|Year : 2018 | Volume
| Issue : 3 | Page : 334-343
Newer β-Lactam/β-Lactamase inhibitor for multidrug-resistant gram-negative infections: Challenges, implications and surveillance strategy for India
Balaji Veeraraghavan1, Agila Kumari Pragasam1, Yamuna Devi Bakthavatchalam1, Shalini Anandan1, V Ramasubramanian2, Subramanian Swaminathan3, Ram Gopalakrishnan2, Rajeev Soman4, OC Abraham5, Vinod C Ohri6, Kamini Walia6
1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Infectious Diseases, Apollo Hospital, Chennai, Tamil Nadu, India
3 Department of Infectious Diseases, Global Hospital, Chennai, Tamil Nadu, India
4 Department of Infectious Diseases, PD Hinduja Hospital, Mumbai, Maharashtra, India
5 Department of Medicine (Unit -1), Christian Medical College, Vellore, Tamil Nadu, India
6 Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi, India
|Date of Web Publication||14-Nov-2018|
Dr. Kamini Walia
Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi
Source of Support: None, Conflict of Interest: None
Antimicrobial resistance (AMR) is a major public health concern across the globe, and it is increasing at an alarming rate. Multiple classes of antimicrobials have been used for the treatment of infectious diseases. Rise in the AMR limits its use and hence the prerequisite for the newer agents to combat drug resistance. Among the infections caused by Gram-negative organisms, beta-lactams are one of the most commonly used agents. However, the presence of diverse beta-lactamases hinders its use for therapy. To overcome these enzymes, beta-lactamase inhibitors are being discovered. The aim of this document is to address the burden of AMR in India and interventions to fight against this battle. This document addresses and summarises the following: The current scenario of AMR in India (antimicrobial susceptibility, resistance mechanisms and molecular epidemiology of common pathogens); contentious issues in the use of beta-lactam/beta-lactamase inhibitor as an carbapenem sparing agent; role of newer beta-lactam/beta-lactamase inhibitor agents with its appropriateness to Indian scenario and; the Indian Council of Medical Research interventions to combat drug resistance in terms of surveillance and infection control as a national response to AMR. This document evidences the need for improved national surveillance system and country-specific newer agents to fight against the AMR.
Keywords: Antimicrobial resistance, carbapenemase, India, newer beta-lactam/beta-lactamase inhibitor, surveillance
|How to cite this article:|
Veeraraghavan B, Pragasam AK, Bakthavatchalam YD, Anandan S, Ramasubramanian V, Swaminathan S, Gopalakrishnan R, Soman R, Abraham O C, Ohri VC, Walia K. Newer β-Lactam/β-Lactamase inhibitor for multidrug-resistant gram-negative infections: Challenges, implications and surveillance strategy for India. Indian J Med Microbiol 2018;36:334-43
|How to cite this URL:|
Veeraraghavan B, Pragasam AK, Bakthavatchalam YD, Anandan S, Ramasubramanian V, Swaminathan S, Gopalakrishnan R, Soman R, Abraham O C, Ohri VC, Walia K. Newer β-Lactam/β-Lactamase inhibitor for multidrug-resistant gram-negative infections: Challenges, implications and surveillance strategy for India. Indian J Med Microbiol [serial online] 2018 [cited 2020 May 29];36:334-43. Available from: http://www.ijmm.org/text.asp?2018/36/3/334/245392
| ~ Introduction|| |
β-lactams are one of the most commonly used antimicrobial agents in the management of infectious diseases. Structural modifications being made with the existing β-lactams is a strategy to overcome the resistance mechanisms and increase the spectrum of activity. However, evolving β-lactamases variants overcome these structural modifications. Among the β-lactamases, a hierarchy of original spectrum β-lactamases (OSBLs), extended spectrum β-lactamases (ESBLs), AmpCs and carbapenemase exist. This explains the substrate specificity that confers resistance to each of these agents. β-lactamases are classified into four major classes (A, B, C and D) depending on their hydrolytic profile with β-lactams.,, Enzymatic inactivation of β-lactams by β-lactamases has emerged as a significant clinical threat as they are diverse and can rapidly disseminate. Antimicrobial resistance (AMR) spread is mainly driven by the mobile genetic elements (MGEs) that carry AMR determinants across different bacterial pathogens through integrons, insertion elements, transposons and plasmids.,, To circumvent the emergence of resistance, novel and broad-spectrum β-lactamase inhibitors (βLIs) are being developed in combination with β-lactams to restore their activity.
