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  Table of Contents  
Year : 2019  |  Volume : 37  |  Issue : 1  |  Page : 72-90

Colistin-sparing approaches with newer antimicrobials to treat carbapenem-resistant organisms: Current evidence and future prospects

1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Infectious Diseases, Global Hospital, Chennai, Tamil Nadu, India
3 Department of Pediatrics, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India

Date of Web Publication16-Aug-2019

Correspondence Address:
Dr. Balaji Veeraraghavan
Department of Clinical Microbiology, Christian Medical College, Vellore - 632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_19_215

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 ~ Abstract 

Antimicrobial resistance is on the rise across the globe. Increasing incidence of infections due to carbapenem resistance organisms is becoming difficult to treat, due to the limited availability of therapeutic agents. Very few agents such as colistin, fosfomycin, tigecycline and minocycline are widely used, despite its toxicity. However, with the availability of novel antimicrobials, beta-lactam/beta-lactamase inhibitor-based and non-beta-lactam-based agents could be of great relief. This review covers three important aspects which include (i) current management of carbapenem-resistant infections, (ii) determination of specific types of carbapenemases produced by multidrug-resistant and extensively drug-resistant Gram-negative pathogens and (iii) the currently available novel beta-lactam/beta-lactamase inhibitors and non-beta-lactam-based agents' laboratory findings, clinical outcome and implications.

Keywords: Antimicrobial resistance, colistin, India, NDM, newer antimicrobials, Oxa48-like

How to cite this article:
Veeraraghavan B, Pragasam AK, Bakthavatchalam YD, Anandan S, Swaminathan S, Sundaram B. Colistin-sparing approaches with newer antimicrobials to treat carbapenem-resistant organisms: Current evidence and future prospects. Indian J Med Microbiol 2019;37:72-90

How to cite this URL:
Veeraraghavan B, Pragasam AK, Bakthavatchalam YD, Anandan S, Swaminathan S, Sundaram B. Colistin-sparing approaches with newer antimicrobials to treat carbapenem-resistant organisms: Current evidence and future prospects. Indian J Med Microbiol [serial online] 2019 [cited 2021 Feb 27];37:72-90. Available from:

 ~ Introduction Top

Global spread of carbapenem-resistant organisms (CRO) has become a major public health concern posing challenge for clinicians in management.[1] Due to the limited therapeutic options, morbidity and mortality rates associated with CRO are being increasingly reported. Of the CROs, carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA) and carbapenem-resistant Acinetobacter baumannii (CRAB) are categorized and prioritized as the most urgent threat by the World Health Organization.[1] The key factor driving the surge of CREs is the excessive reliance on carbapenems for the treatment of piperacillin–tazobactam and cefoperazone–sulbactam-resistant Enterobacteriaceae. There is a critical need of developing newer carbapenem-sparing therapies within the beta-lactams group.[2] CREs are now posing a newer threat in the form of colistin-resistant Klebsiella spp.[3]

Notably, molecular mechanisms of resistance contributing for carbapenem resistance in these three clinically important pathogens are diverse. Among CRE, blaKPC, blaNDM and blaOXA48-like are the predominant carbapenemases seen with geographical differences noted with these enzymes.[4],[5] In CRPA, carbapenemase-mediated blaVIM, blaIMP and blaNDM are predominant, followed by non-carbapenemase-mediated mechanisms such as loss of porin, efflux overexpression and derepression of chromosomal AmpC.[6],[7],[8],[9] In CRAB, class D oxacillinases such as blaOXA-23, blaOXA-24, blaOXA-51 and blaOXA-58 are predominant, followed by blaNDM and non-carbapenemases-mediated mechanisms such as efflux pumps and porin loss.[7],[8]

Of all the beta-lactamases with carbapenemase activity identified till date, serine-based beta-lactamases are most commonly seen in Western countries, which was class A carbapenemases blaKPC, first identified in Klebsiella pneumoniae in the US in 1996. Class B (metallo beta-lactamases [MBLs]) and class D (Oxacillinases) carbapenemases are common in Indian subcontinent.[10],[11] Among the MBLs, blaNDM was the common, first identified in 2002 in India and seen in many Gram-negative organisms including non-fermenters. Class D carbapenemases, blaOxa48-like, are predominantly seen in Escherichia coli and Klebsiella spp., but not in non-fermenters.[11] In the global context, blaKPC has been identified as the greatest of all carbapenemases, spread in several parts of the United States and widespread in South and Central America, the Middle East and China; Italy and Greece have highest rates among the European countries.[10] Similarly, MBLs (blaNDM) are widespread in Asian subcontinents (India-epidemic), South East Asian countries, as well as in Denmark, Romania, Poland, Turkey, Greece, France and Belgium.[12] Class D carbapenemases (blaOxa48-like) are prevalent among Indian Subcontinent and some parts of Europe and as well as in France, Spain and Belgium. In the current scenario, blaKPC, blaNDM and blaOXA48-like are the three major carbapenemases contributing for a significant emerging threat across the globe. Other than these, blaVIM, blaIMP in P. aeruginosa and blaOXA-23/24/51/58 in A. baumannii are the MBL and class D carbapenemases commonly reported across different geographical locations respectively.

