Polymyxin B resistance rates in carbapenem‑resistant Pseudomonas aeruginosa isolates and a comparison between Etest® and broth microdilution methods of antimicrobial susceptibility testing
- Authors:
- Published online on: May 20, 2020 https://doi.org/10.3892/etm.2020.8777
- Pages: 762-769
Abstract
Introduction
Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative non-fermenting bacillus that is prevalent in the community and hospital environment. Carbapenem-resistant P. aeruginosa (CRPA) is a major cause of life-threatening infections worldwide (1,2). CRPA is considered to be a multidrug resistant (MDR) pathogen, as it is intrinsically resistant to different types of antimicrobial drugs. CRPA also has the capacity to develop resistance to various antimicrobial agents, thereby reducing the number of available treatment options. In the previous decade, the resistance rate of carbapenem has increased 3-fold in various countries, including the United States of America (USA), Singapore, Brazil, Iran and China, reaching 50-80% in certain areas (3-6). Since the 1950s, polymyxins have been popular for the treatment of carbapenem-resistant enterobacteriaceae (CRE) infections (7). However, their use has been restricted, due to significant neurotoxicity and nephrotoxicity. With an increasing number of CRE infections observed over recent years, polymyxin B and colistin have become increasingly popular treatment choices. Although the resistance rate of polymyxin B is low in most countries, it appears to be increasing. Globally, the polymyxin B resistance rate is <5%; however, it has been reported to be 50% in Singapore. Therefore, clinicians should be vigilant in regards to the rising rate of resistance (3-6, 8). Identifying an appropriate method for antimicrobial susceptibility testing (AST) of polymyxin B and colistin is important for the treatment of CRPA infections.
A reliable method for testing polymyxin susceptibility remains elusive. In 2017, the Clinical and Laboratory Standards Institute® (CLSI®) no longer considered the disc diffusion (DD) method to be appropriate for colistin susceptibility testing. Furthermore, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) did not previously deem DD to be an appropriate method for colistin susceptibility testing (9). CLSI and EUCAST guidelines have suggested broth microdilution (BMD) as the reference method for polymyxin B and colistin susceptibility testing (9). However, technical issues have been reported by clinicians worldwide, as polymyxin B and colistin adhere to microtiter plates, contributing to inaccurate results. Therefore, many clinical laboratories have used Etest® strips as an alternative method.
Studies describing the use of Etest® for polymyxin B testing in CRPA are scarce and previous data have disputed the reliability of this method (10,11). In addition, EUCAST has revised the breakpoints for colistin in its guidelines of 2017 and 2018 (9,12). As novel data has been generated over the last two years, it is necessary to compare the Etest® and BMD methods in accordance with CLSI/EUCAST standards in larger CRPA populations. The present study analyzed CRPA resistance to polymyxin B in the Suzhou district of China. A comparison analysis of polymyxin B resistance rates from different countries or regions was also performed to determine resistance trends. Additionally, the present study assessed the effectiveness and reliability of Etest® in a clinical laboratory setting.
Materials and methods
Bacterial isolates
A total of 50 non-duplicated clinical CRPA isolates that were non-susceptible (resistant or intermediate) to any carbapenem (imipenem or meropenem) were identified and collected from patients admitted to the First Affiliated Hospital of Soochow University, the leading tertiary hospital of Suzhou district with 3,000 beds, between October 2017 and February 2019. All isolates were stored at -80˚C in 10% glycerol and sub-cultured twice prior to testing. Isolates were identified using an automated system (Vitek2 compact; bioMérieux). P. aeruginosa [American Type culture collection (ATCC)® 27853™; 0.5-4 µg/ml] and Escherichia coli (ATCC® 25922™; 0.25-2 µg/ml) served as quality control strains in the 2 susceptibility methods assessed. The present study was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University and was performed in accordance with the 1975 Declaration of Helsinki. All patients provided written informed consent.