Among the βLIs, three generations have been developed for clinical utility. The first generation includes the classical βLIs such as clavulanate, sulbactam and tazobactam which have a β-lactam ring in their structure to exert a competitive inhibition-based strategy. Second generation βLIs are the non-β-lactam (βL)-based βLIs that lack a β-lactam ring in their structure. These are derived from diazabicyclooctanes and include avibactam, relebactam, zidebactam and nacubactam. The third generation includes non-βL/βLIs-vaborbactam, a derivative of the boronic acid compound. The properties of these aforementioned inhibitors and their substrate profiles are summarised in [Table 1].
At present, commercially available Food and Drug Administration (FDA) approved βL/βLIs are ampicillin/sulbactam, amoxicillin/clavulanate, ticarcillin/clavulanate, piperacillin/tazobactam and novel agents include ceftolozane/tazobactam, ceftazidime/avibactam and meropenem/vaborbactam. Agents in the pipeline are imipenem-cilastatin/relebactam and aztreonam/avibactam.
Current antimicrobial susceptibility profile, resistance mechanisms and molecular epidemiology of Gram-negative bacteria in India
Among the infections caused by Gram-negative bacteria (GNB), the most common drug-resistant organisms are Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae) and non-fermentors (Pseudomonas aeruginosa, Acinetobacter baumannii). ESBL rates are as high as 70% in E. coli and K. pneumoniae. Carbapenem resistance (CR) rates were found significantly varied with different organisms (10%, 40%, 25% and 70% for E. coli, K. pneumoniae, P. aeruginosa and A. baumannii, respectively). This wide variation (from 10% to 70%) in CR poses a challenge in the choice of empiric therapy., The hypermucoviscous phenotype of K. pnuemoniae further complicates the management perspective, as it is not only highly virulent but also resistant., In addition, colistin non-susceptibility among CR-GNB is a worrisome issue. A high colistin resistance rate of up to 40% is seen among CR-K. pneumoniae, while up to 10% in CR-E. coli, and <5% each of CR-P. aeruginosa and CR-A. baumannii, respectively. This pose further challenges in the indication and choice for combination therapy [Table 2].
|Table 2: Current antimicrobial susceptibility profile, molecular resistance mechanisms, common mobile genetic elements and lineages observed in India|
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Similar to wide-ranging susceptibility profile among the common clinical pathogens, the AMR mechanism also varies for each bacterial pathogen. Among the ESBLs, (i) blaSHV, blaTEM, blaOXA-1 (inhibitor resistant [IRT] enzyme) and blaCTX-M-15 are common in E. coli and K. pneumoniae, (ii) blaVEB in P. aeruginosa and (iii) blaTEM and blaPER in A. baumannii prevails. While among carbapenemase, (i) blaNDM and blaOXA-48 like in E. coli and (ii) blaOXA-48like and blaNDM in K. pneumoniae, (iii) blaVIM, blaNDM and blaIMP in P. aeruginosa (other than efflux and porin) and (iv) blaOXA-23/24like and blaNDM in A. baumannii are common [Table 2]. Diverse profile in terms of resistance mechanisms and its determinants further challenge the choice of empiric therapy for a successful clinical outcome. Therefore, it is essential to understand the rates and type of resistance being encountered for a particular geographical location to enable appropriate choice of βL/βLI agents.
MGEs play a major role in acquisition and dissemination of AMR [Table 2]. These include plasmids, transposons, integrons and insertional elements. Among carbapenem-resistant E. coli, IncF plasmids are common (93%) followed by Col (43%) and IncL plasmids (40%). In K. pneumoniae, ColKP3 is common (44%) followed by IncF and IncR (24%). Similarly, IncP plasmids are observed in P. aeruginosa. Among P. aeruginosa and A. baumannii integrons play a major role in carbapenemase dissemination. Class I integrons are involved in the dissemination of blaVIM, blaNDM, blaIMP and blaOXA-23/24-like in P. aeruginosa and A. baumannii, respectively. In addition A. baumannii has a strong association of ISAba1 insertional element with blaOXA-23/24 like [Table 2].