Due to the alarming rise of carbapenem resistance, management of CRO infections becomes a challenge. Polymyxin is considered as last resort, being increasingly used despite its toxicity. Two groups of polymyxins are currently being used in clinical practice; this includes polymyxin B and polymyxin E (otherwise called as colistin).In vitro susceptibility testing of both colistin and polymyxin B are challenging.[13],[14] These are positively charged peptide molecules which act by binding to the negatively charged lipopolysaccharides (LPS), displacing the magnesium ions leading to loss of cell wall integrity, thereby cell death. Rise in carbapenem resistance leads to increased usage of colistin, which eventually increases colistin resistance. In certain places such as India, Italy and Greece, colistin resistance among carbapenem-resistant K. pneumoniae exceeds 35%.[15]

Colistin resistance occurs due to the changes in the LPS, by replacement of negatively charged phosphate with positively charged L-Ara4N and PetN molecules. This changes the net negative charge of the LPS, thereby preventing the interaction of colistin with LPS, resulting in resistance. LPS modification was studied to be mediated by chromosomal mechanisms, until the mcr-1 (encodes for phosphoethanolamine transferase) identification, which is plasmid mediated. Unlike plasmid-mediated mcr-1, chromosomal-mediated ones are complex and regulated by multiple factors. Genes or pathways involved in colistin resistance vary with each organism.[13] Colistin resistance mechanisms studied among the most clinically important Gram-negative pathogens include K. pneumoniae (mgrB, pmrA/B, phoP/Q, crrA/B/C), P. aeruginosa (pmrA/B, phoP/Q, parR/S, colR/S, cprR/S) and A. baumannii (pmrA/B, lpxA/C/D, lpsB). The presence of multiple mutations in multiple genes triggers the pathways involved in LPS modifications for the incorporation of PetN and L-Ara4N in place of phosphate molecule in LPS. Identification of colistin resistance mechanisms is either by targeted sequencing of multiple genes or by whole genome sequencing technologies, which is cumbersome for resource-limited laboratories.

Handling of colistin challenges involves both laboratory as well as therapeutic management. Laboratory challenges include MIC determination, batch-to-batch variation of colistin, adherence to the microtitre plates and determination of resistance mechanisms.[16] The therapeutic challenge includes high nephrotoxicity and neurotoxicity; optimizing dosage; promotion of resistance during sub-optimal dosage; lack of universal harmonization of dosing units with respect to critically ill individuals; narrow therapeutic window and low mutant prevention concentration.[17] Due to these reasons, colistin is given as a combination therapy with an additional agent to overcome all the aforementioned challenges faced with colistin monotherapy. These can be overcome with the availability of the newer agents.

This review covers three important aspects: (i) current management of carbapenem-resistant infections, (ii) determination of specific types of carbapenemases produced by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative pathogens and (iii) the currently available novel beta-lactam/beta-lactamase inhibitors and non-beta-lactam-based agents' laboratory findings, clinical outcome and implications.

 ~ Current Management Of Carbapenem-Resistant Infections Top

Non-beta-lactam agent-based approach for CRO pathogens with differential spectrum of activity is used. This includes minocycline, tigecycline, fosfomycin and colistin.


Minocycline is an older tetracycline, which acts by inhibiting bacterial protein synthesis. This is one among the few agents available to treat infections due to CRO.[18] Minocycline is available as oral and intravenous (IV) formulations, with the oral form bioavailability being 95% with ideal serum, tissue concentrations and notable central nervous system penetration. Although minocycline is bacteriostatic,in vitro combination testing with meropenem (Mer) or colistin has proven to show synergistic bactericidal effect. Among the three clinically important CROs, minocycline is effective against CRE and CRAB, but not against CRPA as it is intrinsically resistant to tetracycline agents. Therefore, its utility against CRE and CRAB is of interest.

For Enterobacteriaceae, a global 'Tigecycline Evaluation and Surveillance Trial, Antimicrobial Testing Leadership and Surveillance (TEST/ATLAS)' study reported 71.4% of susceptibility for K. pneumoniae, with 52.2% susceptibility against CR-K. pneumoniae (CRKp) in vitro, which is promising.[19] In a study from Southern India, 65% susceptibility to minocycline was noted for NDM and Oxa48-like producing CRKp. In contrast, 12% susceptibility was reported in Detroit, among KPC-producing CRKp.[18] Such high variations were noted among the different geographical locations with different carbapenemase being endemic. A clinical study done in 9 patients with CRKp has shown 67% reasonable clinical cure with minocycline.[20]In vitro activity of minocycline against CRE and CRAB was studied; however, there is limited information to prove its usefulness for clinical management. Further clinical studies and randomised control trial (RCT) should investigate itsin vivo effectiveness against CRE and CRAB.

