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 ~  Abstract
 ~ Introduction
 ~ Methodology
 ~ Results
 ~ Discussion
 ~ Conclusion
 ~  References
 ~  Article Figures

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  Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 38  |  Issue : 3  |  Page : 313-318
 

Expected plazomicin susceptibility in India based on the prevailing aminoglycoside resistance mechanisms in Gram-negative organisms derived from whole-genome sequencing


1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of General Medicine (Unit.V), Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission22-Aug-2020
Date of Decision01-Sep-2020
Date of Acceptance01-Oct-2020
Date of Web Publication4-Nov-2020

Correspondence Address:
Dr. Balaji Veeraraghavan
Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_20_384

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 ~ Abstract 


Background: Aminoglycoside resistance is a growing challenge, and it is commonly mediated by the aminoglycoside-modifying enzymes (AMEs), followed by 16S rRNA methyl transferase. Plazomicin, a novel aminoglycoside agent approved by the Food and Drug Administration for complicated urinary tract infections is proven to overcome resistance mediated by AMEs but not due to 16S rRNA methyl transferase (16SRMTases). We undertook this study to predict the efficacy of plazomicin in India based on the antimicrobial resistance profile derived from whole-genome sequencing (WGS). Methodology: A total of 386 clinical isolates of Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii subjected to WGS were screened for aminoglycoside-resistance mechanisms such as AMEs and 16SRMTases and its association with carbapenemases. Results: AMEs was present in all E. coli, A. baumannii and in 90% of K. pneumoniae. In addition, up to 47% of E. coli and 38% of K. pneumoniae co-carried 16SRMTases with AMEs genes. However, A. baumannii showed 87% of isolates co-harbouring 16SRMTase. bla NDM, bla Oxa-48-like and bla Oxa-23-like were the most predominant carbapenemases in E. coli, K. pneumoniae and A. baumannii, respectively. Notably, 48% of NDM-producing E. coli and 35% of Oxa-48-like producing K. pneumoniae were identified to co-harbour AMEs + RMTAses, where plazomicin may not be useful. Conclusion: Overall, 53%, 62% and 14% of carbapenemase-producing E. coli, K. pneumoniae and A. baumannii harbours only AMEs, indicating the role of plazomicin use. Plazomicin can be used both for ESBLs as “carbapenem-sparing agent” and carbapenemase producers as “colistin-sparing agent.” For optimal use, it is essential to know the molecular epidemiology of resistance in a given geographical region where plazomicin empirical therapy is considered.


Keywords: 16S rRNA methyl transferases, aminoglycoside-modifying enzymes, aminoglycosides, carbapenemases, India, plazomicin, susceptibility


How to cite this article:
Pragasam AK, Jennifer S L, Solaimalai D, Muthuirulandi Sethuvel DP, Rachel T, Elangovan D, Vasudevan K, Gunasekaran K, Veeraraghavan B. Expected plazomicin susceptibility in India based on the prevailing aminoglycoside resistance mechanisms in Gram-negative organisms derived from whole-genome sequencing. Indian J Med Microbiol 2020;38:313-8

How to cite this URL:
Pragasam AK, Jennifer S L, Solaimalai D, Muthuirulandi Sethuvel DP, Rachel T, Elangovan D, Vasudevan K, Gunasekaran K, Veeraraghavan B. Expected plazomicin susceptibility in India based on the prevailing aminoglycoside resistance mechanisms in Gram-negative organisms derived from whole-genome sequencing. Indian J Med Microbiol [serial online] 2020 [cited 2020 Nov 24];38:313-8. Available from: https://www.ijmm.org/text.asp?2020/38/3/313/299843