In addition, knowledge on the epidemiology and genotypes of drug-resistant clones circulating in a geographical setting is of great importance. AMR determinants act as 'king makers' in influencing a particular genotype/clone to dominate locally, regionally and globally. Therefore, certain AMR determinants are lineage and/or clonal specific. In India, data pertaining to the clonal types (genotypes) or lineages are limited. Recently, ICMR has initiated the mapping of the isolates. The early data show that so-called 'international high risk clones' carrying AMR genes are found in India. These include (i) ST131 in E. coli, (ii) ST357, ST235, ST244, ST233 and ST111 in P. aeruginosa and (iv) ST457, ST195 in A. baumannii. While in K. pneumoniae, ST253 (international clone carrying blaKPC) is not seen as of yet in India. However, certain Indian specific predominant clones are also identified. These include (i) ST167 in E. coli, (ii) ST14 and ST231 in K. pneumoniae, (iii) ST664, ST1047, ST823 and ST773 in P. aeruginosa and (iv) ST862 in A. baumannii. The details described are summarised in [Table 2].,
Considering the high burden of AMR in the Indian setting, it is challenging to decide the appropriate empirical therapy especially when third-generation cephalosporins are resistant. The choice varies between βL/βLIs and a carbapenem. The general consensus is to use a βL/βLIs when the infection is less severe and to prefer a carbapenem for more severe infections. βL/βLIs agents have been the preferred agents even for directed therapy for ESBL producers, in a bid to conserve higher class of drugs such as carbapenems, tigecycline and colistin. The choice of carbapenems for ESBL infections as recommended agents has been based on scanty evidence and in countries like India where ESBL infections are endemic, clinicians are always on the look-out for carbapenem sparing agents.
Contentious issues in the use of β-lactams/β-lactamase inhibitors as carbapenem sparing agent in treating extended spectrum β-lactamase producers: Experience from piperacillin/tazobactam
ESBLs are generally inhibited by tazobactam, although production of multiple ESBLs and co-production of AmpC β-lactamase may limit the effectiveness of P/T combination. Additional contentious issues are (i) occurrence of inhibitor resistance enzymes (e.g. TEM-IRT), (ii) inoculum effect that may overwhelm the inhibitor activity, during severe infections where the bacterial population is high and (iii) false-negative ESBL detection when AmpC is produced [Table 3].
|Table 3: Contentious issues in β-lactam/β-lactamase inhibitor as carbapenem sparing agent in extended spectrum β-lactamases producers: Experience from piperacillin/tazobactam|
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Before 2010, Clinical and Laboratory Standards Institute (CLSI) guidelines suggested that confirmed ESBL-positive isolates are to be reported as resistant to all penicillins, cephalosporins and aztreonam; and not committed about βL/βLI. In 2010, CLSI breakpoints for many of these agents including extended spectrum cephalosporinase were lowered to enhance the detection of non-susceptibility and preclude the need for ESBL confirmatory testing (CLSI 2010, M100-S20). Indeed, CLSI has a higher ceftazidime and cefepime breakpoints than those of EUCAST and there is a common suggestion not to routinely test for ESBLs from both the CLSI and EUCAST expert group on AMR.
Over the years, multiple observational studies demonstrated the non-inferiority of P/T to carbapenem in treating ESBL infection. The use of P/T was prevalent for ESBL infections till recently when the MERINO trial showed that P/T is inferior to carbapenems for serious infections even though minimum inhibitory concentration (MIC) were in the susceptible range that predicted clinical success.
Based on the recent findings, expert opinion suggests ESBL testing and report susceptibility in conjunction with the latest revised breakpoints. Thus, ESBL negative with a susceptible MIC range would guide clinical success. Alternatively, even if βL/βLI is susceptible, when a third-generation cephalosporin is resistant, carbapenem are preferred. This is because, ESBL can be masked by the co-production of AmpC; moreover, a high inoculum effect and the presence of blaOXA-1 co-production may compromise βL/βLI effectiveness.
Other challenges include (i) optimal dosing regimen of P/T against ESBL producers, wherein a different dosing of P/T at 4.5 g q6h is followed to treat ESBL infection, not the licensed dose of 4.5 g q8h, (ii) time above the MIC is the important determinant of the activity of β-lactams, and increasing the time above the MIC substantially decreases mortality and (iii) impact of different resistant mechanisms on P/T susceptibility have been proposed; CTX-M-15 producing Enterobacteriaceae and blaOXAβ-lactamase harbouring E. coli are more resistant in comparison to blaCTX-M-14 (ESBL) producers [Table 3].