For A. baumannii, many investigations have been done, including a global multicentric TEST/ATLAS study, which revealed 84.5% susceptibility towards minocycline which was the highest.[19] Another study reported 72.1% and 81.4% susceptibility against A. baumannii in the US and Thailand, respectively.[21] However, limited information is available on its in vitro efficacy against CRAB, as the studies reported the overall susceptibility rates of susceptible and resistant A. baumannii isolates. For A. baumannii infections, minocycline dosage of 100–200 mg twice daily intravenously in combination of colistin has shown bactericidal activity and enhanced effects.[22] A recent review[23] on studies evaluating minocycline with and without combination against MDR-AB has found 78.2% of clinical success and 50%–89% of microbiological success, respectively.[23] This was based on 124 patients with respiratory tract infections, while it needs validation for bacteremic conditions. As a new IV minocycline formulation approved by Food and Drug Administration (FDA) is available, a pharmacokinetic study Acute Care Unit MINocycline is ongoing to determine optimal dosing in critically ill individuals.[24] More clinical and in vitro evaluation of minocycline efficacy against CRAB is required.


Tigecycline has been approved for the treatment of complicated skin and skin structure infections (cSSSI), complicated intra-abdominal infections (cIAI) and community-acquired pneumonia. This broad-spectrum glycylcycline is considered as a bacteriostatic agent and serves as a poor substrate for tetracycline-specific efflux pumps.[25] Tigecycline has potent in vitro activity against CRE (except Proteus spp., Providencia spp. and Morganella morganii) and A. baumannii[26] but not against P. aeruginosa.[25],[27] A SENTRY antimicrobial surveillance study has reported that 96.8%–98% of CRE were susceptible to tigecycline with the MIC50/90 of 0.5/2 μg/ml.[28],[29] On the other hand, tigecycline susceptibility of 74.4% to A. baumannii was demonstrated with MIC50/90 of 2/4 μg/ml, respectively.[28],[29]In vitro testing of tigecycline using different methods produced varying tigecycline MICs against Acinetobacter sp.[30] Notably, a study has reported a ≥4-fold increased tigecycline MIC in A. baumannii using E-test, compared to the reference broth microdilution method.[31] Recently, TEST study reported ≤1.3% of tigecycline resistance in Enterobacteriaceae.[32]

The use of tigecycline in treating CRE bloodstream infection is considered as off-label. Pharmacokinetic limitations including sub-optimal concentration of tigecycline in serum, pulmonary epithelial lining fluid and bone greatly limit its clinical use.[33],[34],[35] Subsequently, tigecycline monotherapy is not recommended owing to its high clinical failure and increased risk of mortality.[36],[37] The FDA issued a warning describing tigecycline-associated mortality risk than other antimicrobials.[38],[39] Thus, tigecycline in combination or high-dose therapy is recommended for treating severe Gram-negative infections. The most common combinations used with tigecycline for treating CRE infections are colistin, carbapenem and aminoglycosides.[40]

There are no RCTs comparing the efficacy of tigecycline alone or in combination in treating severe MDR Gram-negative infections. In general, several studies have investigated the clinical efficacy and safety of tigecycline in treating CRE infection and reported conflicting findings. A systemic review and meta-analysis on the efficacy of tigecycline against CRE infection has reported that tigecycline-based combination therapy are more effective than monotherapy.[41] Further, tigecycline combination therapy was reported with lower mortality than monotherapy.[42] Consistently, tigecycline-based therapy for the treatment of MDR and XDR A. baumannii pneumonia was reported with higher mortality rate.[43]

High dose of tigecycline regimen with the use of an initial dose of 200 mg followed by 100 mg twice daily was reported with improved clinical efficacy and reduced adverse events.[44] This was in line with a phase II randomised trial of hospital-acquired pneumonia, with increased cure rates for patients treated with high-dose tigecycline compared to standard dose in combination with imipenem.[45] A prospective study of thirty patients with severe intra-abdominal infection caused by KPC-producing K. pneumoniae has reported that the combination of high-dose tigecycline with colistin showed lower mortality than the standard dose of tigecycline.[46] In a multicentric observational study including 125 KPC producing K. pneumoniae, significant reduction in 30-day mortality was observed for combinations of tigecycline with colistin and meropenem.[47] Recently, a similar observation was noticed in a retrospective study, including patient with nosocomial CRKp bloodstream infections.[48]


Fosfomycin has been approved by FDA for the treatment of uncomplicated urinary tract infection (UTI). Two different forms of fosfomycin are available for clinical use, fosfomycin calcium for oral use and fosfomycin disodium for IV use. Fosfomycin has a bioavailability of 30%–37%, and approximately, 30%–60% is excreted unchanged in urine.[49] Fosfomycin has a longer half-life of 4–8 h and good distribution in serum, kidney, bladder, lungs, bone and cerebrospinal fluid (CSF).[50],[51],[52] Fosfomycin is considered as the broad-spectrum antibiotic with good pharmacokinetic profile and potentially useful for treating deep-seated infections. However, hypokalemia and hypernatremia given with IV fosfomycin requires monitoring of electrolytes, especially in intensive care unit (ICU) patients.[53]

