Distribution pattern of carbapenemases and solitary contribution to resistance in clinical strains of Acinetobacter baumannii

Introduction

Acinetobacter baumannii (A. baumannii) is an important nosocomial pathogen. Clinically, it causes ventilator-associated pneumonia, surgical wound infection, meningitis etc., especially in immune-compromised patients (1,2). As reported in reviews dating back to the 1970s, hospital-acquired pneumonia, especial ventilator-associated pneumonia, was the most common infection caused by A. baumannii (3). According to data of China Bacterial Resistance Monitoring Network (CHINET), A. baumannii accounted for 9.08% of the total clinical pathogenic isolates and became the third most gram-negative bacteria in the clinical bacteria in 2019 in China.

The risk factors of A. baumannii infection include invasive operations, surgical treatment and immunosuppression etc. Patients with severe basic diseases in intensive care unit (ICU) commonly need a variety of invasive surgeries and the use of high-dose broad-spectrum antibiotics, which usually leads to internal microecological imbalance and high risk of A. baumannii infection. Infection of A. baumannii always means a prolonged hospital stay and high mortality. The mortality rate of A. baumannii infection is 7.8% to 23% in hospital and 10% to 43% in ICU (4).

The powerful resistance of A. baumannii has been becoming a serious public health problem. Multidrug resistant (MDR), extensively drug resistant and even pan drug resistant strains have been commonly emerging in clinical wards, especially in ICU wards. Carbapenems, such as imipenem and meropenem, either alone or in combination with other category of antibiotics, were once effective therapeutic regimens for A. baumannii infections. However, clinical isolates of carbapenem-resistant A. baumannii (CRAB) have notably increased in recent years, and data from CHINET showed that resistance rate to imipenem has increased to 73.6% and 75.1% in 2019 in China. The CRAB epidemic has become a critical infection problem.

Several resistance mechanisms are involved in A. baumannii carbapenem resistance. Generally, production of carbapenemase is thought to be an effective way. Common carbapenemases include OXA-type carbapenemases (5-9) and metallo-β-lactamases (MBLs) (5,10,11). In addition, up-regulated expression of efflux pump genes (especially AdeABC pump), and down-regulated expression of porin genes may also be associated with carbapenem resistance (12-15).

Surveillance of carbapenemase harboring pattern is necessary for guiding targeted clinical medication in different geographical origin. The drug resistance of A. baumannii isolates in different areas is different. There were several reports about carbapenemase harboring pattern in A. baumannii in different areas. However, as far as we know, few studies have focused on the distribution pattern of carbapenem in southern China and the specific contribution of different carbapenems to carbapenem antibiotic resistance. This study aims to investigate the distribution pattern of carbapenemases to evaluate (using statistical methods) their solitary contribution to carbapenem resistance.

We present the following article in accordance with the MDAR reporting checklist (available at https://dx.doi.org/10.21037/apm-21-1805).

Methods

Isolation and identification of strains

In total, 125 non-repetitive strains of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex were collected from the patients of ICU of a tertiary hospital, Shenzhen, China, from July 2018 to June 2019. The specimen source included sputum, nasal secretion samples, etc.

The collected strains were inoculated on McConkey plate, and the single colony overnight was used for identification. According to the manufacturer’s guidelines, 125 isolates were identified as Acinetobacter calcoaceticus-Acinetobacter baumannii complex using the AutoMicrobic system Gram-Negative Identification Card on microbiology analyzer VITEK 2 system (Biomerieux, France). 112 in 125 isolates were further confirmed as A. baumannii by rpoB gene sequence analysis assays according to previous established polymerase chain reaction (PCR) conditions.

This study was approved by the Ethics Committee of the First Affiliated Hospital of Shenzhen University (ID: 20200511007). This was a retrospective study obtaining data from hospital’s information system. The results of this study may benefit patients with A. baumannii infection and may lead to better therapeutic outcomes. The requirement for informed consent of patients in this study was waived. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).