 ~ Introduction Top


India is considered as an epicentre of antimicrobial resistance (AMR) where multidrug-resistant Gram-negative bacterial infection remains a public health threat, as the bacteria evolves with multiple new modes of molecular resistance mechanisms.[1] Continuous evolution of betalactamases-mediated resistance has limited the utility of beta-lactam-based agents for the management of infections. This led to the search of alternative agents such as aminoglycosides, another potent broad spectrum, bactericidal antimicrobial similar to beta lactams.[2],[3] However, resistance to aminoglycosides has emerged by means of classical aminoglycoside-modifying enzymes (AMEs). These include aminoglycoside phosphoryl transferase (APH), acetyl transferase and nucleotidyl transferase.[4],[5] Until 2010, AMEs was the only resistance mechanisms reported with differential resistance spectrum to each of the aminoglycoside agent [Figure 1]. Later in 2010, the emergence of 16S-ribosomal-RNA-methyl-transferases (16S-RMTases) conferring resistance virtually to all aminoglycoside agents has been identified. Till date, ten different RMTases, namely armA, rmtA to rmt H and npmA have been identified in Enterobacterales and non-fermentors.[6] Compared to AMEs, emergence of 16S-RMTases has severely affected the utility of aminoglycosides.[7],[8],[9],[10],[11]
Figure 1: Aminoglycoside resistance spectrum by various aminoglycoside-modifying enzymes and 16S rRNA methyl transferase against amikacin, gentamicin, tobramycin and plazomicin. Boxes-colored red indicates resistance conferred by the respective aminoglycoside-modifying enzymes. AAC: Aminoglycoside acetyl transferase, AAD: Aminoglycoside adenylate transferase, APH: Aminoglycoside phosphoryl transferase, ANT: Aminoglycoside nucleotidyl transferase

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Plazomicin, a new aminoglycoside approved for the clinical use by the Food and Drug Administration (FDA) in 2018 for complicated urinary tract infections (cUTIs) and limited or no alternative treatment options.[12],[13] Plazomicin offers an advantage in dosage as intravenous 30 min infusion once daily.[14] It demonstrated activity against Gram-negative bacteria, including strains that express the wide range of AMEs.[15] However, it is not active against bacteria that produce 16S-RMTases and/or strains those expresses efflux pumps.[16],[17],[18] Plazomicin has demonstrated potentin vitro activity against Enterobacterales with MIC90 being ≤1 μg/ml (except Proteus mirabilis and Morganella morgannii) that was below the susceptible breakpoint cutoff set by FDA, which is ≤2 μg/ml.[19] Notably, plazomicin exhibited lessin vitro activity against the problematic nosocomial pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii (MIC90: 128 μg/ml).

We undertook this study to determine the aminoglycoside resistance profile among ESBL and carbapenemase (especially blaNDMand blaOxa-48-like) producing organisms. This would aid in predicting the expected plazomicin susceptibility in India. The objectives of this study were to determine the aminoglycosides molecular-resistance mechanisms (AMEs and 16S-RMTases) and its association with carbapenemase producers from whole-genome sequencing (WGS) for Escherichia coli, Klebsiella pneumoniae and A. baumannii and to estimate the expected efficacy of plazomicin for empirical aminoglycoside choice in ESBL and carbapenemase-producing E. coli, K. pneumoniae and A. baumannii in India.