Fosfomycin has potent bacterial activity against E. coli and Klebsiella spp., and susceptibility to other Enterobacteriaceae was less frequently reported, while A. baumannii is intrinsically resistant to fosfomycin.[49] Fosfomycin lacks cross-resistance to other antimicrobials. Generally, fosfomycin is more active against E. coli (100%) than K. pneumoniae (90.5%).[34] An in vitro testing has reported that 72% of CRE were susceptible to fosfomycin with the MIC50/90 of 8/512 μg/ml.[54]

Recently, IV fosfomycin has been studied extensively and gained much clinical significance in treating MDR Enterobacteriaceae infection. There are no RCTs which are available on the clinical efficacy and safety of fosfomycin, compared to other antimicrobial agents. However, a recent systematic review and meta-analysis reported that there is no difference in clinical and microbiological cure between fosfomycin and other comparator antibiotics.[55] Most of the studies which support the use of IV fosfomycin were from observational studies included with the limited number of patients. Generally, in most of these, fosfomycin was used as a part of combination regimen. The most common dose used for treating severe infection is 4 g IV q 6–8 h and adjusted based on the renal insufficiency.[56] Prospective and retrospective studies have reported the clinical cure, ranging from 50% to 90% and all-cause mortality of 18.3%–40% in patients treated with IV fosfomycin.[57]

A prospective observational study involving 48 critically ill patients were treated with fosfomycin and reported the clinical success and microbiological eradication in 54% and 56% of cases, respectively.[58] Similarly, a multi-centre prospective study reported a clinical cure of 76.8% in ICU patient treated with fosfomycin.[59] A combination of fosfomycin with high-dose doripenem (4 h infusion) resulted in a clinical cure of 61% and microbiological eradication of 70% in healthcare-associated pneumonia/ventilator-associated pneumonia cases infected with CRPA.[60],[61] Moreover, good penetration of fosfomycin into lung tissues anticipated its potential utility in treating MDR pneumonia. A key benefit of fosfomycin is based on the combination with other antimicrobial agents. A multicenter prospective study in 11 ICUs evaluated the combination of fosfomycin with tigecycline and colistin in Europe.[62] This observational study documented the clinical success and microbiological eradication in 56.5% and 43.5% of cases, respectively. Fosfomycin can be a better alternative to the nephrotoxic agents such as aminoglycosides and polymyxin.

 ~ Determination Of Specific Types Of Carbapenemases Produced By Multidrug-Resistant And Extensively Drug-Resistant Gram - Negative Pathogens Top

With the rising trend of carbapenemase-mediated resistance, it is imperative to identify the specific moleuclar mechanisms among GN-ESKAPE pathogens for appropriate therapy and for infection control purposes. In this antimicrobial resistance era, especially for Gram-negative CROs, specific enzyme target testing is must as the spectrum of beta-lactamase (BL)/BL inhibitors (BLI) varies widely. Therefore, it is imperative to determine the specific type of carbapenemases produced by MDR and XDR Gram-negative pathogens. Most of these tests are FDA cleared/Conformité Européenne (CE) marked [Table 1]. Detection is based on two methods in vitro, either by identifying the presence of gene encoding carbapenemases by molecular methods or by identifying enzymatic activity of carbapenemases production by phenotypic tests. However, not majority of these tests can be employed directly on specimens; rather, the isolation of bacterial pathogen is required.
Table 1: Nucleic acid and non-nucleic acid-based assays as point of care testing for detection of carbapenem resistance in Gram-negative organisms

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Molecular-based detection

Multiple studies have reported the nucleic acid amplification-based detection assays to identify genes encoding carbapenemases in the last decade. These tests offer several advantages over culture-based phenotypic assays in terms of rapid turnaround time and definitive identification of carbapenemase gene including variants. In addition, some tests favours the use of direct clinical specimens for screening of carbapenemase genes without culturing the specimens. The details are summarized in [Table 1]. The most common test currently in use is GeneXpert Carba-R, as it identifies all the top five carbapenemases including Oxa48-like variants that are common in Indian settings.

Non-nucleic acid-based tests for carbapenemase detection

Non-nucleic acid-based tests require pure bacterial cultures for carbapenemases' detection. Multiple tests that are being developed and reported are detailed in [Table 1]. In a high-resource laboratory, Accelerate and MALDI-TOF can be used, while in case of resource-limited settings, CarbaNP test can be of use. Notably, CarbaNP is the only rapid test that has obtained CE-in vitro diagnostics certification to be used in clinical settings. However, it has a limitation in detecting Oxa48-like producers which are endemic in India; hence, its utility is reduced. Overall, it is essential to employ any of the reliable and affordable tests, to identify the type of carbapenemase produced by the infected organisms. This would aid in guiding the clinician to choose the right agents for management, to achieve clinical success.

