Indian Journal of Medical Microbiology Home 

[Download PDF]
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

Balaji Veeraraghavan1, Agila Kumari Pragasam1, Yamuna Devi Bakthavatchalam1, Shalini Anandan1, Subramanian Swaminathan2, Balasubramanian Sundaram3,  
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

Correspondence Address:
Dr. Balaji Veeraraghavan
Department of Clinical Microbiology, Christian Medical College, Vellore - 632 004, Tamil Nadu


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.

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 2020 Jul 13 ];37:72-90
Available from:

Full Text


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

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

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}

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}

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}{Table 4}

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.


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.


1World Health Organization. Antimicrobial Resistance: Global Report on Surveillance. Geneva, Switzerland: World Health Organization; 2014.
2Harris PN, Tambyah PA, Paterson DL. B-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: Time for a reappraisal in the era of few antibiotic options? Lancet Infect Dis 2015;15:475-85.
3Nagvekar VC, Modi T, Singh S. Colistin resistance: A growing threat. Crit Care Update 2019;30:21.
4Logan LK, Weinstein RA. The epidemiology of carbapenem-resistant Enterobacteriaceae: The impact and evolution of a global menace. J Infect Dis 2017;215:S28-36.
5Iovleva A, Doi Y. Carbapenem-resistant Enterobacteriaceae. Clin Lab Med 2017;37:303-15.
6Patel PK, Patel TS, Kaye KS. Pseudomonas aeruginosa – Difficult to outmanoeuvre. Indian J Med Microbiol 2018;36:301-2.
7Pragasam AK, Veeraraghavan B, Anandan S, Narasiman V, Sistla S, Kapil A, et al. Dominance of international high-risk clones in carbapenemase-producing Pseudomonas aeruginosa: Multicentric molecular epidemiology report from India. Indian J Med Microbiol 2018;36:344-51.
8Pragasam AK, Veeraraghavan B, Nalini E, Anandan S, Kaye KS. An update on antimicrobial resistance and the role of newer antimicrobial agents for Pseudomonas aeruginosa. Indian J Med Microbiol 2018;36:303-16.
9Pragasam AK, Vijayakumar S, Bakthavatchalam YD, Kapil A, Das BK, Ray P, et al. Molecular characterisation of antimicrobial resistance in Pseudomonas aeruginosa and Acinetobacter baumannii during 2014 and 2015 collected across India. Indian J Med Microbiol 2016;34:433-41.
10Munoz-Price LS, Poirel L, Bonomo RA, Schwaber MJ, Daikos GL, Cormican M, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;13:785-96.
11Mairi A, Pantel A, Sotto A, Lavigne JP, Touati A. OXA-48-like carbapenemases producing Enterobacteriaceae in different niches. Eur J Clin Microbiol Infect Dis 2018;37:587-604.
12Lee CR, Lee JH, Park KS, Kim YB, Jeong BC, Lee SH. Global dissemination of carbapenemase-producing Klebsiella pneumoniae: Epidemiology, genetic context, treatment options, and detection methods. Front Microbiol 2016;7:895.
13Bakthavatchalam YD, Pragasam AK, Biswas I, Veeraraghavan B. Polymyxin susceptibility testing, interpretative breakpoints and resistance mechanisms: An update. J Glob Antimicrob Resist 2018;12:124-36.
14Poirel L, Jayol A, Nordmann P. Polymyxins: Antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev 2017;30:557-96.
15Giamarellou H. Epidemiology of infections caused by polymyxin-resistant pathogens. Int J Antimicrob Agents 2016;48:614-21.
16Bakthavatchalam YD, Veeraraghavan B. Challenges, issues and warnings from CLSI and EUCAST working group on polymyxin susceptibility testing. J Clin Diagn Res 2017;11:DL03-4.
17Velkov T, Roberts KD, Thompson PE, Li J. Polymyxins: A new hope in combating gram-negative superbugs? Future Med Chem 2016;8:1017-25.
18Shankar C, Nabarro LE, Anandan S, Veeraraghavan B. Minocycline and tigecycline: What is their role in the treatment of carbapenem-resistant gram-negative organisms? Microb Drug Resist 2017;23:437-46.
19Hoban DJ, Reinert RR, Bouchillon SK, Dowzicky MJ. Global in vitro activity of tigecycline and comparator agents: Tigecycline evaluation and surveillance trial 2004-2013. Ann Clin Microbiol Antimicrob 2015;14:27.
20Pogue JM, Neelakanta A, Mynatt RP, Sharma S, Lephart P, Kaye KS. Carbapenem-resistance in gram-negative bacilli and intravenous minocycline: An antimicrobial stewardship approach at the Detroit medical center. Clin Infect Dis 2014;59 Suppl 6:S388-93.
