Introduction

Pseudomonas aeruginosa (P. aeruginosa) is prevalent in human skin, respiratory and digestive tracts and is a common non-fermenting gram-negative bacillus causing bloodstream infections in hospitals.1,2 These infections progress rapidly, carrying a high mortality rate of up to 30%, imposing significant medical and economic burdens worldwide.3–7P. aeruginosa has shown resistance to a broad range of widely used beta-lactam antibiotics. During clinical treatment, this strain may also develop resistance to other classes of antibiotics, such as carbapenems.8,9 Delayed, inappropriate empirical treatment at the initial stage of bloodstream infections is a risk factor for carbapenem resistance in P. aeruginosa and correlates with poor prognosis.3,8,9 Due to its complex material transport and metabolic system, P. aeruginosa is inherently resistant to many antibiotics, and prolonged antibiotic use often induces drug-resistant mutations.3 Acquiring resistance heightens the challenge of treating P. aeruginosa bloodstream infections and independently raises the risk of mortality.10,11 Therefore, judicious antibiotic use is vital to curb the development of resistance and enhance patient outcomes.3,5,6,9 The antibacterial resistance patterns of P. aeruginosa vary in relation to regional medication preferences.1,12–14 Resistance of P. aeruginosa from bloodstream infections varies globally.5,7,9 This study retrospectively analyzed clinical distribution patterns and drug resistance in P. aeruginosa isolated from blood specimens in 75 hebei Province hospitals from 2016 to 2021. The goal is to analyze the antibiotic resistance trends in Hebei Province, to provide guidance for prudent antimicrobial drug utilization in clinical practice and inform anti-infective decision-making.

Material and Methods Bacterial Origin

P. aeruginosa was isolated from blood specimens of 75 hospitals across Hebei Province, China, between 2016 and 2021. Duplicate strains from the same patient were excluded, and 2208 strains were obtained.

Bacterial Identification and Antibiotic Susceptibility Assays

We used the Vitek 2 system (bioMérieux, France), Phoenix 100 system (BD Biosciences, USA), and the disc agar diffusion test was performed using Mueller–Hinton (MH) medium (Oxoid, UK) according to CLSI M100 202215 for isolate identification and antimicrobial susceptibility testing. P. aeruginosa ATCC27853 served as the quality control strain. Carbapenem-resistant P. aeruginosa (CRPA) was defined as an isolate resistant to imipenem and/or meropenem.

Age Group

Patients were categorized into five age groups according to the criteria of the International Standard Interim Guidelines for Age Classification16 and the China Antimicrobial Resistance Surveillance Trial: newborns (≤28 days), children (28 days to 14 years), young adults (15–47 years), middle-aged adults (48–64 years), and older adults (≥65 years).17

Statistical Analysis

Statistical analysis was conducted using WHONET 5.6 and SPSS 24.0. The R × C chi-square test was used to compare drug resistance rates between the groups, and Fisher’s precision probability test was applied when necessary. Trend chi-square tests were used to compare changes in bacterial resistance rates across different years. Statistical significance was set at P<0.05.

Results Patient Distribution of P. aeruginosa Bloodstream Infections

A total of 2208 P. aeruginosa strains were detected in blood specimens from 2016 to 2021. As shown in Table 1, P. aeruginosa was mainly isolated from male patients, with a male-to-female ratio of 2.1:1. These infections were more common in middle-aged and older individuals, with those aged 48 years and above accounting for 76.0% of cases. The median age of the patients was 63 years. Most patients were seen in the hematology (20.7%) and intensive care medicine (18.4%) departments. Patients were distributed as follows: internal medicine (38.8%), surgery (22.7%), gynecology (0.4%), pediatrics (5.9%), intensive care medicine (18.4%), outpatient emergency (5.2%), and other (8.5%).

