Carbapenem Resistance among Enterobacterales Intrinsically Resistant to Polymyxin B in Southern BrazilAbstract
Carbapenem-resistant Enterobacterales are a recognized health threat worldwide, due to high morbidity and mortality rates. After the COVID-19 pandemic, some geographic regions faced an increase in NDM-producing as well as NDM and KPC-co-producing Enterobacterales. Some of these species are intrinsically resistant to polymyxins, limiting significantly therapeutic options. This retrospective study analyzed 347 Enterobacterales resistant or intermediate to meropenem recovered between 2019 and 2023 from patients attending in a tertiary care hospital. The presence of carbapenemases and the susceptibility to ceftazidime-avibactam were assessed. Among members of Morganellaceae, 41.7% were resistant to meropenem while 58.2% were intermediate; most isolates (93.2%) produced NDM. On the other hand, among Serratia spp., resistance to meropenem was higher (78.7%) and isolates produced predominantly KPC (90.6%). Resistance to CAZ-AVI was not observed among isolates producing serine-carbapenemases. Our results reinforce the need for new therapeutic options to treat infections caused by gram-negative bacilli producing metallo-beta-lactamases, especially those intrinsically resistant to polymyxins.
Keywords:
carbapenemase; Enterobacterales; intrinsic resistance; polymyxins.
HIGHLIGHTS
Most of carbapenem resistant Morganellaceae are NDM-producer.
Morganellaceae resistant to ceftazidime-avibactam cannot me treated with polymyxins.
INTRODUCTION
Carbapenem-resistant Enterobacterales (CRE) are classified by the World Health Organization (WHO) as critical priority, representing a major threat to public health due to limited treatment options, high disease burden (mortality and morbidity) and growing resistance trends, with few or no promising therapeutic candidates. Infections by these pathogens can also be particularly difficult to prevent and are highly transmissible [1].
Indeed, to establish an effective therapy against CRE is a nightmare in some clinical situations, despite the recent approval of new generation of beta-lactam and beta-lactamase inhibitors, such as ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, among others [2,3]. The emergence and dissemination of Enterobacterales carrying blaNDM, solely or in combination with genes coding serine-carbapenemases, mainly KPC, are of particular concern as the metallo-beta-lactamases (MBL) are not inhibited by most new beta-lactam and beta-lactamase antibiotics [4-6]. In these situations, polymyxins-centered schemes are still of clinical importance, despite the recognized toxicity of polymyxins [7-10]. However, some microorganisms are intrinsically resistant to polymyxins, such as members of Morganellaceae (Morganella spp., Proteus spp., Providencia spp.), as well as Serratia spp.[11].
In Brazil, besides imipenem-cilastatin-relebactam (IMI-REL) recently approval [12], ceftazidime-avibactam (CAZ-AVI) is the only new combination of beta-lactam and beta-lactamase inhibitor in clinical use. Isolates producing KPC are endemic in Brazil, but a few studies have indicated that the country is facing an epidemiological change considering carbapenemases, with isolates producing NDM becoming more common, mainly after the COVID-19 pandemic. Moreover, it has been observed an important emergence of Enterobacterales coproducing metallo-beta-lactamases along with KPC, [13-15]. In these situations, treatment options are, indeed, scarce. The association of CAZ-AVI and aztreonam has shown promising results in vivo. However, its use is limited in lowand middle-income countries due to the cost of CAZ-AVI. Hence, polymyxins would be required. However, whenever intrinsically resistant species are considered, no treatment option may be available at all.
Therefore, we aimed to assess the occurrence of carbapenemases among Enterobacterales intrinsically resistant to polymyxins, which are resistant or intermediate (susceptible with increased exposure) to meropenem. Moreover, we determined their susceptibility to CAZ-AVI.
MATERIAL AND METHODS
This is a retrospective, cross-sectional study carried out in a tertiary hospital in southern Brazil. It included Enterobacterales resistant (R) or intermediate (I; susceptible with increased exposure) to meropenem (MEM) recovered from inpatients attending the hospital from 2019 to 2023. Isolates were identified by MALDI-TOF (Vitek-MS, bioMérieux) and the susceptibility profile to meropenem was evaluated by disk diffusion with results interpreted according to the European Committee on Antimicrobial Susceptibility Tests (EUCAST) [16].
Susceptibility to CAZ-AVI was assessed by disk diffusion [17] for isolates recovered from 2021, as it was the year the drug was introduced into the hospital routine. Besides, isolates identified as Serratia sp. had their minimum inhibitory concentration (MIC) to tigecycline (TGC) evaluated by broth microdilution [18].
The presence of carbapenemase genes was evaluated by real-time multiplex polymerase chain reaction with high-resolution melting (HRM-qPCR) and/or immunochromatographic assay with NG-Test® CARBA 5 (NG Biotech). HRM-qPCR searched for blaKPC, blaGES, blaNDM-1, blaIMP, blaVIM and blaOXA-48-like genes, as previously described [19], while NG-Test® CARBA 5 targeted KPC, OXA, VIM, IMP and NDM.