Susceptibility testing
All susceptibility testing was conducted in accordance with the CSLI® recommendations (12). The range of susceptible, resistant and intermediate polymyxin B concentrations were ≤2, ≥8 and 4 µg/ml, respectively. Additionally, the carbapenems that were assessed (imipenem or meropenem) demonstrated the same ranges as polymyxin B (susceptible, ≤2 µg/ml; resistant, ≥8 µg/ml; intermediate, 4 µg/ml). BMD was performed using a cation-adjusted Mueller Hinton II broth (Wenzhou Kangtai Biotechnology Co., Ltd.) in accordance with CLSI® guidelines. Each test was duplicated and a third test was performed for discrepant minimal inhibitory concentrations (MICs) or for MICs exceeding 1 log2 dilution. The polymyxin B Etest® (Wenzhou Kangtai Biotechnology Co., Ltd.) was performed in the clinical microbiology laboratory in accordance with the manufacturer's protocol. The results were compared with those obtained via BMD.
Search strategy
The PubMed and Embase databases updated on April 2019 were searched using the following terms: ‘Pseudomonas aeruginosa’ or ‘Polymyxin B’, together with ‘antimicrobial resistance’. Entire manuscripts associated with the resistance rate of polymyxin B and P. aeruginosa infection were then identified.
Selection of literature
The titles and abstracts of previous studies obtained from PubMed and Embase were reviewed. If the titles appeared to be associated with the research strategy abstracts were reviewed. If abstracts correlated with the research strategy the full texts were reviewed. The inclusion criteria were as follows: i) An original article or research article; ii) short communications; and iii) correspondence or letters. The exclusion criteria were as follows: i) Reviews or case reports; and ii) animal experiments.
Statistical analysis
The present study utilized CLSI® susceptibility breakpoints in CRPA isolates to obtain all descriptive statistics including susceptibility (%), resistance (%), the MIC90 concentration (mg/l) and the range (mg/l). Essential agreement (EA) was defined as samples with MICs that were equivalent to the ± 1-log2 dilution between the polymyxin B Etest® methodology and the reference method. A result was deemed inconsistent if there was a difference of ± 2-log2 in the dilution of results. Categorical agreement (CA) was determined if the results from both methods belonged to the same category of susceptibility. A serious major error rate was defined as the percentage of CRPA isolates reported to be susceptible using the Etest® method, but resistant when using the reference method (false susceptibility). A major error rate was defined as the percentage of CRPA isolates reported to be resistant using the Etest® method, but susceptible using the reference method (false resistance). Finally, a minor error rate was determined if acceptable levels were defined as <1.5% for very major errors, <3% for major errors and <10% for minor errors, all of which were indicated in the CLSI® document M23-A2(9). The odds ratio and 95% confidence interval (CI) were determined to evaluate the association power. The χ2 test-based Q-statistic and I2 statistics were also utilized as previously described (13,14). If there was no evident heterogeneity, the fixed-effects model was applied (15). If there was heterogeneity, a random-effects model was utilized (16). All statistics were performed using Stata software (v.14.0; StataCorp LLC).
Results
Bacterial isolates
In total, 50 CRPA clinical isolates were collected from the First Affiliated Hospital of Soochow University. The isolates were obtained from different clinical departments and specimen types (Figs. 1 and 2), and were determined to be non-susceptible to imipenem or meropenem. Fig. 3 presents the resistance rate of CRPA isolates to several antibacterial agents.
EA and CA
Following BMD, only 2 isolates were determined to be non-susceptible to polymyxin B according to CLSI® criteria (both 4.0 mg/l). The susceptibility rate reached 96.0 and 98.0%, as determined via BMD and Etest® methods, respectively. The EA and CA reached 98.0%. No very major or major errors were detected in the 50 CRPA strains. Furthermore, only 2.0% minor errors were detected (Tables I and II). The detailed results of antimicrobial susceptibility testing are provided in Table III.
 | Table IIIAntimicrobial susceptibility testing of Etest® and BMD from carbapenem-resistant Pseudomonas aeruginosaisolates. |
A total of 34 previous studies assessing the resistance rate of polymyxin B in P. aeruginosa were reviewed and analyzed (Table IV) (4-6,8,17-46). The process used to search the literature is presented in Fig. 4. The results revealed that the resistance rate of polymyxin B was relatively low in the majority of countries and regions, with the exception of Singapore. The resistance rate of polymyxin B in Singapore reached 53% (95% CI, 12-93%). A summary of the susceptibility analyses in different countries or regions is presented in Table V.