Table 1 General Data of Patients With P. aeruginosa Infection

Antibacterial Resistance Patterns and Their Changing Trends

P. aeruginosa isolates exhibited low-to-moderate resistance (ranging from 3.8 to 26.8%) to commonly used antibiotics between 2016 and 2021. Except for ticarcillin/clavulanic acid (26.8%) and aztreonam (22.8%), the 6-year average resistance rates of the remaining antibiotics were below 20.0%. Among these, polymyxin B and amikacin showed good in vitro bacterial inhibitory activities, with low resistance rates of 3.5% and 4.8%, respectively (Table 2). Over the six-year period, resistance rates decreased significantly for aminoglycosides, fluoroquinolones, and carbapenems, but resistance to ticarcillin/clavulanic acid increased by 15.1% (Table 3, Figure 1). CRPA decreased from 19.6% in 2016 to 17.9% in 2021, indicating an overall declining trend (χ2=18.423, p=0.002) (Figure 2).

Table 2 Resistant Rates, MIC50 and MIC90 of P. aeruginosa Isolated From Blood Specimens to Antimicrobial Agents in Hebei Province, 2016–2021

Table 3 Antibacterial Resistant Rates of P. aeruginosa Isolated From Blood Specimens in Hebei Province, 2016–2021

Figure 1 Line graph illustrating the antibiotic resistance rates of P. aeruginosa isolates from blood specimens in Hebei Province from 2016 to 2021. The graph displays the percentage of resistant isolates for each year against antibiotics. Each data point represents the annual resistance rate, and the lines connect these points to show trends over the six-year period. The legend inset provides a key to the different antibiotics, with each line styled uniquely for clarity.

Figure 2 The trend of CRPA resistance rates. From 2016 to 2021, the resistance rate of CRPA decreased from 19.6% in 2016 to 17.9% in 2021, indicating an overall downward trend.

Abbreviation: CRPA, Carbapenem-resistant P. aeruginosa.

Departmental Variation in Antibacterial Resistance

As shown in Table 4, Figure 3, except for polymyxin B, there were significant differences in the resistance rates of other antibiotics to P. aeruginosa in different departments. The resistance rates of the isolates to meropenem, imipenem and amikacin were highest in the department of critical care medicine. In addition to the aforementioned antibiotics, the resistance rates of isolates to β-lactamase inhibitors, cephalosporins, aminoglycosides, and fluoroquinolones were highest in the pediatric department.

Table 4 Antibacterial Resistant Rates of P. aeruginosa Isolated From Blood Specimens by Different Departments in Hebei Province, 2016–2021

Figure 3 Departmental variation in antibacterial resistance. The bar chart shows the distribution of drug-resistant P. aeruginosa isolated from blood specimens in various departments in Hebei Province from 2016 to 2021. X-axis labels indicate different departments, and Y-axis indicates the rate of resistance, where strains isolated from Department of Critical Care Medicine and Pediatric department were multi-drug resistant strains.

Age-Related Antibacterial Resistance Patterns

As shown in Table 5, Figure 4, while resistance rates to ceftazidime, amikacin, and polymyxin were consistent across different age groups, newborn patients showed severe drug resistance rates (>75.0%) to piperacillin, piperacillin/tazobactam, aztreonam, gentamicin, ciprofloxacin, and levofloxacin. In contrast, pediatric patients exhibited relatively low resistance rates (<10.0%) to these antibiotics.

Table 5 Antibacterial Resistance Rate of P. aeruginosa Isolated From Blood Specimens of Patients of Different Age Groups in Hebei Province, 2016–2021

Figure 4 Age-related antibacterial resistance patterns. The bar chart shows the distribution of drug-resistant P. aeruginosa isolates from blood specimens of patients across different age groups in Hebei Province from 2016 to 2021. The X-axis labels indicate the age groups, and Y-axis indicates the rate of resistance. The newborn group showed extremely high resistance rates to piperacillin, piperacillin/tazobactam, aztreonam, gentamicin, ciprofloxacin, and levofloxacin, all exceeding 75.0%.