Current experience with food and drug administration approved newer β-lactams/β-lactamase inhibitor
Most of the currently available βLIs are potentially active against Class A β-lactamase, remaining ineffective against Metallo β-lactamase and blaOXA-48 like producers. A surveillance study has documented the potent in vitro activity of ceftazidime/avibactam against ESBLs, AmpC and carbapenemases (blaKPC, blaGES and blaOXA-48-like alone or multiple) producing Enterobacteriaceae in all combinations, but not active against metallo-β-lactamase. The effectiveness of these newer βL/βLI against each of the molecular mechanisms are summarised in [Table 4]. Clinical interpretative breakpoints provided by CLSI is summarised in [Table 5].
|Table 4: New β-lactam/β-lactamase inhibitor and its spectrum of activity against multi-drug resistant Enterobacteriaceae, Pseudomonas spp. and multi-drug resistant Acinetobacter spp.|
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|Table 5: Clinical interpretative criteria of newer β-lactam/β-lactamase inhibitors from Clinical and Laboratory Standards Institute guideline 2018|
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In K. pneumoniae, a recent in vitro study demonstrated that ceftazidime-avibactam remains highly active against carbapenem-resistant hypervirulent epidemic clone ST11. In addition, a potent in vitro activity of ceftazidime-avibactam against OXA-48 producers, in the absence of ESBL co-production has been demonstrated. However, emerging resistance to ceftazidime-avibactam was reported in CTX-M-14 and OXA-48 co-producing K. pneumoniae strains, and a KPC-3 variant containing D179Y mutation also confers resistance to ceftazidime-avibactam. Further, an interplay between increased efflux of AcrAB and OqxAB pumps and loss of porins OmpK35/36 in K. pneumoniae contributes to the ceftazidime-avibactam resistance.
In P. aeruginosa, ceftazidime-avibactam remains active against hyper-producing AmpC (chromosomal) P. aeruginosa with alterations in OprD or drug efflux. However, Ceftolozane-tazobactam appears to be more potent than ceftazidime-avibactam against AmpC producing P. aeruginosa., Yet, in vivo emergence of ceftolozane-tazobactam resistance in a cases with multidrug-resistant (MDR) P. aeruginosa pneumonia has been reported. Notably, temocillin non-susceptible OXA-48 producers are known to be non-susceptible to ceftolozane.
This is the first FDA approved carbapenem-based βL/βLI. Vaborbactam restores the activity of meropenem against Class A and Class C β-lactamase. It does not enhance the activity of meropenem against metallo β-lactamase or OXA-48 producers. This combination is not effective against AmpC producing and OprD mutant of P. aeruginosa. In K. pneumoniae, the combination OmpK36 inactivation and an increased blaKPC gene copy number contribute for reduced susceptibility to meropenem-vaborbactam.
Recent studies related to the newer β-lactams/β-lactamase inhibitor agents in the pipeline
Aztreonam-avibactam was demonstrated to be superior, inhibiting OXA-48, MBLs, ESBLs, AmpC and KPC producers.,, This combination restores susceptibility of aztreonam against dual carbapenemase-producing Enterobacteriaceae including metallo β-lactamase and OXA-48. In India, OXA-48 is a carbapenemase produced by an increasing number of carbapenemase-producing Enterobacteriaceae, with Klebsiella spp., being the predominant pathogen. Of the blaOXA-48 variants, blaOXA-181 appears to be unique to India. In addition, clonal expansion of E. coli ST38 carrying chromosomally integrated blaOXA-48 was also described. Aztreonam-avibactam can be more effective than ceftazidime-avibactam in treating infection caused by NDM and OXA-48 co-producers. However, the number of in vitro and in vivo studies are limited, and as well yet to be FDA approved.
Imipenem-cilastatin/relebactam is another novel carbapenem based β-lactamase inhibitor. Relebactam, a non-β-lactam serine β-lactamase inhibitor was designed to specifically inhibit Class A and C β-lactamase. The addition of relebactam to imipenem demonstrated good inhibitory activity against KPC and ESBLs producing K. pneumoniae and carbapenem-resistant P. aeruginosa that lack OprD and co-expressing AmpC β-lactamase. In particular, imipenem-relebactam has demonstrated potent in vitro activity against the most common KPC variants KPC-2 and KPC-3., Increased MIC to imipenem-relebactam was documented in K. penumoniae producing AmpC and porin OmpK35/36 mutations. In K. penumoniae, inactivation of OmpK3 porin confers resistance to imipenem-relebactam and meropenem-vaborbactam combinations. However, the carbapenem/βLI including meropenem-vaborbactam and imipenem-relebactam exhibited no activity against OXA-48 producers and/or metallo-β-lactamase producing Gram-negative bacilli.