21Evans SR, Hujer AM, Jiang H, Hill CB, Hujer KM, Mediavilla JR, et al. Informing antibiotic treatment decisions: Evaluating rapid molecular diagnostics to identify susceptibility and resistance to carbapenems against Acinetobacter spp. In PRIMERS III. J Clin Microbiol 2017;55:134-44.
22Ritchie DJ, Garavaglia-Wilson A. A review of intravenous minocycline for treatment of multidrug-resistant Acinetobacter infections. Clin Infect Dis 2014;59 Suppl 6:S374-80.
23Lashinsky JN, Henig O, Pogue JM, Kaye KS. Minocycline for the treatment of multidrug and extensively drug-resistant A. baumannii: A review. Infect Dis Ther 2017;6:199-211.
24Doi Y, Bonomo RA, Hooper DC, Kaye KS, Johnson JR, Clancy CJ, et al. Gram-negative bacterial infections: Research priorities, accomplishments, and future directions of the antibacterial resistance leadership group. Clin Infect Dis 2017;64:S30-5.
25Yahav D, Lador A, Paul M, Leibovici L. Efficacy and safety of tigecycline: A systematic review and meta-analysis. J Antimicrob Chemother 2011;66:1963-71.
26Petrosillo N, Giannella M, Lewis R, Viale P. Treatment of carbapenem-resistant Klebsiella pneumoniae: The state of the art. Expert Rev Anti Infect Ther 2013;11:159-77.
27Dean CR, Visalli MA, Projan SJ, Sum PE, Bradford PA. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob Agents Chemother 2003;47:972-8.
28Sader HS, Castanheira M, Flamm RK, Mendes RE, Farrell DJ, Jones RN. Tigecycline activity tested against carbapenem-resistant Enterobacteriaceae from 18 European nations: Results from the SENTRY surveillance program (2010-2013). Diagn Microbiol Infect Dis 2015;83:183-6.
29Pfaller MA, Huband MD, Streit JM, Flamm RK, Sader HS. Surveillance of tigecycline activity tested against clinical isolates from a global (North America, Europe, Latin America and Asia-Pacific) collection (2016). Int J Antimicrob Agents 2018;51:848-53.
30Marchaim D, Pogue JM, Tzuman O, Hayakawa K, Lephart PR, Salimnia H, et al. Major variation in MICs of tigecycline in gram-negative bacilli as a function of testing method. J Clin Microbiol 2014;52:1617-21.
31Pillar CM, Draghi DC, Dowzicky MJ, Sahm DF.In vitro activity of tigecycline against gram-positive and gram-negative pathogens as evaluated by broth microdilution and etest. J Clin Microbiol 2008;46:2862-7.
32Seifert H, Blondeau J, Dowzicky MJ.In vitro activity of tigecycline and comparators (2014-2016) among key WHO 'priority pathogens' and longitudinal assessment (2004-2016) of antimicrobial resistance: A report from the T.E.S.T. study. Int J Antimicrob Agents 2018;52:474-84.
33Kmeid JG, Youssef MM, Kanafani ZA, Kanj SS. Combination therapy for gram-negative bacteria: What is the evidence? Expert Rev Anti Infect Ther 2013;11:1355-62.
34Falagas ME, Vardakas KZ, Tsiveriotis KP, Triarides NA, Tansarli GS. Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections. Int J Antimicrob Agents 2014;44:1-7.
35Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, Ellis-Grosse EJ. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother 2006;58:1221-9.
36Jean SS, Lee NY, Tang HJ, Lu MC, Ko WC, Hsueh PR, et al. Carbapenem-resistant Enterobacteriaceae infections: Taiwan aspects. Front Microbiol 2018;9:2888.
37Shen F, Han Q, Xie D, Fang M, Zeng H, Deng Y. Efficacy and safety of tigecycline for the treatment of severe infectious diseases: An updated meta-analysis of RCTs. Int J Infect Dis 2015;39:25-33.
38U.S. Food and Drug Administration. FDA Drug Safety Communication: Increased Risk of Death with Tygacil (Tigecycline) Compared to other Antibiotics Used to Treat Similar Infections. U.S. Food and Drug Administration; 01 September, 2010. Available from: [Last accessed on 2012 Sep 26].
39U.S. Food and Drug Administration. Tygacil (Tigecycline): drug Safety Communication – Increased Risk of Death. U.S. Food and Drug Administration; 2013. Available from: [Last Accessed on 2019 May 08].
40Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment options for carbapenem-resistant Enterobacteriaceae infections. Open Forum Infect Dis 2015;2:ofv050.
41Ni W, Han Y, Liu J, Wei C, Zhao J, Cui J, et al. Tigecycline treatment for carbapenem-resistant Enterobacteriaceae infections: A systematic review and meta-analysis. Medicine (Baltimore) 2016;95:e3126.
42Wang J, Pan Y, Shen J, Xu Y. The efficacy and safety of tigecycline for the treatment of bloodstream infections: A systematic review and meta-analysis. Ann Clin Microbiol Antimicrob 2017;16:24.