Discussion
The issue of limited treatment options for CRPA has attracted increasing attention in the previous decade. Despite the neurotoxicity and nephrotoxicity generated by polymyxin B, it remains a viable treatment option to which the majority of CRPA strains remain susceptible (47). However, the resistance rates of antibacterial agents may differ between geographical locations; for example, the resistance rate of polymyxin B is relatively low in the majority of countries and regions, with the exception of Singapore, whose resistance rate has been reported to be as high as 53% (95% CI, 12-93%). Polymyxin B resistance depends on a complicated multi-factorial process that includes polymyxin B exposure, the inappropriate usage of other antibacterial agents, such as carbapenems, and resistance to transmission via plasmids (48). The high resistance rates observed in Singapore may be due to the early usage of polymyxin B in the late 1990 s, which was earlier than the majority of countries and regions globally (22). In addition, polymyxin B is used as the primary polymyxin for the treatment of multidrug-resistant gram-negative infections (22). Locally, the combination of polymyxin B and other antibiotics for the treatment of infections is also common (22). Polymyxin B is rarely administered in the USA, Europe, Africa and Asia for several reasons: i) Physicians in the USA and Europe frequently use polymyxin E to treat patients with CRPA; ii) polymyxin B is only used in Brooklyn and New York city; iii) The majority of Asian countries, including China, have not approved the prescription and sale of polymyxin B (49,50).
The meta-analysis in the present study offers important data regarding the trends in CRPA resistance to polymyxin B in different global regions. Generally, the susceptibility rate of polymyxin B is high in most countries. However, an efficient and reliable method of antibiotic susceptibility testing for polymyxin B has yet to be established. There are several concerns regarding polymyxin B and colistin in vitro susceptibility testing. Firstly, and primarily, conflicting data regarding the AST procedure exists in the literature (12). Secondly, it is not clear which reference method is the most appropriate for making comparisons (51). Thirdly, the testing population that represents the MIC spectrum of polymyxin (highly resistant or highly sensitive) is restricted and inaccessible (51). Fourthly, it is difficult to obtain reproducible susceptibility information due to the heteroresistance exhibited within bacterial isolates (52). Finally, despite the MICs obtained in the present study, a single value may not accurately represent the populations that exhibit heteroresistance.
It has been demonstrated that DD is not a reliable method for susceptibility testing, and the CLSI® and EUCAST do not recommended it for polymyxin B testing (53,54). Although BMD has been recommended as a reference method by the CLSI® and EUCAST, it is time-consuming and laborious procedure, which represents a burden in routine clinical practices. In recent years, the majority of studies have focused their attention on the effectiveness and reliability of Etest® (10,20). However, certain issues remain unresolved. Studies comparing the MIC of Etest® with BMD in CRPA are rare. In addition, there are uncertainties and contrasting opinions surrounding the reliability of the Etest® method. Simar et al (10) demonstrated that the Etest® was not a reliable method for the detection of the polymyxin B MIC in CRPA strains. A high inconsistency rate between polymyxin B Etest® and BMD MICs was also revealed. Additionally, van der Heijden et al (20) revealed that only 1.2% of very major errors were detected and no major errors were determined. However, 48.7% of minor errors were detected, with the EA reaching 61%. It is well known that the acceptable rate of EA and minor errors should be ≥90 and ≤10%, respectively. In the present study, almost no difference was detected between the Etest® and BMD, as the EA reached 98.0%. No very major errors or major errors were identified, and only 2.0% minor errors were detected. All of the measurable indicators including EA, CA, very major errors, major errors and minor errors were within the acceptable level. Despite similarities in the aims and techniques utilized in a previous study by van der Heijden et al (20), the present study was valuable, as few studies have performed methodological comparisons between BMD and Etest® testing methods for polymyxin B. Furthermore, the breakpoint of polymyxin B MIC antibiotic susceptibility tests was updated in the 2017 edition of the CLSI® (12). As new data have been generated in the past decade, it is necessary to compare the Etest® with BMD methods using the new CLSI/EUCAST standards for CRPA strains.
