Editor’s Note: In recent years, the detection rate of carbapenem-resistant Gram-negative bacteria (CRO) in China has remained high, posing serious challenges to clinical treatments and patient outcomes. The limited therapeutic options have left many clinical needs unmet. At the recent Fourth National Conference on Bacterial and Fungal Infections organized by the Chinese Medical Association (BISC 2024), Professor Yunsong Yu from Zhejiang Provincial People’s Hospital delivered a presentation titled “The Current Epidemic Situation and Challenges of Carbapenem-Resistant Organisms (CRO) Infections in China.” Professor Yu detailed the prevalence and treatment status of CRO in China and explored the clinical challenges and strategies in depth.
1. Prevalence and Treatment Status of CRO in China
The high detection and mortality rates of CRO
In recent years, the overall detection rate of CRO in clinical settings in China has been trending upwards, especially in 2023 during the high incidence of COVID-19 and influenza outbreaks, which has further accentuated this trend. In ICUs across the country, a significant proportion of severe COVID-19 and influenza patients have isolated carbapenem-resistant Acinetobacter baumannii (CRAB) from respiratory samples, and many patients eventually die from subsequent CRAB bloodstream infections. This dire situation highlights the significant threat that CRO infections pose to patients in China.
According to data from the China Antimicrobial Surveillance Network (CHINET), the detection rate of carbapenem-resistant Klebsiella pneumoniae (CRKP) is high in various provinces, reaching over 40% in some areas; in some provinces, the detection rate of CRAB even exceeds 75%, presenting severe challenges for treating hospital infections. The high-risk groups for CRO infections primarily include patients post-neurosurgery, ICU patients with severe conditions, solid organ transplant recipients, patients undergoing chemotherapy for hematological malignancies or bone marrow transplantation, burn victims, and a small proportion of patients post-endoscopic retrograde cholangiopancreatography (ERCP). Additionally, prolonged hospital stays, ICU admissions, intubation, mechanical ventilation, and antimicrobial treatment also increase the risk of CRO infections.
CRO infections not only significantly increase the hospitalization duration and treatment costs for patients but also severely impact the survival of critically ill patients and those with immunodeficiencies, such as hematological malignancies. Studies from both within and outside China show that the 28-day mortality rate for hematological malignancy patients with CRO bloodstream infections ranges between 47.37% and 78.26%. Similarly, solid organ transplant recipients face a severe threat from CRO infections. The mortality rate following carbapenem-resistant Enterobacteriaceae (CRE) infections post-liver transplant can reach 51%, and the one-year survival rate for transplant recipients with CRKP infections is significantly lower than for those uninfected.
In terms of CRO colonization leading to secondary pneumonia and bloodstream infections, research in Europe indicates that most CRO pneumonia cases are hospital-acquired pneumonias (HAP), and CRO bloodstream infections are an independent risk factor for mortality in hospital-acquired pneumonia. In patients with ventilator-associated pneumonia (VAP) caused by CRAB, 35% develop secondary Acinetobacter baumannii bloodstream infections, with a mortality rate exceeding 30% for these secondary infection cases. Moreover, patients with multiple drug-resistant Acinetobacter baumannii (MDR-AB) bloodstream infections have a 30-day mortality rate as high as 70%. Domestic studies also indicate that a high proportion of ICU patients with CRKP pneumonia develop secondary bloodstream infections, which are an independent risk factor for mortality.
2. Treatment Strategies and Current Status for CRO Infections
To improve the prognosis of CRO infections, it is necessary to adopt a multidisciplinary team (MDT) approach to achieve early diagnosis, prompt treatment, appropriate drug dosing, timely removal of foreign bodies, and local drainage. Additionally, when treating infections caused by extensively drug-resistant Gram-negative bacteria (XDR-GNB), it is crucial to distinguish between infection and colonization, select drugs based on the minimum inhibitory concentration (MIC), use early combination therapy guided by pharmacokinetics/pharmacodynamics (PK/PD), and adjust drug use for patients with liver or kidney dysfunction and the elderly.