Novel Beta-Lactam/Beta-lactamase Inhibitors and Non-beta-Lactam Agents – Laboratory Findings, Clinical Outcome and Implications

Currently, there are few beta-lactam/beta-lactamase inhibitors and non-beta-lactam-based newer agents undergoing various phases of clinical trial. Novel BL/BLI includes ceftazidime/avibactam (Czd/Avi), aztreonam/Avi, Mer/vaborbactam (Vab), imipenem/relebactam mer/nacubactam and cefepime/zidebactam [Table 2]. Among non-beta-lactam-based agents, cefiderocol, eravacycline and plazomicin are under clinical trials.[80] The current laboratory findings, clinical outcome and its implication of all these agents are detailed as follows.
Table 2: Spectrum of beta-lactam/beta-lactamase inhibitor agent against specific type of beta-lactamases encountered among GN-ESKAPE organisms

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Beta-lactam–beta-lactamase inhibitor agents (stratified based on its activity against class A, B and D carbapenemases)

The present clinically available first-generation BLI are clavulanate, sulbactam and tazobactam. Clinically available BL/BLI agents include amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanate and cefoperazone/sulbactam; but these have a narrow spectrum activity. These agents are active against class A beta-lactamases (SHV, TEM, CTX-M) such as extended-spectrum beta-lactamases (ESBLs) but generally less effective against class A, B and D beta-lactamases with carbapenemase activity.[81] Due to the rising carbapenemase rates, strategies to circumvent these were derived with the use of second-generation BLI that was a non-beta-lactam-based BLI molecule. These are derivatives of diazobicyclooctanes (DBOs) which lacks a beta–lactam-based ring in its structure.[82]

First of these inhibitors, 'Avibactam-Avi' has a broader spectrum of activity than first generation BLIs. Avi potently inhibits class A penicillinases, ESBLs and serine carbapenemases (class A-KPC), but poorly inhibits class C cephalosporinase and some class D oxacillinases.[83] Other DBOs such as relebactam, zidebactam and nacubactam display similar activity to Avi, with relebactam having limited activity against class D Oxa48-like carbapenemases. Importantly, zidebactam and nacubactam also targets penicillin-binding proteins (PBPs) of many Gram-negative bacteria and thus have a beta-lactam enhancer (BLE) activity, in addition to beta-lactamase inhibitor action.[84],[85] Unlike classical BLI like clavulanate, DBOs do not induce intrinsic chromosomally encoded ampC expression under clinically relevant concentrations, which is notable.[85] Subsequent third-generation BLI is also non-beta–lactam-based BLI, which are the boronic acid derivatives, namely Vab (formerly RPX7009).[86] It has an excellent inhibitory activity against serine carbapenemases. The activities of multiple effective BL/BLI combinations and non-BL agents against each class of carbapenemases are discussed below in detail. [Table 3] summarizes the in vitro BL/BLI combinations evaluated against several beta lactamases producing organisms. Clinical studies conducted for these newer agents are detailed in [Table 4].
Table 3: In vitro laboratory studies of all the newer agents considered for colistin-sparing management

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Table 4: Clinical cure and microbiological eradication of colistin-sparing agents, an evidenced from randomised clinical trials/pre-clinical trials

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Beta-lactam/beta-lactamase inhibitors activity against class A carbapenemases (blaKPC)

Class A serine carbapenemases (blaKPC) have the ability to hydrolyse all beta-lactams and are usually not inhibited by the classical first-generation BLIs such as clavulanate, sulbactam and tazobactam. Among the FDA-approved newer combination agents, both Czd/Avi and Mer/Vab are active against KPC producers, with Czd/Avi being the first agent available in the market to treat CRE.[87],[88] Among the agents in various phases of clinical trials, aztreonam/Avi, imipenem/relebactam, ceftaroline/Avi, cefepime/zidebactam, Mer/Vab and Mer/nacubactam, all are active against class A serine carbapenemase (KPC) producers. At present, all the newer agents approved by FDA and agents that are in the pipeline remain highly active against KPC producers. However, these agents will be greatly useful in the United States, South and Central America, where class A serine carbapenemase – blaKPC is endemic.

