Editor’s note:
Nocardia is a conditional pathogen, and infections are common in immunocompromised populations such as organ transplant recipients. Professor Chunrong Ju and her team at the First Affiliated Hospital of Guangzhou Medical University’s Respiratory and Critical Care Department and Transplant Department previously reported cases of Nocardia infection in lung transplant recipients (LTR) among the East Asian population [1,2]. During the 2023 IDWeek congress, Dr. Chun-rong Ju further presented the clinical outcomes of 18 LTR Nocardia infection patients who received treatment with the novel oxazolidinone-class drugs Linezolid or Contezolid. The results indicated that these novel oxazolidinone drugs were effective during prolonged anti-infection therapy in such patients and had fewer toxic side effects, including bone marrow suppression [3].
Research Introduction
Nocardia infections are more common in immunocompromised populations, especially in lung transplant recipients (LTR). Nocardia infection can lead to tissue and organ damage in the human body, resulting in Nocardiosis. This disease requires a long course of antimicrobial therapy, particularly in immunocompromised individuals, which can last from 4 to 12 months. Prolonged use of antimicrobial drugs can make patients intolerant to the drug’s side effects or increase adverse events. Linezolid, an oxazolidinone-class antimicrobial, maintains good sensitivity to Nocardia but has serious long-term side effects. Contezolid is a novel oxazolidinone-class antimicrobial with potentially lower toxicity than Linezolid and has been approved in China. This study describes the use of Contezolid in the treatment of Nocardiosis in LTR patients.
This study retrospectively analyzed clinical data from adult LTR patients with Nocardiosis at a large transplant center in China from January 2018 to December 2022. Nocardiosis was diagnosed using clinical symptoms, high-resolution CT imaging, sputum, and bronchoalveolar lavage fluid (BALF) sample smears, sputum and BALF samples, peripheral blood specimens, and/or tissue specimens. Nocardia species were identified using metagenomic next-generation sequencing (mNGS). Drug susceptibility was tested using E-test for combination sulfamethoxazole-trimethoprim (TMP-SMX), imipenem, and Linezolid, while Kirby-Bauer was used for testing other drugs’ susceptibility. Patients were closely followed throughout the treatment period, including during hospital and home-based care. Cure was defined as clinical symptom relief, two consecutive negative cultures in CT scans and BALF.
During the study period, a total of 18 solid organ transplant recipients were diagnosed with Nocardiosis, with 14 cases of pulmonary Nocardiosis and 4 cases of disseminated Nocardiosis. Eight different Nocardia species were identified. All eight strains of Nocardia were resistant to at least one common antimicrobial drug (Table 1), with most common resistance seen in Nocardia brasiliensis (5/8). Linezolid was the only drug active against all Nocardia species. Initial treatment typically involved combination therapy based on TMP-SMX, which was later reduced to continued monotherapy based on susceptibility results. The total duration of combination therapy was 18 days (range: 14-25). Eleven patients received Linezolid, and nine patients received Contezolid treatment. Four patients switched from Linezolid to Contezolid due to platelet reduction (n=4), anemia (n=1), and white blood cell reduction (n=4). The median treatment duration for patients receiving Contezolid was 110 days (range: 90-210). Sixteen out of 18 patients achieved cure, including all patients receiving Contezolid. Patient characteristics, treatments, and outcomes are presented in Table 2.
The results of this study suggest that Contezolid can be used for the long-term treatment of Nocardiosis in lung transplant recipients.
Words from Author
Nocardia is a group of aerobic, Gram-positive rods that mainly cause localized or disseminated infections by inhalation through the respiratory tract or invasion through damaged skin, and it is commonly found in immunocompromised populations such as solid organ transplant (SOT) and hematopoietic stem cell transplant recipients. Our previous single-center retrospective study showed that the incidence of Nocardiosis in lung transplant recipients was 4.2% (13/316), higher than in other SOT recipients such as kidney and liver transplant recipients [2]. Guidelines also recommend that Nocardia infection in SOT recipients should be highly prioritized to reduce the risk of transplant failure and death caused by infection.