RESULTS
Overall, 3,495 Enterobacterales resistant or intermediate to meropenem were recovered. Of these, 347 (9.9%) were intrinsically resistant to polymyxins and most of them (70.3%; 244/347) were identified as Serratia spp. (243 S. marcescens and 1 Serratia sp.) (Table 1). The remaining 103 isolates included the genus of the Morganellaceae family (Table 2), identified as follows: 42 Morganella morganii, 33 Proteus spp. (32 P. mirabilis and 1 Proteus sp.) and 28 Providencia spp. (12 P. rettgeri, 15 P. stuartii and 1 Providencia sp.). Clinical samples included blood (7.2%), specimens from respiratory tract (43.8%), urine (23.6%), rectal swab (10.7%) and others (14.7%).
Susceptibility profile of Serratia spp. to meropenem, tigecycline and ceftazidime-avibactam.
Among members of Morganellaceae, 58.2% (60/103) were intermediate and 41.7% (43/103) were resistant to meropenem. Overall, most isolates (93.2%; 96/103) produced MBL, regardless susceptibility to meropenem (I or R), alone or in combination with serine-carbapenemases: NDM (90.3%; 93/103), NDM + VIM (1.0%; 1/103), NDM + IMP + GES (1.0%; 1/103) and NDM + OXA-48-like (1.0%; 1/103). Only 2.9% of these isolates produced KPC (3/103), while 4 isolates (3.8%) had no carbapenemases detected: 7.0% (3/43) among isolates resistant to meropenem and 2.3% (1/60) among those susceptible with increased exposure (I) to the antibiotic.
On the other hand, among Serratia spp., resistance to meropenem was higher (78.7%; 192/244). Most isolates produced carbapenemases (97.5%; 238/244), predominantly KPC (90.6%; 221/244). NDM was produced by 5.3% (13/244), and 4 isolates (1.6%) co-produced NDM and KPC.
Regarding susceptibility to CAZ-AVI, in 2021, clinicians demanded 31 susceptibility tests, for which 41.9% (13/31) were resistant in vitro. In 2022, among 65 isolates evaluated, resistance to CAZ-AVI was observed in 50.8% (33/65). Finally, in 2023, 54.3% (38/70) of the isolates were resistant. All isolates were NDM producers.
Tigecycline MICs among S. marcescens were >0.5 µg/mL in 71.3% (149/209) of the isolates evaluated. Among them, 75.2% (112/149) were resistant to meropenem.
DISCUSSION
Polymyxins-centered therapies have been reintroduced in the therapeutic pipeline for CRE treatment. The occurrence of resistance to the new combinations of beta-lactam and beta-lactamase inhibitors, is mainly due to the dissemination of isolates producing MBL which, along with economic issues, sustain the clinical relevance of polymyxins [7,9,15,20]. However, for CRE that are intrinsically resistant to polymyxin B this is not a valid option [11].
Our data reinforces those treating infections caused by Morganellaceae family is a nightmare, as CAZ-AVI is not an option because the expressive production of NDM among these isolates. The use of the association of CAZ-AVI with aztreonam is limited by cost issues in many regions. Such data corroborate with previous studies where NDM production is the main mechanism of carbapenem resistance in Proteus, Morganella and Providencia [21,22]. Results of the Study for Monitoring Antimicrobial Resistance Trends (SMARTS) demonstrated a predominance of NDM-1, compared to KPC-2, in species of the Morganellaceae family, especially M. morganii (42.9%) [22]. In another study with the latter species, resistance to carbapenems was associated mainly with the presence of MBL, produced by 86.1% of carbapenem resistant isolates, being blaNDM the most prevalent gene (86.6%), mainly P. stuartii (61.5%), followed by P. mirabilis (20%) [21].
On the other hand, among isolates collected as part of a global surveillance study from 2012 to 2014 163 Enterobacterales encoding MBL variants were detected, but only 4 isolates intrinsically resistant to polymyxin B had blaNDM-1 gene (2 S. marcescens, 1 P. mirabilis and 1 P. rettgeri). According to the EUCAST, only 2.8% of NDM positive Enterobacterales were susceptible to meropenem, while tigecycline and colistin retained greater activity against these isolates (61.1% and 86.1%, respectively), however, most isolates were not intrinsically resistant to polymyxins [16].
Furthermore, we had several NDM producers with intermediate susceptibility to meropenem, requiring increased exposure to the antimicrobial to obtain an effective treatment. The association most used is meropenem and polymyxin B [23-25], which would not be effective in cases of bacteria intrinsically resistant to Polymyxin B. Our data corroborate with other data from Southern Brazil, were meropenem MIC50 was 8 µg/mL (susceptible, increased exposure) among NDM producers [26]. Besides, the first NDM-1 isolate in Brazil, in 2013, was a P. rettgeri susceptible to meropenem (MIC = 0.75 µg/mL) [27]. A recent study from Western Romania showed MICs ≥4 µg/mL (I or R to meropenem) in isolates of P. mirabilis, P. stuarti and P. rettgeri [21]. Besides these species, M. morganii with intermediate susceptibility to meropenem have been also reported [28]. However, our data was not compatible with those of other international studies, where NDM producers have high resistance to carbapenems, although such studies evaluate, in the majority, species such as K. pneumoniae and E. coli [22].