In vitro efficacy for Mer/Vab and Czd/Avi tested against CRE (KPC producers) revealed overall susceptibility to be 99% and 98.2% with MIC50 as 0.06 μg/ml and 1 μg/ml and MIC90 as 1 μg/ml and 4 μg/ml, respectively.[89] Among the several KPC variants (KPC-2, 3, 5, 6, 9, 18) tested, 93.5% susceptibility was noted for mer/vab. In addition, activity of mer/vab for KPC with AmpC and ESBL coproducers also revealed >90% susceptibility, which is highly promising. Comparatively, MIC90 of mer/vab was four times more potent than MIC90 of czd/avi and >64 times compared to carbapenem alone (Mer). Another study reported similar profile with >90% susceptibility against KPC producers.[90],[91]

Beta-lactam/beta-lactamase inhibitors activity against class B carbapenemases (Metallo beta–lactamases – blaNDM, blaVIM, blaIMP etc.,)

Among all the newer BL/BLI, aztreonam/Avi is active against MBLs-producing organisms. Aztreonam is the only monobactam agent approved by FDA and has the advantage of being a poor substrate and less hydrolysed by MBLs, hence a suitable target against MBL producers when coupled with an active BLI. Avi is a potent inhibitor of many beta-lactamases such as ESBLs, AmpC and class A carbapenemases. Since carbapenemases are often coproduced with any of the latter enzymes, aztreonam's activity is retained against MBL and hence effective. Two global studies evaluating in vitro efficacy of aztreonam/Avi has been done. Studies have found MIC50 and MIC90 of MBL-positive Enterobacteriaceae to be 0.12 μg/ml and 1 μg/ml, respectively.[92],[93] Another study[94] showed MIC50 and MIC90 to be 0.5 μg/ml and 1 μg/ml, respectively, for Enterobacteriaceae producing MBL + Oxa-48 + AmpC + ESBL + Original spectrum beta-lactamases (OSBLs). However, the number of isolates tested was minimal (n = 23). Coproducers of MBL (NDM) plus class A carbapenemases (KPC) showed MIC50 and MIC90 to be 0.12 μg/ml and 1 μg/ml, respectively. Similarly, coproducers of MBL (NDM) with class D carbapenemases (Oxa48-like) were shown to have MIC50 and MIC90 as 0.5 μg/ml and 4 μg/ml, respectively.[95],[96],[97],[98] These studies shows promising results with excellentin vitro activity of aztreonam/Avi combinations against wide range of CRE. However, these findings needs to be validated on testing large number of isolates carrying MBL with other diverse beta-lactamases genes.

In case of Czd/Avi, very limited in vitro activity was found against MBL producers. Susceptibility rates of 2.8% and 9.2% were observed for MBL producing P. aeruginosa and Enterobacteriaceae, respectively.[94] No other agent such as ceftolozane/tazobactam, imipenem/relebactam ceftaroline/Avi and Mer/Vab were found to have in vitro activity against MBL-producing organisms.

Beta-lactam/beta-lactamase inhibitors' activity against class D carbapenemases (Oxacillinases)

Oxacillinases seen among Enterobacteriaceae (blaOxa48-like)

Among the several newer agents, Czd/Avi is active against some class D oxacillinases such as blaOxa48-like.In vitro studies evaluating the efficacy, 'International Network for Optimal Resistance Monitoring (INFORM) study' have found this agent to be highly active against Oxa48-like producing Enterobacteriaceae with >90% susceptibility and MIC50 and MIC90 to be 0.5 and 1 μg/ml, respectively.[94] Similarly, aztreonam/Avi was also found to have high in vitro activity against Oxa48-like carbapenemases. Surveillance study 'INFORM' has reported activity of aztreonam/Avi against Oxa48-like producers with several beta-lactamases coproduced, and MIC ranged from 0.5 to 1 μg/ml. However, the numbers of isolates tested are less, and it requires validation by testing against large number of isolates.[94]

WCK 4282 is a novel high-dose combination of cefepime 2 g and tazobactam 2 g intended to be administered every 8 h through 90-min infusion. The relative stability of cefepime towards several β-lactamases, high-dose tazobactam and longer infusion endows the combination potent activity against ESBL Enterobacteriaceae including those resistant to piperacillin–tazobactam and cefoperazone–sulbactam.[96] Typically, WCK 4282 is 8–16 times more active than piperacillin–tazobactam against strains expressing multiple ESBLs or combination of ESBLs + class C β-lactamases. This combination is active against certain carbapenem-resistant OXA-48/181 and KPC expressing Enterobacteriaceae. WCK 4282 is well placed to be developed as workhorse antibiotic in high ESBL organisms prevalent nosocomial settings.[97]

This combination has been developed for providing most suitable first-line empiric β-lactam-based therapy for the management of mixed ESBL and ESBL plus class C β-lactamase expressing Enterobacteriaceae. With the reasonable coverage of KPCs and OXA 48/181 expressing pathogens, it would provide a carbapenem sparing therapy. This conserves the KPC-specific newer agents for the management of KPC infections.

Oxacillinases seen among Acinetobacter baumannii (blaOXA-23, 24, 58 like

In vitro activity of Czd/Avi and aztreonam/Avi against CRAB producing class D oxacillinases such as blaOXA-23, blaOXA-24 and blaOXA-58 is limited, which is a concern since CRAB has limited effective agents for management. Diminished activity of 12% susceptibility rates against blaOXA-23-producing A. baumannii has been reported.

