This study presents novel findings regarding the prevalence and dynamics of KPN resistance across multiple PICUs in China. A comprehensive analysis of more than 260,000 strains over 7 years (i.e., from 2016 to 2022) revealed that most of the top 10 frequently identified strains belonged to the category of Gram-negative bacteria. Notably, with a detection rate of 8–11%, KPN consistently maintained its position within the top three isolated Gram-negative strains from 2016 to 2020. This finding is comparable to the 14.7% detection rate[4] that was observed in large-scale studies of adults but falls below the prevalence reported by the National Bacterial Resistance Surveillance Network for children and neonates in China between 2014 and 2017 (16.8–19.8%)[1]. These results suggest that KPN has emerged as a significant pathogen in pediatric infections. Furthermore, our study reveals no discernible patterns of seasonality or sex disparity in KPN infections within the PICUs. Among the children affected by KPN infections, infants accounted for 55.7% of cases, whereas the detection rates were similar for children aged 1–5 years and older children. The primary origins of KPN strains that were obtained from adult hospitalized patients were blood (28.4%), lower respiratory tract (21.8%), wounds (21.3%), and urine (14.7%)[4]. This investigation indicated that the primary sites for detecting KPN in the PICUs were the lower respiratory tract (71.1%), blood (8.6%), and urinary tract (7.1%), indicating significant differences in primary sites compared with adults.
KPN demonstrated varying levels of resistance to commonly used antimicrobial agents. The three agents with the highest antibiotic resistance rates were polymyxin B, tigecycline, and polymyxin, all of which exhibited resistance rates below 10%. Currently, polymyxin B and tigecycline are considered last-resort therapeutic options for the management of CRKP infections[5]. However, clinicians must consider various factors, including nephrotoxicity, attainable in vivo plasma concentrations, and the emergence of resistance during treatment. Notably, a study in adults indicated that treatment failure may still occur despite the susceptibility of isolates to tigecycline. Within this study, resistance to polymyxin E and polymyxin B gradually increased from 2016 to 2022, evolving from complete sensitivity to resistance rates of 5.9% and 3.8%, respectively. These figures closely align with the reported 5.02% resistance rate for polymyxins in adults[6]. Colistin remains the second-line option for CRKP[7]. Recent reports have indicated that initiating polymyxin B combination therapy within 48 hours of a CRKP bacteremia diagnosis significantly enhances bacterial clearance rates (65.22% vs 29.41%, p = 0.02) and reduces 30-day mortality (39.13% vs. 70.59%, p = 0.02) compared with delaying administration over 48 hours[8]. The resistance rate to tigecycline gradually declined from 5.8% in 2016 to 1.2% in 2022. Analysis of carbapenem-resistant Klebsiella pneumoniae (CPKP) resistance to other antibiotics over 7 years demonstrated that CPKP remained fully susceptible to polymyxin B, whereas the cross-resistance rate to tigecycline was 2%, close to the reported resistance rates of 4%[9]–4.24%[10] of CPKP to tigecycline in adults.
Carbapenems have been identified as the most potent β-lactam antibiotics for the treatment of Enterobacteriaceae infections. However, in recent years, invasive iatrogenic procedures and the increased prevalence of irrational antimicrobial drug usage in clinical settings have led to a significant rise in the resistance of KPN to carbapenem antibiotics. A Chinese monitoring study that spanned 16 years (i.e., from 2005 to 2020) revealed a continuous increase in the resistance rate of KPN to imipenem and meropenem. Specifically, the resistance rates for imipenem and meropenem rose from 3.0% and 2.9%, respectively, in 2005 to 25.0% and 26.3%, respectively, in 2018. However, a downward trajectory was observed in 2019 and 2020, with resistance rates remaining markedly elevated at 23.2% and 24.2% for imipenem and meropenem, respectively, in 2020[11]. Within the scope of this investigation, the collective resistance rates of KPN to carbapenem antibiotics were ranked as follows: meropenem > imipenem > ertapenem. A comparable decline in resistance rates was noted between 2018 and 2020 and was potentially attributable to the implementation of heightened isolation protocols and improved hand hygiene practices amid the coronavirus disease 2019 pandemic. Over 3 years, a consistent annual increase was observed in the resistance rates of KPN to three antibiotics. Specifically, the resistance rate of ertapenem rose from 14.8–35.2%, and the resistance trends of meropenem, ertapenem, and imipenem showed similar increasing resistance rates (from 33.1%, 18.9%, and 27.7% in 2020 to 40.2%, 35.2%, and 33.8% in 2022, respectively). These resistance rates surpassed those reported in previous studies in adult populations[11].