Discussion

P. aeruginosa bloodstream infections are prevalent in immunocompromised patients,10,18 particularly in hematology inpatients with hematopoietic malignancies such as leukemia and lymphomas. This study found that, from 2016 to 2021, a total of 2208 non-repetitive P. aeruginosa strains were isolated from blood specimens in Hebei province. Patients were mainly attending haematology (20.7%) and intensive care medicine (18.4%) departments and were predominantly middle-aged and elderly (≥48 years old, accounting for 76.0% of the total) and male (accounting for 67.3% of the total). These patients have impaired immune function due to chemotherapy.19 Some studies have found that gram-negative bloodstream infections occur in approximately 50% of hematologic disorder patients, often due to P. aeruginosa.10,18 ICU patients, who are critically ill and frequently subjected to invasive diagnostic and therapeutic procedures, are also at high risk for bloodstream infections.11 Notably, as seen in previous studies,11,20,21 male patients in this study significantly outnumbered females, suggesting higher susceptibility to P. aeruginosa bloodstream infections among males.

Over a period of six years, the resistance rates of P. aeruginosa in Hebei to aminoglycosides, fluoroquinolones, and various antimicrobial drugs (aminoglycosides, fluoroquinolones, and carbapenems) declined but susceptibility levels remained high nevertheless. Surveillance data from 2021 showed that, except for relatively high resistance rates to ticarcillin/clavulanic acid (35.5%) and amitrazine (21.8%), the resistance rates of P. aeruginosa to all commonly used antimicrobials remained below 18%. These rates were lower than those reported by the Drug Resistance Surveillance Network in the United States,22 hospitals in Yazd, Iran,23 and northeastern Ethiopia,24 but slightly higher than those reported in Fujian,25 Guangzhou,13 and Ningxia,26 China. We observed a lower rate of resistance to aminoglycosides, which remained below 10%. Aminoglycosides such as amikacin alone have limited efficacy in treating bloodstream infections and may increase patient mortality.6 Combining them with β-lactams, which remain active, can improve a patient's prognosis.14,27

CRPA is classified by the WHO as one of the bacteria for which new treatment strategies are most critically needed.28 In this study, CRPA increased from 19.6% (2016–2017) to 24.1% but decreased year by year, reaching 13.9% by 2020, which is lower than the national average.1,29 However, a 4.0% increase in CRPA from 2020 to 2021 warrants vigilance. Prolonged carbapenem use, particularly imipenem, can induce resistance in P. aeruginosa through loss of membrane pore proteins or efflux system overexpression.12 Bacterial resistance elevates patient mortality.3–5 Combining carbapenems and fluoroquinolones can reduce the risk of resistance and improve prognosis.8,30

Drug-resistant bacteria rates are higher in intensive care patients due to extended disease duration and increased antibiotic use.31 In this study, resistance to P. aeruginosa in intensive care was higher than that in other departments for only three antibiotics: meropenem, imipenem, and amikacin. However, resistance to other commonly used antimicrobials is high in pediatric patients. Neonatal P. aeruginosa isolates are generally highly resistant, with resistance rates to some beta-lactamase inhibitors, aminoglycosides, and fluoroquinolones exceeding 75%, whereas resistance rates in children are relatively low. These results suggest that patients of different age groups may require different treatment regimens. In Hebei province, the empirical treatment of P. aeruginosa bloodstream infections with β-lactamase inhibitor analogs may increase the risk of treatment failure or delayed treatment in newborns. In the field of neonatal bloodstream infection treatment, the World Health Organization (WHO) recommends the combined use of ampicillin and gentamicin or the selection of third-generation cephalosporins (such as cefotaxime, ceftriaxone) as the preferred treatment regimen.32,33 However, in recent years, the incidence of global neonatal multidrug-resistant bacterial infections has significantly increased.32,34 Bacterial resistance to current empirical treatment regimens is growing stronger, leading to persistently high mortality rates from neonatal sepsis and meningitis. Therefore, there is an urgent need to develop new empirical treatment regimens.32–35 However, due to CRPA, such as the loss of porin proteins, high expression of efflux pumps, mutations in penicillin-binding proteins, and enzyme production, the survey results from the Chinese Antimicrobial Resistance Surveillance Network (CHINET) show that the sensitivity of CRPA to ceftazidime/avibactam is 65.7%.36 Studies indicate that immunosuppressants can promote the evolutionary pathways of bacterial resistance and treatment failure,37 and the neonatal immune system is not fully developed. Additionally, neonatal care units more frequently use broad-spectrum antibiotics, which may be related to the significant resistance seen in neonates. Unfortunately, the reasons for the differences in drug resistance between neonates and children remain unclear. In future, we will conduct a molecular epidemiological investigation of P. aeruginosa from blood specimens of pediatric patients and initially explore the potential causes of the resistance discrepancy in conjunction with clinical information and antibiotic use in children.