Cefepime/zidebactam exhibits selective and high affinity Gram-negative PBP2 binding and as well acts as an inhibitor of certain class A and class C β-lactamases. The PBP2-binding activity of zidebactam has been demonstrated in A. baumannii, P. aeruginosa and Enterobacteriaceae.[85],[98] Combining zidebactam with PBP3-binding cefepime results in concomitant inactivation of multiple PBPs leading to rapid cidality. The synergistic inactivation of PBPs continues to operate even in the presence of cefepime hydrolysing and zidebactam non-inhibitable β-lactamases such as MBL, OXA-48/181 and A. baumannii derived class D β-lactamases.

Based on the novel β-lactam enhancer mechanism, a PK/PD susceptibility break point of 64 μg/mL is proposed. Based on this therapeutic scope, it would cover a wide range of Gram-negative pathogens expressing all the known resistance mechanisms. In this regard, the type of resistance mechanism expressed by a Gram-negative pathogen is of little therapeutic consequence. Using the existing high-dose cefepime break point, an in vitro susceptibility of 44% was reported in A. baumannii.[96] However, based on proposed break point, it is expected to cover >95% of A. baumannii strains irrespective of type of OXA-type carbapenemase (Oxa23/24/58) produced.

Non–beta-lactam/beta-lactamase inhibitor-based agents


Cefiderocol is a novel catechol-substituted siderophore cephalosporin, which has a potent activity against MDR Gram-negative organisms, including CRE, CRPA and CRAB.[139] Cefiderocol acts by binding to PBPs and thereby inhibiting cell wall synthesis, like other beta-lactams. However, its uniqueness lies in the way it enters the bacterial periplasmic space as a result of its siderophore-like property, and it also has enhanced stability against beta-lactamases. Although the chemical structure is similar to third (Ceftazidime)- and fourth (Cefepime)-generation cephalosporins, it is stable against AmpC, ESBLs and carbapenemases. Preliminary testing of isolates such as K. pneumoniae, E. coli, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, and Serratia marcescens were all found to have an MIC of ≤1 μg/ml.[140] However, subsequent testing against class A carbapenemase-producing isolates (KPC) was reported with MIC of ≤4 μg/ml, class B carbapenemases with MIC of ≤2 μg/ml, including some isolates coharbouring class D carbapenemases such as Oxa48-like.[141]

Against CRE, several in vitro studies have evaluated the activity of cefiderocol against carbapenem non-susceptible Enterobacteriaceae, with MIC50 and MIC90 to be 1 μg/ml and 4 μg/ml, respectively. Cefiderocol activity against CRPA was found to have lowest MIC50/MIC90 such as 0.25/1, 0.12/1 and 0.12/2 μg/ml, respectively, as reported by various studies. In contrast, activities against CRAB have reported with differential MIC50 and MIC90 profile. MIC50/MIC90 of CRAB were found to be 0.5/2 μg/ml and 0.12/1 μg/ml as reported by two studies, while it was 0.25/8 μg/ml against MDR A. baumannii. As of now, cefidercol is the only promising agent with excellent in vitro activity against class D oxacillinase-producing A. baumannii.[114],[113],[36],[89]

[Table 3] summarizes the overall in vitro activities reported by various studies for all the novel antimicrobial agents. [Table 4] summarizes the clinical studies conducted with these novel agents.


Eravacycline is a novel fully synthetic fluorocycline, consisting of tetracycline core scaffold with modifications in the tetracycline D ring. This helps in enhanced in vitro activity against Gram-positive and Gram-negative organisms. It also overcomes certain acquired tetracycline resistance mechanisms such as efflux pumps and ribosomal protection mechanisms. IV eravacycline is approved for clinical use against cIAIs in adults. Unlike tetracyclines, eravacycline exhibits bacteriostatic activity in addition to bactericidal activity in vitro against certain strains of E. coli, K. pneumoniae and A. baumannii. P. aeruginosa is not susceptible to eravacycline.

Eravacycline has broad-spectrum activity against ESBL, AmpC and carbapenemase including KPC, metallo-β-lactamase and OXA-type carbapenemase (Oxa48-like in Enterobacteriaceae, OXA-23, 24, 51, 58 like in A. baumannii)[142] A potent activity was demonstrated against CRE, MDR A. baumannii and CRAB. Compared to carbapenem resistance, a 2-fold lower eravacycline MIC was seen in carbapenem-susceptible Enterobacteriaceae and A. baumannii.[143] An in vitro study demonstrated that eravacycline is 2–4-fold more active than tigecycline against CRE and CRAB.[117]

A Canadian national surveillance (CANWARD) study reported 2–4-fold lower MIC90 for eravacycline than tigecycline against Enterobacteriaceae.[143] Subsequently, a largest global surveillance study on A. baumannii reported two-fold lower MIC90 for eravacycline (2 μg/ml) than tigecycline (4 μg/ml).[144],[145] Interestingly, potent activity of eravacycline was demonstrated against OXA-23/24/51/58 producing A. baumannii with MIC90 of 1 μg/ml. Eravacycline has the potential to become useful for the treatment of CR Acinetobacter spp for which the treatment options are limited. Upregulation of efflux or reduced permeability contributes for increased eravacycline MIC. In K. pneumoniae, overexpression of oqxA/B, macA/B and the efflux pump regulator gene ram A resulted in the development of eravacycline heteroresistance and resistance. A four-fold increased MIC was observed in K. pneumoniae with oqxA/B and macA/B upregulation.[146]