Carbapenems serve as the initial treatment for multidrug-resistant KPN. Dynamic observations have revealed a notable alteration in the resistance rate of KPN to carbapenems. CRKP has two primary resistance mechanisms: the synthesis of carbapenemases such as KPC, NDM, VIM, IMP, and OXA-48 for carbapenem hydrolysis and the synthesis of extended-spectrum β-lactamases or AmpC enzymes combined with structural mutations. The first mechanism predominantly contributes to CRKP's resistance to carbapenems. Resistance genes can disseminate across diverse bacterial strains via conjugation, transformation, and transduction and drive a gradual escalation in resistance rates[12, 13]. According to the surveillance findings of the China Antimicrobial Resistance Surveillance System and the National Bacterial Resistance Monitoring Network, the prevalence of CPKP rose from 3.2% in 2011 to 7.6% in 2015[14]. CPKP has been documented as the cause in 55.0% of carbapenem-resistant Enterobacteriaceae (CRE) cases in children[15]; NDM was the predominant carbapenemase (67.6%), followed by KPC (26.4%). Multicenter studies in adults have indicated that CPKP is responsible for 66.7%[16]–77.0%[17] of CRE cases, whereas 77%[16]–90.8%[6] of CRKP cases were found to be KPC producers. In the context of PICUs, children often present with underlying diseases and undergo multiple invasive procedures, resulting in prolonged antibiotic usage. Consequently, the risk of hospital-acquired KPN infections, particularly CRKP, is heightened. The study findings indicate that the detection rate of CPKP in PICUs ranged from 2.4–3.8%, with a progressive increase in the proportion of KPN detected annually (i.e., from 26.2% in 2019 to 38.3% in 2022). Reports have indicated that adult patients in the intensive care unit who carry KPN strains have a proportion of CRKP as high as 54%[18].
This study further revealed a gradual decline in the resistance rates to amoxicillin/clavulanic acid over the years (i.e., from 69.9% in 2016 to 48.0% in 2021). In contrast, the resistance rates to piperacillin/tazobactam remained relatively stable at approximately 33.0% over 7 years, lower than the rates reported in adults (71.4% and 84.9%[4], respectively). Furthermore, the resistance rates of KPN to cefotaxime, cefuroxime, and ceftriaxone all exceeded 60%. The resistance rate to ceftriaxone grew consistently over the years, reaching a level comparable to that of cefotaxime and cefuroxime by 2022. The relatively stable resistance rates of ceftazidime and cefepime of approximately 50% over 7 years may be attributable to their frequent empirical usage in clinical settings. Notably, the resistance rate of cefoperazone-sulbactam, among the enzyme inhibitor combination formulations, experienced an overall decline from 43.9% in 2016 to 12.2% in 2021, before experiencing a subsequent increase to 25.7% in 2022, which may be associated with the usage rate of cefoperazone-sulbactam in clinical practice.
