Carrimycin in a Patient with Acute Myeloid Leukemia Complicated with Life-Threatening Mixed Perianal Infection: A Case Report and Literature Review

Introduction

Perianal infections are common complications in patients with acute myeloid leukemia (AML), particularly during the bone marrow suppression phase. Immunodeficiency, barrier damage, and anatomical location further facilitate the occurrence of perianal infection, with an incidence of 9.2%–27%.^1,2 Perianal infection is often accompanied by severe pain, swelling, and constipation, affecting the patients’ quality of life.^3,4 In severe cases, it may endanger the patient’s life, with a mortality rate as high as 16%.⁵

The most frequently detected pathogens in patients with perianal infections are Escherichia coli, Enterococcus, Bacteroides, and Klebsiella pneumoniae in descending order of pathogenicity.^2,6,7 Pathogen cultivation and antibiotic sensitivity tests can be used to guide the selection of antibiotics. However, even in the antibiotic-sensitive strains, the efficacy is not always ideal in patients with severe bone marrow suppression, which greatly increases the difficulty of treatment.

Carrimycin is a genetically engineered macrolide that has been gradually explored and tentatively applied in clinical practice for patients with ineffective therapeutic strategies.⁸ In fact, it was also used during the SARS-CoV-2 pandemic, but its therapeutic efficacy was controversial. Here, we present a case of mixed perianal infection in a patient with neutropenic AML who was successfully treated with carrimycin. Additionally, we summarize and speculate on the possible mechanisms of function based on previous studies involving carrimycin.

Case Presentation

A 58-year-old male patient was admitted to our hospital with AML-M0 (intermediate risk subgroup), characterized by a chromosomal profile of 47, XY, +4, t (7;14), (q21; q32) and a FLT3-ITD mutation in c.1779_1780insGGGCCCGGGCCT with a 30.08% variant allele frequency, having previously undergone two courses of chemotherapy including venetoclax+azacytidine+sorafenib and idarubicin+azacytidine+sorafenib without achieving disease remission. He complained of severe perianal pain and fever which began five days prior to admission. The patient presented with fever (38.2°C), tachycardia (100 beats per minute), hypoxemia (90%), and hypotension (82/53 mmHg). A large ulceration, accompanied by redness and swelling of the adjacent skin, was observed in the perianal area, with tenderness noted but fluctuating sensation being absent. Laboratory examinations showed a white blood cell count of 256000/μL, neutrophil count of 100/μL, hemoglobin of 78 g/L, platelet count of 4000/μL, peripheral blast cell percent of 30%, C-reactive protein (CRP) level of 81.02 mg/dL, and procalcitonin (PCT) level of 3.14 mg/dL. β-D-glucan, galactomannan (G/GM) tests and perianal microbiome screen were negative. Pelvic MR imaging showed an anal fistula (Figure 1), and pulmonary computed tomography (CT) revealed scattered inflammation in both lungs (Supplemental Figure 1A). A subsequent bone marrow biopsy revealed a high proportion of blast cells (89%). Hence, the patient was diagnosed with AML combined with perianal infection and pneumonia.

Figure 1 Pelvis MR images on admission. Notes: Axial (A) and coronal (B) T2-weighted fat-saturated transverse images with contrast demonstrated an anal fistula, with the peripheral enhancing cystic lesion (arrow) showing inflammatory changes in the perianal region.

On admission, the patient was treated with meropenem and linezolid, the antibacterial spectrum of which covered gram-positive and gram-negative bacteria, Pseudomonas, and anaerobes. Three days later, perianal skin wound secretion cultures revealed Escherichia coli, Klebsiella pneumoniae, and Morganella morganii, and antibiotic sensitivity tests showed susceptibility (Supplemental Table 1). However, the patient developed cool and moist limbs, shock, and sustained a high body temperature peak above 38°C, indicating that the infection remained uncontrolled. We switched linezolid to tigecycline and initiated empirical antifungal treatment with voriconazole. The patient was simultaneously administered aggressive supportive treatment including adequate splanchnic perfusion, vasopressors and blood product transfusions. On the 7th day, the patient’s condition continued to deteriorate while repeat pulmonary CT showed significant absorption of the inflammatory lesions (Supplemental Figure 1B). Therefore, we attempted to switch the antibiotics to polymyxin and carrimycin. The following day, the patient’s temperature dropped below 37°C, while the CRP and PCT values significantly decreased while neutrophil levels increased. And common adverse drug reactions, such as gastrointestinal reactions, neurological reactions, and laboratory abnormalities, were not detected. Consequently, we initiated chemotherapy with venetoclax and sorafenib. After a week of maintaining stable temperature control, with CRP and PCT values near normal levels, we switched from carrimycin to omycycline owing to the financial constraints faced by the patient.