Murine thigh infection models have described that area under the plasma concentration-time curve (AUC)/MIC is the best predictor of eravacycline PK/PD.[147],[148] A mean AUC/MIC magnitude associated with 1 log10 of bacterial killing were 27.97 and 32.6, respectively. In addition, the tissue distribution of eravacycline in rabbit model showed good concentrations in lung tissues, liver and bile, urine and renal cortex.[149] In addition, a PK study on bronchopulmonary disposition of IV eravacycline in healthy controls demonstrated higher levels in epithelial lining fluid (6 fold) and alveolar macrophages (50 fold) than plasma.[150] These evidences suggest that eravacycline in patient with respiratory infections would be beneficial. However, animal lung infection model is not available for better understanding of eravacycline PK/PD.

Recently, eravacycline has been approved for the treatment of cIAIs by FDA. The recommended dose is 1 mg/kg body weight, administered every 12 h by IV infusion over 60 min in patient without hepatic impairment. The Cmax concentration was attained within 1 h of infusion and the mean half-life elimination of 20 h.[151] A plasma concentration of 2125 ng/ml can be achieved with the recommended dose on day 1.[152]

In the clinical trials (IGNITE 1 and IGNITE 4), a good clinical response was reported in patients treated with eravacycline, as compared to Mer/ertapenem.[134],[135] However, preliminary results of IGNITE 2 and 3 showed poor bioavailability and reduced efficacy of eravacycline in complicated UTI (cUTI), as compared to levofloxacin.[153] Collectively, available evidence showed potent efficacy of eravacycline in treating cIAI, but not for cUTI.

In light of intrinsic limitations of dose limiting toxicity/tolerability, risk of therapy associated resistance development as well as PK-PD inadequacies, non-β-lactam agents such as colistin/polymyxin, aminoglycosides, tetracyclines and fosfomycin would never be able to occupy the prime position as preferred therapeutic agents for life-threatening infections. Such therapies would always remain adjunct therapies to be used in combination.


Plazomicin is a novel semi-synthetic parental aminoglycoside, which acts as bacterial protein synthesis inhibitors, and displays dose-dependent bactericidal activity. Plazomicin has a structural modification enhancing its stability against interaction with the classical aminoglycoside-modifying enzymes such as aminoglycoside O-nucleotidyltransferases, aminoglycoside acetyltransferase and aminoglycoside phosphotransferase while it becomes resistant against 16S rRNA methyl transferase producers. Plazomicin greatly inhibits CRE, but less active against P. aeruginosa and A. baumannii.[154] Recently, a surveillance study reported the potent activity of plazomicin against 99% of CRE.[119] However, plazomicin is not effective against NDM producers as it also cocarries 16S rRNA methyl transferases in the same plasmid.[155]

Plazomicin was approved by FDA for cUTI including acute pyelonephritis (AP). The recommended dose of plazomicin in patient without renal impairment is 15 mg/kg IV q24 h infused over 30 min for 4–7 days. Plazomicin is mostly unmetabolized in the body, and the renal clearance was estimated to be 4.19 L/h that accounts for 86.9% of plazomicin total clearance.[120] Two clinical trials have reported the non-inferiority of plazomicin to Mer and levofloxacin in treating cUTI and AP [Table 4]. However, FDA rejected the use of plazomicin indication for BSI, and the clinical trial[121] was terminated after 2 years of recruitment. FDA stated that the CARE study does not provide substantial evidence on the effectiveness of plazomicin for the treatment of BSI. Because of the small sample size, no formal hypothesis testing was performed for this trial.[138] CARE's primary endpoints were a combination of all-cause mortality and significant disease-related complications at 28 days. In this study, plazomicin was associated with significantly better overall outcomes than colistin. Collectively, these data suggest that plazomicin could offer an important new treatment option for patients with serious infections due to carbapenem-resistant Enterobacteriaceae.

 ~ Conclusion Top

It is now evident that there are multiple novel agents approved and in the pipeline for approval for clinical use against drug-resistant infections. However, very few agents are available that would suit Indian settings with respect to the molecular mechanisms of antimicrobial resistance. It is now possible that with the available resources and advancements, implementing rapid detection of carbapenemases followed by targeted therapy would improve the likely chances of clinical outcomes. This would also aid in preventing inappropriate use of newer agents where it is not indicated. To conclude, as we are in the post-antibiotic era, judicious use of these newer antimicrobial agents must be monitored.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 ~ References Top

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  [Table 1], [Table 2], [Table 3], [Table 4]


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