Antimicrobial susceptibility test (AST)

AST of these isolates was determined by an automated broth microdilution method (gram-negative susceptibility cards) using the VITEK 2 system. Susceptibility interpretation was based on clinical breakpoint from the Clinical and Laboratory Standards Institute (CLSI 2019, 29^th edition; DocumentM100). These antimicrobials included cefazolin, cefotetan, ampicillin + sulbactam, piperacillin + tazobactam, ceftriaxone, ceftazidime, cefepime, ciprofloxacin, levofloxacin, tobramycin, gentamycin, nitrofurantoin. Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 were used as quality control.

According to AST result, 112 strains were divided into carbapenem-susceptible A. baumannii (CSAB) group and CRAB group.

Detection of carbapenemase gene

Common carbapenemase genes of A. baumannii, including bla_OXA-51-like, bla_OXA-23-like, bla_OXA-24-like, bla_OXA-58-like, bla_SIM, bla_VIM, bla_IMP, bla_NDM-1 and ISAba1/bla_OXA-51-like were detected according to previously established PCR conditions (13,16,17). All PCR primers used in this study were listed in Table 1. Four A. baumannii strains, ab606, ab608, ab609, and SZE, were used as positive quality control strains.

Table 1 Primer sequences and amplicon size
Full table

Statistical analysis

Stata/SE 15.1 (StataCorp LLC, TX, USA) was used for data entry and statistical analysis. All tests were two-tailed, and a P value ≤0.05 was considered statistically significant. Sample demographic and disease characteristic were compared using Pearson’s chi-square test. AST and harboring of resistance genes were compared between the CSAB and CRAB group using Fisher-Exact test. Logistic Regression was used to assess the relations between harboring of resistance gene and antimicrobial susceptibility result. General regression model was used to make multivariate regression analysis of resistance genes and antimicrobial susceptibility results to calculate the risk ratio (RR).

Results

Clinical characteristics of A. baumannii strains

As summarized in Table 2, a total of 112 patients were included in this study, including 70 males (62.5%) and 42 females (37.5%). Seventy-eight (69.6%) patients were over 60 years old and 32 (28.6%) were between 16 to 59 years old. The causes of ICU admission were respiratory distress in 37 cases (33.0%), poor general condition in 27 cases (24.1%), trauma in 29 cases (25.9%), and other causes in 19 cases (17.0%).

Table 2 Sample demographic and disease characteristic
Full table

AST

AST results of 112 A. baumannii strains are summarized in Figure 1. Of the 112 isolates, 21 strains (18.8%) were in CSAB group and 91 strains (81.2%) in CRAB group. CRAB strains showed almost 100% resistant to cephalosporins (ceftriaxone, ceftazidime, cefepime), over 70% resistant to quinolones (ciprofloxacin, levofloxacin) and aminoglycosides (tobramycin, gentamicin). In this study, there was evidence that the combination preparation such as sulbactam and cefoperazone was a reasonable choice for the treatment of CRAB infection.

Figure 1 Percentage of antibiotic sensitivity of CSAB and CRAB strains. CSAB, carbapenem-susceptible A. baumannii; CRAB, carbapenem-resistant A. baumannii; A. baumannii, Acinetobacter baumannii; AK, amikacin; TCC, ticarcillin-clavulanic acid; AMS, ampicillin-sulbactam; TZP, piperacillin-tazobactam; CRO, ceftriaxone; CAZ, ceftazidime; FEP, cefepime; CIP, ciprofloxacin; LEV, levofloxacin; TOB, tobramycin; GM, gentamicin; MEM, meropenem; MH, minocycline.

Distribution of carbapenemase

As shown in Table 3, bla_SIM, bla_VIM and bla_IMP genes were not detected in any of the 112 isolates, and bla_OXA-51-like gene was found in all 112 (100.0%) isolates. The positive rate of bla_OXA-23-like was 93.4% in CRAB group, and 19% in CSAB group. Compared with CSAB, CRAB strains showed a statistically significant increasing distribution of bla_OXA-23-like (P<0.001) and ISAba1/bla_OXA-51-like (P=0.024), respectively. Bla_OXA-24-like and bla_OXA-58-like were found in 2.2% strains, which belonged to CRAB group, and bla_NDM-1 gene was detected in 8.8% strains. No bla_SIM, bla_VIM and bla_IMP genes were detected in these isolates.