Ceftazidime-avibactam (CAZ-AVI) is a novel combination of a beta-lactam antibiotic and a beta-lactamase inhibitor that has gained significant usage in clinical settings for the targeted treatment of challenging Gram-negative infections caused by carbapenemase-producing Klebsiella pneumoniae (KPC-Kp), OXA-48-producing Enterobacterales, and difficult-to-treat Pseudomonas aeruginosa[19]. Since its development, CAZ-AVI has been used extensively in clinical practice, and initial clinical studies have demonstrated its favorable clinical and antimicrobial effectiveness[20, 21]. A review by Burcu Isler suggested that CAZ-AVI is the most effective treatment option for OXA-48-producing CRKP[7]. In adults, studies that have examined the treatment of infections caused by KPC-Kp strains indicate no significant difference in mortality rates between patients who were treated solely with CAZ-AVI and those who received combination regimens (26.1% vs 25.0%)[22]. Additionally, extending the infusion time of CAZ-AVI to a minimum of 3 hours can improve survival outcomes[22]. CAZ-AVI is well tolerated in newborns and children under 5 years of age[23]; however, real-world studies on pediatric KPN infections are scarce, and many studies have reported the emergence of resistance[24–26]. A multicenter study in adults revealed a 3.7% resistance rate of CPKP to CAZ/AVI[27]. However, on the basis of data collected between 2019 and 2022, this study indicated that the resistance rate of KPN to CAZ-AVI ranged from 9.1–20.8%. Although this rate is significantly more favorable than that observed with other enzyme inhibitor combination formulations, it remains considerably higher than the resistance rate reported in adults. This phenomenon may be attributed to the composition of this study's participants, who primarily originated from PICUs where children's medical conditions are more intricate and necessitate longer hospital stays and more frequent invasive procedures compared with outpatient treatment and treatment in general wards.
KPN had a relatively elevated sensitivity toward aminoglycosides and fluoroquinolones, although a declining trend has been observed in recent years. Specifically, the resistance rates for amikacin and levofloxacin in 2022 were 9.1% and 25.7% respectively, deviating significantly from the rates reported among adult populations[4]. However, the clinical use of these two drug classes is highly restricted in young children. Fosfomycin is a bactericidal antibiotic that is commonly used for simple urinary tract infections caused by sensitive bacteria[28]. The efficacy of fosfomycin against multidrug-resistant bacteria has been established in recent years, making it a recommended alternative for the treatment of CRKP infections[29]. This study revealed a gradual rise in fosfomycin resistance (i.e., within the 18–27% range) among KPNs. Moreover, the cross-resistance rate between meropenem and fosfomycin reached 37%, thus discouraging the use of these agents for CPKP infections in the PICUs.
Given the limited medication choices available for children, this population faces significant constraints. Carbapenem antibiotics are the ultimate therapeutic option for managing infections induced by Gram-negative multidrug-resistant bacteria. The escalating prevalence of CPKP infections imposes a substantial financial strain on patients and amplifies mortality rates among afflicted individuals. This predicament represents a formidable obstacle to pediatric anti-infection therapies and constitutes a significant global public health concern. This study aimed to assess the potential cross-resistance of the widely used carbapenem antibiotic meropenem with other antibiotics. The objective was to predict the resistance patterns of alternative antibiotics in cases in which initial treatment with meropenem was ineffective. The findings indicated the differing likelihood for KPN strains that are resistant to meropenem to exhibit resistance to other antibiotics. Specifically, the cross-resistance rates were as follows: polymyxin B (0%), tigecycline (2%), imipenem (16%), amikacin (27%), fosfomycin (37%), and levofloxacin (41%). Hence, using carbapenems in conjunction with other antimicrobial agents is advised for the management of infections caused by multidrug-resistant strains, as substantiated by combined drug susceptibility findings. Prior research has demonstrated the efficacy of treating CRKP infections with combination therapy that involves tigecycline and polymyxin or carbapenems in conjunction with aminoglycosides. Hence, using carbapenems in conjunction with other antimicrobial agents for the management of infections caused by multidrug-resistant strains is recommended, as substantiated by combined drug susceptibility findings. Prior research[30] has demonstrated the efficacy of treating CRKP infections using combination therapy involving tigecycline and polymyxin or carbapenems in conjunction with aminoglycosides.
This article is a comprehensive examination and evaluation of the resistance patterns exhibited by KPN strains in multi-center PICUs in China over 6 years. The study findings are pivotal for elucidating the distribution characteristics of KPN strains and the alterations in antibiotic-resistant bacteria within PICUs. Moreover, the outcomes of this research offer valuable guidance for the appropriate use of antibiotics in clinical settings. Notably, this study focuses on the analysis of bacterial strains and does not fully incorporate clinical data into its analysis.