The resistance mechanisms of CRO are highly complex, involving various enzyme types. Therefore, drug selection must be differentiated based on the enzyme-producing type of the bacterial strain. Additionally, due to the differences in patient populations across various hospitals and departments, the enzyme types produced by CRO also vary, necessitating differentiated drug selection based on specific circumstances. For a long time, the resistance rates of domestic CRO strains to most antimicrobial drugs have remained high, severely limiting the options available for treatment, thereby increasing the difficulty of clinical management. Traditionally, the commonly used drugs for treating CRO infections include ceftazidime-avibactam, polymyxins, and tigecycline, known as the “triumvirate.” However, each drug has its unique advantages and drawbacks, thus careful selection is required in clinical applications based on the specific conditions and type of infection of the patient.
Ceftazidime-avibactam is effective in treating infections caused by susceptible strains and when dosed appropriately, especially in treating bloodstream infections, demonstrating good efficacy and low side effects. However, ceftazidime-avibactam is ineffective against Acinetobacter baumannii and metallo-β-lactamase-producing strains, limiting its application range. Additionally, its concentrations in the lungs and brain are relatively low, and clinical studies on its efficacy in treating brain infections are very limited, requiring further exploration. Ceftazidime-avibactam shows poor efficacy in patients with CRE pneumonia and those undergoing continuous renal replacement therapy (CRRT), mainly due to inappropriate dosing. Therefore, the application of ceftazidime-avibactam emphasizes the rationalization of dosage and administration methods and the monitoring of therapeutic drug concentrations (TDM) to maximize its effectiveness.
Polymyxins exhibit good antimicrobial activity, but their heterogenous resistance issues can somewhat affect their therapeutic efficacy. Additionally, the nephrotoxicity of polymyxins cannot be overlooked; a related meta-analysis shows that their nephrotoxic risk is 2.23 times that of non-polymyxin antimicrobials. Although increasing the dose can improve therapeutic effects, it also raises the risk of nephrotoxicity. Therefore, using polymyxins also requires TDM to ensure safe and effective medication. Since the intravenous administration of polymyxins results in low lung tissue concentration, and due to their large molecular weight, which hinders passage through the blood-brain barrier, the local drug concentration for lung or brain infections must be increased by combining intravenous administration with aerosolization or intrathecal or intraventricular administration.
Tigecycline has suboptimal distribution concentrations in serum and alveolar lining fluid, and clinically, increasing the dosage is often necessary to enhance its efficacy. The challenges with tigecycline susceptibility testing include the difficulty of standardizing tests, which require the use of sensitizing liquids to ensure accuracy, and the controversy over susceptibility breakpoints. Professor Yunsong Yu believes that even the breakpoints set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are only applicable to sites like the peritoneum where tigecycline concentrations are high. Domestic experts have found through Monte Carlo simulations that the recommended dose of tigecycline is ineffective against CRKP HAP, and doubling the dose (100 mg, every 12 hours) achieves a higher probability of target attainment (PTA) and cumulative response percentage (CFR). However, high doses of tigecycline can lead to adverse effects such as gastrointestinal reactions, liver damage, and coagulation abnormalities, requiring close monitoring of the patient’s prothrombin and other indicators.
Challenges and Strategies for CRO Infections
Although current antimicrobial drugs play a crucial role in the clinical treatment of CRO infections, they do not fully meet treatment needs. In addition to the “triumvirate,” the newly approved antimicrobial drug eravacycline in China has shown strong in vitro antimicrobial activity against CRO, offering new options for clinical treatment. Additionally, among various drugs under development, new β-lactamase inhibitor combinations such as ceftazidime-vaborbactam and the novel polymyxin SPR206 also show potential therapeutic value. In the future, these three could form a “new triumvirate,” further expanding the treatment options for clinical CRO infections and providing more effective antimicrobial drugs.