Table 3 Distribution pattern of carbapenemases
Full table

Univariate logistic analysis and multivariate regression analysis for carbapenem resistance

As presented in Table 4, bla_OXA-23-like, bla_OXA-24-like, ISAba1/bla_OXA-51-like, and adeB were included to perform the univariate logistic and multivariate regression analyses. Two variables, bla_OXA-24-like and bla_OXA-58-like, were dropped automatically by Stata/SE statistical software.

Table 4 Univariate logistic and multivariate regression analyses for carbapenem resistance
Full table

Based on the result of multivariate regression analysis, carrying bla_OXA-23-like and ISAba1/bla_OXA-51-like might increase the possibility of carbapenem resistance by 2.16 times [adjusted RR =2.16; 95% confidence interval (CI): 1.04–4.51] and 1.29 times (adjusted RR =1.29; 95% CI: 1.07–1.56), respectively.

Discussion

A. baumannii is an important nosocomial pathogen, which can cause ventilator-associated pneumonia, surgical wound infection, meningitis etc. A. baumannii can enter the bloodstream and cause bacteremia, which may further develop into sepsis. A. baumannii infection leads to a high clinical mortality. In this decade, an increasing number of pan-drug resistant isolates have been reported globally. This indicated that A. baumannii strains with powerful resistance ability have been becoming a serious problem for clinical infection control. As reported, relevant mechanisms to carbapenem resistance include enzyme-hydrolyzing, overproduction of efflux pump, changing of outer membrane and biofilm formation (16-18). Monitoring molecular characteristic is necessary for taking effective measures to control clinical infection. In view of the complex mechanism of drug resistance, it is difficult to evaluate the contribution of different carbapenem enzymes. In this study, we found carrying bla_OXA-23-like and ISAba1/bla_OXA-51-like might increase the possibility of carbapenem resistance by 2.16 times (adjusted RR=2.16; 95% CI: 1.04–4.51) and 1.29 times (adjusted RR=1.29; 95% CI: 1.07–1.56), respectively. Compared with CSAB strains, CRAB strains showed a statistically significant increasing distribution of bla_OXA-23-like (P<0.001) and ISAba1/bla_OXA-51-like (P=0.024).

Elderly patients with underlying diseases, highly selective antibiotics and mechanical ventilation, are an important population for nosocomial infection of A baumannii. In this study, we found 69.9% of A. baumannii infected patients were ≥60 years old, and most of them had fundamental illness. We also found that 62.5% of infected patients were male and had an extended period of hospitalization, which was consistent with the report of Wisplinghoff et al. (19).

Carbapenem was once regarded as main antibacterial drug for A. baumannii infection (20), but the susceptibility has decreased in the recent years. In this study, 81.3% of A. baumannii isolates were CRAB, which was consistent with the report in Thailand (21). The resistance rate of ceftazidime and other third generation cephalosporins was over 75%, and that of solitary quinolones or aminoglycosides was basically over 60%.

Clinically, a combination of different category of antibiotic is common option for CRAB infection (22). The combination of cefoperazone and sulbactam showed a good performance in treating infection of CRAB. Tigecycline and polymyxin are other drugs commonly used in CRAB infection. Nevertheless, the effect of tigecycline remains controversial. Some research concluded that tigecycline was be effective, but other clinical research regarded tigecycline might be associated with higher in-hospital mortality and lower microbial eradication rate (23,24).

Strong resistance of A. baumannii is due to its genomic plasticity. Under selective pressure of antibiotics, A. baumannii can acquire resistance through two ways: (I) integration of resistance determinants by horizontal transfer of mobile elements (25); and (II) regulation intrinsic resistance mechanisms, including up-regulation of some intrinsic hydrolases and efflux pumps, down-regulation of membrane permeability, formation of biofilm (1,2,26-29).

Carbapenemases are β-lactamases that confer resistance to carbapenem, penicillin and cephalosporin. According to the Ambler classification system, common carbapenemases in A. baumannii include B class (MBLs) and D class (OXA-type carbapenemases). The former includes bla_SIM, bla_VIM, bla_IMP, and bla_NDM. The latter includes bla_OXA-51-like, bla_OXA-23-like, bla_OXA-24-like, and bla_OXA-58-like. Bla_OXA-23-like gene cluster (encoding OXA-23, OXA-27 and OXA-49) has been shown to contribute to carbapenem resistance. Bla_OXA-24-like is another OXA type carbapenemase gene cluster, which encodes OXA-24, -25, -26, and -40.