 ~ Methodology Top


Phenotypic testing

A total of 383 clinical isolates of E. coli (n = 129), K. pneumoniae (n = 129) and A. baumannii (n = 128) collected from different clinical specimens between 2016 and 2020, published previously and are available in the public domain.[20] In addition, some of the genomes that have been submitted in the Genbank has been assigned accession number, however will be released public within 1 year.[21] These isolates have been previously characterised for the susceptibility profile and molecular resistance mechanisms as mentioned below. Antimicrobial susceptibility testing for different classes of antibiotics such as cephalosporin (cefotaxime- 0 μg and ceftazidime – 30 μg); β-lactam/β-lactamase inhibitors (piperacillin/tazobactam – 100/10 μg), carbapenems (imipenem – 10 μg and meropenem – 10 μg) and aminoglycosides (amikacin – 30 μg, gentamicin – 10 μg, and tobramycin – 10 μg) was performed for all the isolates by Kirby–Bauer disk-diffusion method according to Clinical Laboratory Standards Institute guidelines 2018.[22] Isolates resistant to aminoglycosides (amikacin ≤16 mm, gentamicin ≤12 mm and tobramycin ≤12 mm) were included in the study for further characterisation. Genomic DNA was isolated from the bacterial cultures grown in the blood agar medium overnight at 37°C using Qiagen kit extraction method, as per the manufacturer's instruction. Following which, WGS was performed using IIon Torrent PGM sequencer (Life Technologies, Carlsbad, CA) using 200 bp read chemistry. Sequencing was carried out as per the protocol recommended by Life Technologies. Raw reads were assembled de novo using Assembler SPAdes software version 4.4.0.1 in Torrent suite server version 4.4.3.[23] The genomes were annotated using Patric database (Pathosystems Resource Integration Centre-https://www.patricbrc.org). Following the WGS, Res-Finder was used to identify the acquired antibiotic resistance genes.[24] The threshold for identifying a match between the input genome and a gene in the ResFinder database was set to be 80% identity. This in silico screening strategy is employed to determine the prevalence and to estimate the genetic diversity of the molecular determinants of antibiotic resistance in clinical isolates. The genes conferring resistance to aminoglycosides (AMEs and RMTases) and carbapenemases (blaNDM, blaIMP, blaKPC, blaVIM and blaOXA-48-like) were segregated, and analysis was carried out to calculate the association between multiple antibiotic-resistant determinants. The ratio of the co-expression of carbapenemase gene variants and AMEs along with the presence or absence of 16S-rRNA methylases was assessed to predict the expected efficacy of plazomicin.


 ~ Results Top


A total of 386 clinical isolates of E. coli, K. pneumoniae and A. baumannii previously subject to WGS were screened for AMR mechanisms. Of the E. coli (n = 129), K. pneumoniae (n = 129) and A. baumannii (n = 128) genomes analysed, 57% (n = 74), 78% (n = 100) and 92% (n = 118) were carbapenem resistant (CR) [Figure 2]a and [Figure 2]b. In CR-E. coli (n = 74), NDM was the most predominant carbapenemase (76%), followed by co-producers of NDM + Oxa-48 like (15%) and Oxa-48-like (9%). In CR-K. pneumoniae (n = 100), Oxa-48-like (57%) was common, followed by NDM + Oxa-48-like (27%), NDM (15%) and KPC (1%). In contrast, Oxa-23like was present in all the CR-A. baumannii isolates (except one), within which 35% were identified as co-producers of NDM + Oxa-23-like. Further, detailed analysis of aminoglycoside resistance mechanisms has been carried out with the special emphasis on association with carbapenem-resistance mechanisms.
Figure 2: (a and b) represents the distribution of antimicrobial resistance profile of carbapenem resistant and susceptible E. coli and K. pneumonia producing aminoglycoside-modifying enzymes and 16S rRNA methyl transferase. (c and d) represents the profile of aminoglycoside-modifying enzymes and 16S rRNA methyl transferase against specific carbapenemase producers such as NDM, OXA-48-like and NDM + OXA-48-like in E. coli and K. pneumonia. AAC: Aminoglycoside acetyl transferase, AAD: Aminoglycoside adenylate transferase, APH: Aminoglycoside phosphoryl transferase, ANT: Aminoglycoside nucleotidyl transferase

