. Therefore, local administration can be selected. These methods include aerosol inhalation, intrabronchial instillation, and other routes of administration [20]. In addition, surgery combined with antifungal treatment can improve the survival rate of patients with pulmonary mucormycosis [21]. However, surgery is limited to patients with localized lung disease and is not suitable for disseminated pulmonary mucormycosis [22]. The efficacy of using amphotericin B to treat mucormycosis is certain [23]; however, systemic intravenous use of amphotericin B can cause severe renal damage and gastrointestinal discomfort and other adverse reactions, which limits such therapy. According to published case reports, the non-first-line treatment method for pulmonary mucormycosis is local instillation of amphotericin B. Previous case reports have demonstrated that amphotericin B locally instilled through the bronchus can directly act on lung lesions at high concentrations, allowing patients to avoid potential systemic toxicity, receive a reduced total antifungal dose and treatment time, achieve significant clinical effects, and even reach a cured state [24–26]. There are also reports that local injection of amphotericin B into the orbit after intraorbital Mucor infection can save a patient’s eyes and life [27]. In our patient, the dosage of amphotericin B cholesterol was gradually increased to 50 mg, 100 mg, and 150 mg, and amphotericin B liposomes were pumped through the subclavian deep-vein puncture catheter. The efficacy of intravenously pumped liposomal amphotericin B was not significant, as shown by the chest CT findings. Treatment was supplemented with local nebulized inhalation of amphotericin B and intravenous posaconazole, followed by a repeat chest CT, which revealed that the absorption of the lung lesions was still unremarkable. On the basis of previous reports that topical antifungal drugs are more effective than intravenous infusion and studies proving the effectiveness and safety of topical amphotericin B [28], we used pulmonary cavity intrainjection of amphotericin B for the treatment of pulmonary mucormycosis. Through this method, the drug can be directly injected into the cavity of the infected part of the lung, which can increase the concentration of the drug in the infected part and increase its therapeutic effect. Moreover, compared with oral and intravenous infusions of antifungal drugs, intracavitary injections of drugs can reduce systemic adverse effects. Therefore, when intravenous antifungal drugs are not effective, the patient’s systemic condition should be actively assessed to determine whether surgery is feasible. If surgery cannot be tolerated, local drug treatment can be considered to delay the development of lung lesions and create additional treatment opportunities.

Conclusions

In summary, we have shown that systemic combined local medication (ie, the use of intravenous amphotericin B infusion, nebulized inhalation, and CT-guided percutaneous lung puncture biopsy with intracavitary injection of amphotericin B) can be an effective therapeutic regimen in patients with a definitive diagnosis of diffuse pulmonary mucormycosis, the presence of large abscessed cavernous lesions, and lesions that are not in contact with the bronchial tubes (Table 1). Moreover, basal blood glucose control, effective anti-infective therapy, and nutritional support therapy were necessary for this patient. Intracavitary injection of amphotericin B can precisely deliver the drug to the site of infection, and this method can significantly reduce the clinical symptoms of pulmonary mucormycosis, improve the lung lesions, and reduce the rate of recurrence of fungal infections.