The strains of different geographical origin had different carbapenemase harboring patterns. Koirala et al. found bla_OXA-23 (52%) and bla_OXA-40 (28%) were the most frequent genes among carbapenem non-susceptible isolates in Illinois (USA) (30). Indian scholar observed 97.7% of CRAB harboring bla_OXA-23-like gene, bla_NDM-1 (29.1%) and bla_OXA-58-like (3.5%) in India (31). And in Thailand, a pattern of bla_OXA-23 (82.6%), bla_NDM-1 (9.1%), bla_OXA-24 (0.3%) and bla_OXA-58 (6.5%) was reported (21). In this study, we found a pattern of bla_OXA-51-like (100.0%), bla_OXA-23 (93.4%), bla_NDM-1 (8.8%), bla_OXA-24 (2.2%) and bla_OXA-58 (2.2%) in CRAB strains. And the harboring of bla_OXA-23-like increased the possibility of A. baumannii carbapenem resistance by 2.16 times (adjusted RR =2.16; 95% CI: 1.04–4.51) in these strains.

The chromosomal gene bla_OXA-51-like is intrinsic in A. baumannii. Harboring bla_OXA-51-like gene alone can hardly cause carbapenem resistance. ISAba1/bla_OXA-51-like complex is bla_OXA-51-like with an additional genetic element ISAba1 upstream insertion. This structure can result in overexpression of OXA-51-like enzyme and confers resistance to carbapenems. Notably, in this study we detected 27.5% isolates carrying ISAba1/bla_OXA-51-like, which belonged to CRAB group, and no ISAba1/bla_OXA-51-like complex was found in the CSAB strains. Also, the presence of ISAba1/bla_OXA-51-like complex was significantly associated with resistance of carbapenem (adjusted RR =1.29; 95% CI: 1.07–1.56), which indicated that ISAba1/bla_OXA-51-like could play an important role in carbapenem resistance.

Furthermore, over-expression of AdeABC efflux pump was associated with carbapenem resistance. In this study, we found no significant difference in carrying adeB gene between CRAB group and CSAB group (P=0.51>0.05). This result may be because our study only involved the detection of pump gene, but did not discuss the expression of this gene. We will conduct further research on the contribution of overproduction of different efflux pumps in the future.

A. baumannii drug resistance has been increasing in these years, which has brought severe challenge to clinical treatment. To reverse this situation, on the one hand, the use of antibiotics outside the indications should be strictly controlled and antibiotics should be selected according to the results of AST. On the other hand, we should strengthen the surveillance of distribution pattern of drug resistance genes to prevent or delay the emergence of drug-resistant strains.

Limitations

This study had several limitations. Firstly, the source of the strains was only from one hospital, and collection was conducted over a short period of time. Secondly, the regulation of efflux pump gene expression was not discussed in this study. This study only focused on the common drug resistance mechanism of A. baumannii, and did not involve other mechanisms, such as the low production of outer membrane protein affecting membrane permeability and the over production of efflux pump.

Conclusions

A pattern of bla_OXA-51-like (100.0%), bla_OXA-23 (93.4%), bla_NDM-1 (8.8%), bla_OXA-24 (2.2%) and bla_OXA-58 (2.2%) was detected in CRAB strains, and bla_OXA-23-like and ISAba1/bla_OXA-51-like complex might be more relevant to carbapenem resistance in A. baumannii. We also evaluated their solitary contribution to carbapenem resistance by statistical methods. These findings could help to develop effective regimens and prevention strategies for controlling A. baumannii infections.

Acknowledgments

The authors thank the engineers of the medical information system.

Funding: This project was financially supported by a grant from the Shenzhen Science and Technology Foundation (No. JCYJ20190806164011195).

Footnote

Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-1805

Data Sharing Statement: Available at https://dx.doi.org/10.21037/apm-21-1805

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-1805). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Ethics Committee of the First Affiliated Hospital of Shenzhen University (ID: 20200511007). This was a retrospective study obtaining data from hospital’s information system. The requirement for informed consent of patients in this study was waived. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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