The results of the present study differ to those published previously. There are several reasons that may account for this. Firstly, Western countries began administering polymyxins earlier than Asian countries. In 2003, it was reported that at least nine P. aeruginosa isolates were non-susceptible to colistin in Greece (55). Furthermore, in 2005, a marked decrease in polymyxin susceptibility was detected in Brooklyn and New York city, in the USA (17). However, polymyxins have not been employed by clinical physicians in China. The resurgence of polymyxin use in Malaysia occurred in 2009 due to the lack of effective treatment options for MDR gram-negative superbugs (56). Therefore, the sensitivity rate of polymyxins for CRPA in Asian countries has been identified to be increased compared with Western countries. The results of the present study may differ from previous studies due to the resistance mechanisms utilized. For example, Tan et al (53) identified the activity of mobilized colistin resistance (mcr-1), which was a resistance gene in the majority of polymyxin-resistant enterobacteriaceae isolates, but this was not observed in the study by Rojas et al (57). The present study did not investigate mcr-1 and it was challenging to elucidate the resistant mechanisms utilized by polymyxins. At present, the PhoPQ regulatory system is the only mechanism considered to serve an important role in polymyxin resistance (58). Heteroresistance may also have had a significant effect on the results of the present study. Heteroresistance occurs when sensitized bacteria are mixed with a small drug-resistant subpopulation, leading to the unexplained failure of clinical treatment. Heteroresistance is affected by diverse factors including bacteria species, antibacterial agents, resistance phenotypes or mechanisms and local epidemiology (59-61). The present study hypothesized that the discrepancy between BMD and Etest® results may be explained by the fact that BMD is more sensitive to heteroresistant subpopulations than Etest®. However, a small number of heteroresistant colonies growing in the inhibition zone appeared to contribute to the results of the Etest® strip. If equal quantities of heteroresistant and sensitive colonies grew in the specific microtiter wells and turned the wells turbid, then an elevated MIC of polymyxin B would be recorded. Furthermore, the degree of heteroresistance may determine the very major errors, major errors and minor errors between the present study and previous studies. However, studies that assess heteroresistance are scarce and rarely investigate polymyxin B in P. aeruginosa (62).
The identification of feasible and reliable susceptibility testing methods to determine the MIC of polymyxin B are urgently required. The results of the present study identified a good concordance between BMD and Etest®. However, there are certain limitations: The present study is single-center investigation and does not contain genetic data regarding the resistant mechanisms utilized by polymyxins. Furthermore, the CRPA populations in the present study lacked isolates with an MIC of polymyxin B>2 mg/l (n=1). Additionally, detailed information regarding clinical outcome data was not obtained.
Despite the existence of several studies from various geographical regions assessing trends of polymyxin B in the antimicrobial resistance of CRPA, to the best of our knowledge, the present study is the first that provides global data and compares the MIC of Etest® with BMD for CRPA isolates in China. In conclusion, polymyxin B resistance rates are relatively low in the majority of countries and regions, with the exception of Singapore. The Etest® may serve as a potentially reliable clinical method of polymyxin B MIC determination in CRPA.
Acknowledgements
The authors would like to thank Ms Li Yan (Zhangjiagang Hospital of Traditional Chinese Medicine) and Mr Haitao Hu (People's Hospital of Taizhou) who assisted in the collection and organization of the experiment data.
Funding
The present study was supported by the Natural Science Foundation of Jiangsu Province (grant no. BK20170364), the National Natural Science Foundation of China (grant no. 81702065) and Jiangsu Province Medical Innovation Team (grant no. CXTDB2017009).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
LZ and XC conceived and designed the experiments of the current study. XC, QZ, YR and JX performed the experiments, analyzed the data, contributed reagents, materials and analysis tools, and wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and informed consent
Patient data were collected retrospectively from electronic health records. The present study was approved by the Ethics Committee of First Affiliated Hospital of Soochow University and was in accordance with the 1975 Declaration of Helsinki. The patients provided written informed consent.
Patient consent for publication
The patients provided written informed consent.
Competing interests
The authors declare that they have no competing interests.
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