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Among CR-E. coli, all isolates had one or more AMEs, with 40% carrying double, followed by single (38%) and triple (21%) AMEs. Of which, aac, aad (19.1%, n = 14) was the predominant combination with aac(6')lb-cr, aac(3)-lla and aadA5 accounted for 34.6% of isolates. These combinations confer resistance to all aminoglycoside agents amikacin, gentamicin and tobramycin (in addition to cross resistance to fluoroquinolone). Unlike CR-E. coli, 10% of CR-K. pneumoniae did not harbour any AMEs, with 60% carrying dual AMEs, followed by 24% of triple and 16% of single AMEs. In particular, aac, aad (32.2%, n = 29) were the predominant AMEs seen in K. pneumoniae in which aac (6')-Ib, aadA2 was the frequently encountered combination (44.8%). This confers broad-spectrum resistance to amikacin, gentamicin and tobramycin. Similar to CR-E. coli, all CR-A. baumannii harboured one or more AMEs in all the isolates. Of which, 58% harboured single AMEs, followed by triple (35%) and double (8%) AMEs, with aph (7.6%, n = 9) being the common gene, with 56% aph(3“)lb, aph(3”)vl, aph(6”)ld combination were observed.

Overall, among the CR isolates, AMEs were abundantly seen in multiple combinations. Subset analysis of AMEs carrying 16SRMTases revealed a significant proportion of CR organisms co-carries both. Notably, 47% of E. coli and 38% of K. pneumoniae co-carried 16SRMTases with AMEs genes. However, A. baumannii showed a significantly higher proportion of isolates co-harbouring RMTase, being 87%. Although a substantial population co-carried RMTases along with AMEs, difference in the genes encoding RMTases varies with each of the organisms. For instance, rmtB (95%) was the predominant RMTases in E. coli. While in Klebsiella spp, armA was common (up to 70%), followed by rmtF and rmtB. A. baumannii produced exclusively armA and no other variants of RMTases.

Overall, the most common AMEs in Indian isolates are 30% of both aad, aac in E. coli and K. pneumoniae, followed by 82% of aac(6') in A. baumannii. Among aac, AAC(6') is the predominant gene conferring resitance to amikacin, gentamicin, tobramycin with 24%, 25% and 18% each in E. coli, K. pneumoniae and A. baumannii, respectively. Notably, APH variants in E. coli seem to be less and predominantly seen in A. baumannii, with highest being aph(3') and aph(6'). Very few isolates harbored ant(2') and ant(4') variants. Remarkably, aac(2') and aph(2')-IVa (commonly seen in Providencia spp and Enterococci) that confers resistance to all aminoglycosides including plazomicin is not seen in this study collection. Resistance profile of P. aeruginosa was not examined due to limited data availability and impact of efflux pump-mediated drug resistance, a common phenomenon seen in this organism.

Association of aminoglycoside-modifying enzymes and 16S rRNA methyl transferase with carbapenemase

In E. coli, all CR isolates harbored one or more genes encoding for AMEs, with 47% co-harbored 16S RMTases. Interestingly, RMTases distributions were found to be high in isolates carrying NDM + Oxa-48-like (73%) and 48% in NDM [Figure 2]c. This observation was in contrast to Klebsiella spp, wherein 38% of isolates carried RMTases in addition to AMEs in all the isolates. However, RMTases distributions were found to be high in isolates carrying NDM (47%), NDM + Oxa-48-like (37%) and 35% in Oxa-48-like [Figure 2]d. Significantly, the presence of only AMEs (14%) was less in A. baumannii, compared to AMEs with 16S RMTases (85%). The association of presence of carbapenemase-encoding genes with AMEs showed NDM producers are associated with 50% AMEs in E. coli and 53% of Oxa-48 like in K. pneumoniae. The distribution of the different combinations of aminoglycoside modifying enzymes and rRNA methyl transferases in E. coli and K. pneumoniae is given in [Figure 3]. This result highlights the utility of plazomicin in the management of carbapenemase producers, especially the giant killer – NDM and Oxa-48-like producing E. coli and K. pneumoniae. To surmise, 53%, 62% and 14% of carbapenemase-producing E. coli, K. pneumoniae and A. baumannii harbours only AMEs, indicating the role of plazomicin susceptibility in this subset. Conspicuously, maximum plazomicin utility is predicted in CR-K. pneumoniae with 62% carrying only AMEs.
Figure 3: Venn diagram representing the presence of combinations of aminoglycoside modifying enzymes and rRNA methyl transferase in E. coli and K. pneumoniae. AAC: Aminoglycoside acetyl transferase, AAD: Aminoglycoside adenylate transferase, APH: Aminoglycoside phosphoryl transferase, ANT: Aminoglycoside nucleotidyl transferase