From the literature, it can be derived that the newly available βL/βLI effectiveness will largely depend on the appropriate indications. It has a great impact on class A and C β-lactamases producing Gram-negative organisms which are predominantly seen in North America and European countries. However, for Indian setting, these newer βL/βLI agents may be useful against ESBL producers, but not for carbapenemase producers (as NDM and OXA-48 like are predominant). Further, we do have OXA-1 (Inhibitor resistant enzyme) (up to 80% in E. coli), 16S rRNA methyltransferases (pan aminoglycoside resistance conferring enzyme) up to 80% in MDR K. pneumoniae and MDR A. baumannii is noted, which may limit its effectiveness (Unpublished data, V. Balaji) [Table 6].
|Table 6: New β-lactam/β-lactamase inhibitor to India specific Gram-negative organism, will it be beneficial?|
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The effectiveness and best clinical outcomes of empirical therapy with newer βL/βLI can be achieved only with good regional AMR surveillance on molecular information regarding OSBLs, ESBLs, AmpCs, carbapenemases and non-enzymatic mechanisms (porin and efflux) prevalence. The same holds true for targeted therapy also.
Augmenting Indian council of medical research strategy to focus on antimicrobial resistance surveillance for better diagnosis, patient management (empiric and targeted therapy) and molecular epidemiology for local and regional infection control
The available FDA approved newer βL/βLI are useful to treat Class A and C β-lactamase producing organisms and not useful for Class B and D which is widely prevalent. With blaNDM and blaOXA-48like predominating in our country, it is imperative to determine the MIC and to identifying the β-lactamase classes produced by the infecting organism for the appropriate management. This approach facilitates targeted therapy, thereby reducing misuse of available antimicrobials thus contributing to our efforts to combat drug-resistant infections.
To respond national AMR crisis in India, Indian Council of Medical Research (ICMR) in 2012, initiated surveillance of six pathogenic groups and by constituting 6 nodal centres and 20 regional centres. One of the key objectives of the network was to use evidence to guide treatment strategies thereby rationalising antimicrobial use. Establishment of surveillance network was followed by launching a nationwide antimicrobial stewardship programme (AMSP). Having achieved greater success in its first phase [Table 7], the network is now moving to the accelerated phase, for the next 5 years, wherein the focus would be on in improving diagnostic stewardship and infection control. Moving on from phenotypic characterisation and realising the importance of monitoring MICs for better therapeutic outcomes, the network emphasises on the determination of carbapenem MIC and micro broth dilution based MIC determination for colistin isolates, irrespective of the anatomical sites. This would be coupled with molecular characterisation of ESKAPE pathogens to formulate appropriate empirical treatment guideline addressing appropriate indication for newly available βL/βLI drugs. Necessary trainings have been conducted and will continue to form part of capacity building efforts to train the regional labs for technical competency for the complete molecular characterisation of the MDR pathogens.
|Table 7: Consolidating basic and broader strategy with change to focused AMR surveillance (Indian Council of Medical Research) for better diagnostic, patient management (empiric therapy, targeted therapy) and molecular epidemiology for hospital infection control|
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In the next phase of ICMR AMR programme, the impetus would be on moving towards in-depth understanding of molecular mechanisms of resistance, clonality and transmission dynamics. Necessary steps have been initiated towards a revision of Standard Operating Protocol of laboratory diagnosis, next edition of standard treatment guidelines based on current evidence, and expanding the activities under the hospital infection control and AMSPs being undertaken by the network hospitals. Regulation of antibiotics and its misuse in settings outside of health-care continues to be a cause of serious worry. ICMR is working with the relevant stakeholders and respective departments of the government of India to reduce the colistin use in therapy and altogether ban its use as a growth promoter in livestock and poultry. To this effect, a collaborative effort has been initiated with FAO and NEIVDI to establish AMR network for susceptibility testing and molecular characterisation of veterinary pathogens. For the same, a program on integrated surveillance has been initiated.
Unlike in the past, there is now plenty of evidence available from the country which throw light on not only trends and patterns but allows us to monitor the MICs and mechanisms of resistance from key locations. The challenge in the years ahead would be to expand this capacity to other health-care institutions and also use this evidence to create a national treatment strategy to prevent abuse and misuse of antimicrobials as part of the antimicrobial stewardship effort.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]