Tigecycline activity varies from insufficient in Proteus spp., M. morganii and Providencia spp. to variable in other species, such as Serratia spp. Furthermore, these bacteria do not present a cut-off value for this antibiotic, which must be evaluated by epidemiological cut-off value (ECOFF) [29]. Despite that, considering the limited therapeutic options, there is a demand from the Hospital Infection Control Commission requesting that tigecycline be tested for Serratia sp. due to limited therapeutic options. Even though, most of the S. marcescens evaluated had high MICs for TGC.
Carbapenemase-producing S. marcescens and Morganellaceae are increasingly being identified in nosocomial infections. Despite that, these bacteria are not under systematic genomic surveillance yet. A study using a combination of whole-genome sequencing and conjugation experiments demonstrated significant rates of resistance gene transfer, highlighting their role as reservoirs of resistance determinants, which emphasizes the need to strengthen infection control measures [30].
The emergence of these bacteria requires innovative therapeutic strategies. Recent research emphasizes a variety of new therapies, including novel antibiotics, combination therapies, and alternative approaches such as phage therapy and nanotechnology to treat infections caused by multior pan-drug resistant bacteria. These advancements aim to overcome the limitations of existing treatments, essentially focused on antibiotics, which are increasingly scarce, and provide effective solutions against resistant strains [31, 32]. The use of bacteriophages through phage therapy offers a targeted approach with high specificity. Besides, the integration of nanoparticles with phage therapy enhances efficacy and could improve diagnostic capabilities [31]. Additionally, novel compounds like antimicrobial peptides and antisense oligonucleotides are being explored [32]. While these new therapies show promise, the ongoing challenge of antibiotic resistance underscores the need for continued research and development in this critical area. Results of studies such ours reinforce the need of innovative therapies, as new effective antibiotics are unlikely in the short and medium term.
In addition to new therapeutic approaches, research and development of diagnostic tools to determine resistance quickly is extremely necessary, allowing the opportune and effective monitoring and treatment of infections caused by these bacteria. Rapid colorimetric methodologies are widely used to determine the presence of carbapememases. Carba NP test and its derivatives, such as the Carba NP-direct test and the Blue-Carba test, have shown 100% sensitivity and specificity in detecting carbapenemase production in various bacteria. However, they may present subjective results, since the interpretation is operator dependent [33]. Besides, NG-Test Carba 5 and Goldstream K-Set methods demonstrated high sensitivity for detecting major carbapenemase genes in Enterobacterales [34]. On the other hand, new methodologies have been proposed using MALDI-TOF MS method, where bacteria are incubated with the carbapenem and additives like EDTA or phenylboronic acid. The presence of specific waveform peaks indicates carbapenemase activity, in addition to differentiating the type of carbapenemase, providing results in 4h [35].
Machine learning algorithms, such as random forest and support vector machines, enhance the accuracy of MALDI-TOF MS by analyzing peak features, achieving high sensitivity and specificity in distinguishing carbapenem-resistant strains [36].
Bioinformatics platforms can be implemented for monitoring antimicrobial resistance, such as abritAMR Platform, with was developed as an ISO-certified bioinformatics tool for antimicrobial resistance gene detection. It utilizes NCBI's AMRFinderPlus, achieving 99.9% accuracy and 100% specificity in identifying resistance alleles across 1500 bacteria (https://doi.org/10.1038/s41467-022-35713-4). This plataform streamlines bioinformatics processes and is publicly accessible for laboratory use. Besides, the CZ ID Pipeline is an open-source, cloud-based platform that integrates microbial and antimicrobial resistance gene detection using metagenomic next-generation sequencing (mNGS) [37]. It leverages the Comprehensive Antibiotic Resistance Database, facilitating broad detection in clinical and environmental samples.
Our data highlights the need for effective therapeutic options to treat infections caused by NDM-producing Enterobacterales, mainly among those for which polymyxin-centered therapy is not an option because of intrinsic resistance. Although the combination of CAZ-AVI plus aztreonam has a promising role in these cases, the cost related to the use of CAZ-AVI restricts considerably its widespread use.
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Funding:
This research received no external funding.
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Institutional Review Board Statement: Not applicable.
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Informed Consent Statement:
Not applicable.
Acknowledgments:
The authors would like to thank the Laboratory Diagnostic Service of the Hospital de Clínicas de Porto Alegre (SDLab/HCPA) and the bacterial resistance research laboratory (LABRESIS/HCPA).
Use of Generative Artificial Intelligence
The authors declare that no generative artificial intelligence (AI) or AI-assisted technologies were used to generate or modify the scientific content of this manuscript, including the conception of the study, data collection, data analysis, interpretation of results, or creation of original text, figures, tables or graphical abstracts, apart from routine tools for spelling, grammar checking and reference management that do not create original scholarly content.
Data Availability Statement:
Research data are only available upon request for corresponding author.
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Editor-in-Chief:
Paulo Vitor Farago
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Associate Editor:
Sinvaldo Baglie