The increasing resistance of P. aeruginosa to ticarcillin/clavulanic acid and aztreonam poses new challenges to clinical treatment. Ticarcillin/clavulanic acid and aztreonam, as beta-lactam antibiotics, have previously had good effects in treating infections caused by P. aeruginosa. However, with the rise in resistance, the effectiveness of these drugs is limited, and doctors must be more cautious when choosing treatment options. We need to strengthen monitoring and data sharing between provinces to better understand the spread of antibiotic resistance strains.

The limitations of this study are mainly reflected in the analysis of the resistance and resistance rate of P. aeruginosa isolated from blood samples collected in Hebei Province, without exploration of the molecular analysis to identify the mechanisms of resistance. Future research urgently needs to study the resistance mechanisms of P. aeruginosa in order to more accurately grasp the development trend and transmission pathways of its resistance.

Conclusions

In summary, this study indicates that P. aeruginosa bloodstream infections in Hebei Province primarily affected hematology and intensive care patients, mainly those who are middle-aged, elderly, and male. Overall antibacterial resistance to P. aeruginosa showed a downward trend from 2016 to 2021. However, there were variations in drug resistance patterns across departments and age groups. Studies have found that P. aeruginosa isolated from neonatal bloodstream infections exhibits high resistance to certain beta-lactamase inhibitors, aminoglycosides, and fluoroquinolones. Therefore, clinicians should be particularly cautious when prescribing drugs based on clinical experience to avoid exacerbating the risk of generating and spreading resistant strains. These findings emphasize the need for tailored treatment strategies and vigilant antimicrobial stewardship efforts to effectively combat P. aeruginosa infection in this region.

Availability of Data and Materials

The datasets analyzed in this study are available from the corresponding author upon request.

Ethics Approval and Informed Consent

The study protocol was reviewed by the Ethics Committee (IRB) of the Second Hospital of Hebei Medical University. As the project is an observational study and all bacterial strains are cultured from residual samples used in clinical diagnosis, it involves ensuring the confidentiality of patient data and compliance with the Declaration of Helsinki. As the data did not affect patient care, the exemption criteria were met. After consulting the IRB of the Second Hospital of Hebei Medical University, a formal ethical review was approved, and written informed consent was not required (ethical approval No.: 2023-R660).

Acknowledgments

We are grateful for the contributions of the expert committees, working groups, and member organizations of the Hebei Province Antimicrobial Resistance Surveillance System.

Author Contributions

All authors made a significant contribution to the work reported, whether in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas, took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by the Hebei Natural Science Foundation [grant number H2022206358], Hebei Province County level Comprehensive Hospital Suitable Health Technology Promotion Project [grant number 20200018], Hebei Provincial Medical Science Research Project [grant number 20210889], and the Scientific Research Foundation of the Second Hospital of Hebei Medical University [grant number 2HC202225].

Disclosure

The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

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