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 ~ Discussion Top


Aminoglycosides are bactericidal and concentration-dependent antimicrobial agents that have been used for the clinical management for many decades.[25] Although multiple agents are available with different spectrum of activity, the pharmacokinetic properties of all aminoglycosides are very similar. Binding to serum protein is very low and is usually <10%.[26] Furthermore, 40% of the total drug in the body accumulates in the kidney making it an ideal agent for the management of urinary tract infections.[27] While in systemic circulation, serum concentration is decreased, because of the large volume of distribution and hence is not preferred much for sepsis and/or any other intra-abdominal infections.[28] Similarly, the penetration rates into epithelial lining fluid ranges from 32% to 52% of the serum concentration, making it less effective for its utility in pneumonia.[27] However, aminoglycoside-based combination therapy improves the clinical outcome in these conditions.

Studies have identified that the plasmid-mediated 16S RMTases exhibiting a strong linkage with multidrug-resistant phenotypes. Among the ESBLs, TEM, SHV, and CTX-M were the most frequently encountered with 16S RMTases.[5],[6],[29] Similarly, among carbapenemases, NDM is highly associated with 16S RMTases, with vast majority of rmtB in E. coli and armA in K. pneumoniae.[9],[30],[31] However, very limited information is available on Oxa-48-like producers, except one report of NDM + Oxa-48-like co-carriage with 16S RMTases.[32] Recently, a study from US reported overall plazomicin susceptibility of 95%, 56% and 50% of KPC, NDM and Oxa-48-like producers.[33] Similarly, a study from the UK reported 95% of the pan-aminoglycoside-resistant isolates harbouring at least one RMTases, which is significantly higher.[9] However, in the present study, we predict the plazomicin efficacy to be around 53% against NDM-producing E. coli and 47% and 60% against NDM and Oxa-48-like producing K. pneumoniae, respectively. As this prediction is based on the genomic information, furtherin vitro testing will confirm these findings.

In the era of multidrug resistance, plazomicin's availability necessitates its judicious use. Plazomicin could be used both as “carbapenem-sparing agents” for ESBL producing organisms with AMEs and/or as “colistin-sparing agents” for carbapenemase-producing organisms with AMEs. However, its use as carbapenem-sparing agents must be selective with appropriate indications, especially with AMEs being positive and devoid of 16SRMTases. This study analysis reveals resistance mechanisms profile derived from WGS and maximum utility of plazomicin for organisms causing cUTI and other infections.

Although the clinical trial “CARE” study has documented the efficacy of plazomicin in treating CR infections, no molecular resistance mechanisms have been described.[34] Further, the clinical benefits of plazomicin against the carbapenemase producers largely depend on the prevailing resistance mechanisms of AMEs and 16S RMTases-producing organisms present in that particular geographical location. Therefore, it is essential to know the molecular epidemiology of resistance when plazomicin empirical therapy is considered.

Limitation of this study is that, it is based on the whole-genome sequence information; the mere presence of resistance genes does not necessarily substantiate the expression of genes. Therefore, in vitro-based phenotypic susceptibility of plazomicin against these collection must be performed when plazomicin is available in India to confirm the study findings.


 ~ Conclusion Top


This study highlights the utility of plazomicin in an Indian setting with high multidrug-resistance rates. Wherein, 52% of NDM-producing E. coli and 65% of Oxa-48like producing K. pneumoniae identified to harbour AMEs, indicating plazomicin use. However, it is imperative to generate a local cumulative antibiogram and its associated AMEs profile with 16S RMTases, as it varies across different geographical locations. This will help the clinician to precisely choose plazomicin use for its maximum utility. Given the pharmacokinetic-pharmacodynamic profile of plazomicin, it is an ideal choice for cUTI; however, no clinical data are available for other infections.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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