Eravacycline has been structurally modified from the core D-ring of tetracyclines, including the introduction of a fluorine atom at the C7 position and a pyrrolidinyl acetyl amino at the C9 position. It differs from traditional tetracyclines, and the World Health Organization (WHO) has included eravacycline in its list of “Critically Important Antimicrobials for Human Medicine,” classifying
it as a new category of antimicrobial drug, the fluorocycline class.
Global susceptibility data show that eravacycline has stronger antimicrobial activity, with its in vitro activity against Acinetobacter baumannii being four times that of tigecycline and twice that against Klebsiella pneumoniae, Escherichia coli, and Stenotrophomonas maltophilia. Moreover, eravacycline achieves higher tissue concentrations, with its concentrations in the lungs and plasma far exceeding those of tigecycline, and its fAUC/MIC values in the lungs reaching two to four times those of tigecycline. Notably, eravacycline shows less resistance due to its structural modifications that enhance its affinity for bacterial ribosomes and hinder the dissociation of the tet(M) from the ribosome, allowing it to combat the traditional tetracycline resistance mechanisms of efflux pumps and ribosomal protection. This structural modification also provides eravacycline with favorable pharmacokinetic properties, allowing patients with impaired renal function to use it without dose adjustment. Additionally, the combined use of eravacycline with other antimicrobial drugs has demonstrated synergistic effects against various CROs.
Another crucial aspect is the determination of clinical breakpoints. The publication of the ChiCAST eravacycline clinical breakpoints in China is significant for conducting susceptibility testing in clinical microbiology laboratories and for the correct clinical use of eravacycline. These breakpoints are established based on epidemiological survey data in China, thus better meeting the clinical bacterial infection drug needs of the Chinese population and ensuring the accuracy of susceptibility test results.
3.Conclusion
The continuously rising detection rate of CRO, poor patient outcomes, and high resistance rates pose a significant burden on clinical treatment and socio-economic aspects. The development of new antimicrobial drugs offers new strategies to address this challenge. Eravacycline, as a new antimicrobial drug, has demonstrated favorable drug characteristics, safety, and efficacy in preliminary in vitro studies, clinical trials, and real-world research, and has been recommended by multiple authoritative guidelines both domestically and internationally. In the future, with the application of these new drugs, clinical practices will have better and more effective measures to address the challenges posed by CRO infections and improve patient outcomes.
Professor Yunsong Yu
Zhejiang Provincial People’s Hospital
PhD, Qiushi Distinguished Physician, Professor, Doctoral Supervisor, Chief Physician
Department of Infectious Diseases, Zhejiang Provincial People’s Hospital
Academic Positions:
Chairman of the Infectious Diseases Committee, Chinese Association of Medical Education
Vice Chairman of the Committee on Bacterial Infection and Resistance Prevention, Chinese Medical Association
Director of the Zhejiang Provincial Key Laboratory of Microbiology Technology and Bioinformatics
Standing Member of the Infectious Diseases Committee, Chinese Medical Association
Standing Member of the Hospital Infection Control Committee, Chinese Preventive Medicine Association
Chairman of the Hospital Infection Control Committee, Zhejiang Provincial Preventive Medicine Association
Vice Chairman of the Infectious Diseases Committee, Zhejiang Medical Association
Academic Achievements:
Professor Yu has been engaged in clinical work on infectious diseases, especially the diagnosis and treatment of bacterial infectious diseases, with extensive experience since 1990. He has conducted research on the mechanisms of bacterial resistance, infections due to resistant bacteria, and their treatment. As the first author and corresponding author, he has published over 150 SCI-indexed papers in journals such as Lancet Infectious Diseases. He has led 7 projects funded by the National Natural Science Foundation of China (including two major projects), as well as sub-projects under the National Basic Research Program (973 Program), the National High-Tech R&D Program (863 Program), and a ministry-level project of the Ministry of Health. Professor Yu also serves as a peer reviewer for several SCI journals including Lancet Infectious Diseases, Antimicrobial Agents and Chemotherapy, Journal of Antimicrobial Chemotherapy, Journal of Clinical Microbiology, and Journal of Medical Microbiology.