Nocardia comprises several species, including Nocardia brasiliensis, Nocardia farcinica, Nocardia nova, Nocardia cyriacigeorgica, Nocardia pseudobrasiliensis, Nocardia abscessus, Nocardia otitidiscaviarum, and more, with Nocardia brasiliensis being relatively common in lung transplant recipients. Nocardia remains sensitive to most drugs, with sulfamethoxazole-trimethoprim (TMP-SMX), represented by Linezolid, being the first-line therapy. Other commonly used drugs include carbapenems represented by imipenem, semisynthetic tetracyclines represented by minocycline, quinolones represented by moxifloxacin, and oxazolidinone-class drugs represented by Linezolid. Different Nocardia species exhibit varying degrees of cross-resistance. Linezolid, among the oxazolidinone-class drugs, is the only drug that is universally active against all Nocardia species. However, Linezolid has a significant bone marrow suppression effect, including leukopenia, thrombocytopenia, anemia, etc. Patients often experience severe thrombocytopenia after around two weeks of clinical treatment. TMP-SMX also has side effects such as bone marrow suppression, renal function impairment, and skin allergies. The anti-infective treatment of Nocardiosis in SOT recipients is unique in that, on one hand, it requires a long treatment course. Guidelines recommend that single-organ infection patients should receive six months of treatment, with the duration generally lasting from 6 to 12 months based on the site and severity of infection. Patients with disseminated infections, especially those with intracranial infections, need to undergo 8 to 12 months of treatment. Many patients, however, cannot tolerate the drug’s long-term side effects. On the other hand, SOT recipients need to take immunosuppressive drugs long-term to prevent rejection reactions. These drugs themselves have gastrointestinal side effects, bone marrow suppression effects, liver and kidney function impairments, and other side effects. When combined with TMP-SMX or Linezolid, they can result in a “1+1>2” cumulative toxic effect. Moreover, these immunosuppressive drugs are metabolized by CYP450 enzymes, and potential drug interactions exist with Linezolid [4,5]. Therefore, clinical practice requires finding antimicrobial drugs with minimal side effects, reliable efficacy, and fewer drug interactions for such infected patients.
Contezolid is a new generation oxazolidinone-class drug. Preclinical and clinical studies have shown its safety and good tolerance, with fewer bone marrow suppression toxicities compared to Linezolid. In our retrospective study of 18 patients, 11 received Linezolid, and 9 received Contezolid treatment, resulting in a high clinical cure rate (16/18). Importantly, four patients who initially received Linezolid but could not tolerate the bone marrow suppression switched to Contezolid and successfully completed the entire course of treatment. In summary, all patients who received Contezolid treatment achieved cure, indicating that Contezolid has better safety and efficacy in treating Nocardia infections in lung transplant recipients.
References:
[1] Lian Q, Chen A, Xu X, Wei B, Huang D, Kuang M, Cai Y, He J, Ju C. Clinical analysis of 5 cases of Nocardia infection in lung transplant recipients. Chinese Journal of Organ Transplantation. 2021;42(7):417-421. DOI:10.3760/cma.j.cn421203-20200303-00055.
[2] Xu Y, Lian QY, Chen A, et al. Clinical characteristics and treatment strategy of nocardiosis in lung transplant recipients: A single-center experience. IDCases. 2023;32:e01758. Published 2023 Mar 31. doi:10.1016/j.idcr.2023.e01758
[3] Chunrong Ju, et al. Long Term Use of Contezolid in Lung Transplant Recipients Infected with Nocardia Species. IDWeek 2023, Abstract 2710.
[4] Ogu CC, Maxa JL. Drug interactions due to cytochrome P450. Proc (Bayl Univ Med Cent). 2000 Oct;13(4):421-3. doi: 10.1080/08998280.2000.11927719.
[5] Glotzbecker B, Duncan C, Alyea E 3rd, Campbell B, Soiffer R. Important drug interactions in hematopoietic stem cell transplantation: what every physician should know. Biol Blood Marrow Transplant. 2012 Jul;18(7):989-1006. doi: 10.1016/j.bbmt.2011.11.029.
The First Affiliated Hospital of Guangzhou Medical University