On the 21st day, the temperature increased. At this point, peripheral blasts and bone marrow blasts decreased to 1% and 0.5%, respectively. A follow-up pulmonary CT scan exhibited disappearance of the inflammatory lesions (Supplemental Figure 1C). Additionally, a small amount of purulent secretion was observed around the anus, with the secretion culture indicative of Escherichia coli and Klebsiella pneumoniae. In response to the clinical deterioration, we adjusted omycycline to zavicefta while continuing polymyxin based on perianal secretion culture testing. Throughout the treatment period, debridement of perianal abscess was performed twice with the assistance of urologists. Unfortunately, after 9 days of treatment with zavicefta and polymyxin, the fever persisted and the inflammatory markers worsened. We adjusted the anti-infection regimen to polymyxin and carrimycin. Similar outcomes and indicator changes occurred within the next few days, including improvements in temperature, neutrophil count, and CRP and PCT levels. Eventually, the patient was discharged 51 days after admission, achieving complete remission of leukemia, and the perianal ulcers gradually healed with good granulation. His clinical course and perianal ulcer wounds at different time points are presented in Figures 2 and 3.

Figure 2 Clinical course. Abbreviations: CRP, C-reactive protein; PCT, procalcitonin; BM, bone marrow; PB, peripheral blood. Notes: Changes in the inflammatory factors, neutrophil count, blasts, body temperature, anti-infective and chemotherapy regimen during hospitalization.

Figure 3 Gross images of perianal ulcer wounds at different time points. Notes: (A) A large ulceration upon admission, with adjacent skin exhibiting redness and swelling. (B) A ruptured perianal ulcer at the initiation of chemotherapy, with a small amount of purulent secretion. (C and D) illustrated the perianal ulcer wound after the first and second debridement, respectively. (E and F) displayed the ulcerated surface accompanied by new granulation tissue proliferation at discharge, and the wound gradually heals and crusts over during follow-up period, respectively.

Discussion

An immunocompromised state predisposes the patients with AML to opportunistic organisms.⁹ Damage to mucosal and mechanical barriers further facilitates the entry of pathogens.¹⁰ Moreover, unlike other skin and soft tissue infections, perianal infections present unique treatment challenges because of fecal contamination and anatomical features. The patient in the reported case had unstable vital signs and symptoms of mixed perianal infection, almost meeting the diagnostic criteria for sepsis, which can seriously threaten the patient’s life. Although multiple pathogen cultivation and antibiotic sensitivity tests indicated the presence of sensitive strains, the corresponding antibiotics were ineffective. Such situations are common in clinical practice. Helping these patients pass through the severe bone marrow suppression phase smoothly is an urgent problem that needs to be addressed.

Initially, carrimycin was administered tentatively. Surprisingly, both the temperature and inflammatory indicators improved by the second day, aiding in achieving chemotherapy opportunities. The same outcome was observed when the patient experienced granulocyte deficiency after chemotherapy. Even more notable was the speed at which the treatment took effect and the accompanying increase in neutrophil count. Additionally, analysis of the case reveals several interesting issues regarding possible mechanisms.

Firstly, carrimycin, a macrolide antibiotic, affects bacterial protein synthesis by inhibiting peptidyl transferase activity in 50s ribosomes. Its solubility in lipids and extended half-life afford superior penetration and retention, endowing it with more potent antibacterial effects compared to other macrolides.^11,12 This enhanced efficacy likely contributed to the rapid improvement observed the day after application in our reported case. In addition to its antibacterial properties, it exhibits immunomodulatory effects, including the attraction of neutrophils to inflammatory locations, bolstering macrophage phagocytosis,¹³ and a notable increase in HLA-DR and CD8+ T cell levels, thereby modulating immune responses.¹⁴ Remarkably, the patient demonstrated swift neutrophil count recovery following the administration of carrimycin. We hypothesized that carrimycin stimulates neutrophil maturation and release, thus reinforcing the host’s immune defense and aiding in pathogen eradication. Unlike other anti-infectious drugs, it may play a crucial role in the efficacy of antibiotics in patients with severe bone marrow suppression.

Additionally, studies have shown that carrimycin exhibits antitumor activities, potentially via various regulatory pathways, such as JNK2/TIF-IA/POLI, PI3K/AKT/mTOR, and MAPK, which induce cancer cell cycle arrest and apoptosis.^15–17 Existing research on its antitumor effects primarily focuses on solid tumors, such as lung cancer, hepatocellular carcinoma, and oral squamous cell carcinoma. In our case, there was no direct evidence of carrimycin against leukemia cells. The in vivo and in vitro experiments will be performed in future experiments. The breadth of potential applications highlights versatility of carrimycin and underscores the need for continued research on its multifaceted therapeutic benefits.

Conclusion

Carrimycin has emerged as a novel treatment option when conventional antibiotic therapy fails. Our study serves as a treatment reference for similar cases. Moreover, carrimycin operates through multiple mechanisms beyond its antibiotic properties, highlighting its potential for further exploration.