43Chuang YC, Cheng CY, Sheng WH, Sun HY, Wang JT, Chen YC, et al. Effectiveness of tigecycline-based versus colistin – Based therapy for treatment of pneumonia caused by multidrug-resistant Acinetobacter baumannii in a critical setting: A matched cohort analysis. BMC Infect Dis 2014;14:102.
44De Pascale G, Montini L, Pennisi M, Bernini V, Maviglia R, Bello G, et al. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care 2014;18:R90.
45Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother 2013;57:1756-62.
46Di Carlo P, Gulotta G, Casuccio A, Pantuso G, Raineri M, Farulla CA, et al. KPC – 3 Klebsiella pneumoniae ST258 clone infection in postoperative abdominal surgery patients in an intensive care setting: Analysis of a case series of 30 patients. BMC Anesthesiol 2013;13:13.
47Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: Importance of combination therapy. Clin Infect Dis 2012;55:943-50.
48Geng TT, Xu X, Huang M. High-dose tigecycline for the treatment of nosocomial carbapenem-resistant Klebsiella pneumoniae bloodstream infections: A retrospective cohort study. Medicine (Baltimore) 2018;97:e9961.
49Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. Int J Infect Dis 2011;15:e732-9.
50Joukhadar C, Klein N, Dittrich P, Zeitlinger M, Geppert A, Skhirtladze K, et al. Target site penetration of fosfomycin in critically ill patients. J Antimicrob Chemother 2003;51:1247-52.
51Matzi V, Lindenmann J, Porubsky C, Kugler SA, Maier A, Dittrich P, et al. Extracellular concentrations of fosfomycin in lung tissue of septic patients. J Antimicrob Chemother 2010;65:995-8.
52Schintler MV, Traunmüller F, Metzler J, Kreuzwirt G, Spendel S, Mauric O, et al. High fosfomycin concentrations in bone and peripheral soft tissue in diabetic patients presenting with bacterial foot infection. J Antimicrob Chemother 2009;64:574-8.
53Shorr AF, Pogue JM, Mohr JF. Intravenous fosfomycin for the treatment of hospitalized patients with serious infections. Expert Rev Anti Infect Ther 2017;15:935-45.
54Kaase M, Szabados F, Anders A, Gatermann SG. Fosfomycin susceptibility in carbapenem-resistant Enterobacteriaceae from Germany. J Clin Microbiol 2014;52:1893-7.
55Grabein B, Graninger W, Rodríguez Baño J, Dinh A, Liesenfeld DB. Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature. Clin Microbiol Infect 2017;23:363-72.
56Kusachi S, Nagao J, Saida Y, Watanabe M, Okamoto Y, Asai K, et al. Antibiotic time-lag combination therapy with fosfomycin for postoperative intra-abdominal abscesses. J Infect Chemother 2011;17:91-6.
57Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clin Microbiol Rev 2016;29:321-47.
58Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, et al. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing gram-negative bacteria. Int J Antimicrob Agents 2014;43:52-9.
59Dinh A, Salomon J, Bru JP, Bernard L. Fosfomycin: Efficacy against infections caused by multidrug-resistant bacteria. Scand J Infect Dis 2012;44:182-9.
60Apisarnthanarak A, Mundy LM. Carbapenem-resistant Pseudomonas aeruginosa pneumonia with intermediate minimum inhibitory concentrations to doripenem: Combination therapy with high-dose, 4-h infusion of doripenem plus fosfomycin versus intravenous colistin plus fosfomycin. Int J Antimicrob Agents 2012;39:271-2.
61Apisarnthanarak A, Mundy LM. Use of high-dose 4-hour infusion of doripenem, in combination with fosfomycin, for treatment of carbapenem-resistant Pseudomonas aeruginosa pneumonia. Clin Infect Dis 2010;51:1352-4.
62Yamamoto M, Pop-Vicas AE. Treatment for infections with carbapenem-resistant Enterobacteriaceae: What options do we still have? Crit Care 2014;18:229.
63Vanstone GL, Wey E, Mack D, Smith ER, Balakrishnan I. Evaluation of the EntericBio CPE assay for the detection of carbapenemase-producing organisms. J Med Microbiol 2018;67:1728-30.
64Burillo A, Marín M, Cercenado E, Ruiz-Carrascoso G, Pérez-Granda MJ, Oteo J, et al. Evaluation of the xpert carba-R (Cepheid) assay using contrived bronchial specimens from patients with suspicion of ventilator-associated pneumonia for the detection of prevalent carbapenemases. PLoS One 2016;11:e0168473.
65Huang TD, Bogaerts P, Ghilani E, Heinrichs A, Gavage P, Roisin S, et al. Multicentre evaluation of the check-direct CPE® assay for direct screening of carbapenemase-producing Enterobacteriaceae from rectal swabs. J Antimicrob Chemother 2015;70:1669-73.
66Rösner S, Gehlweiler K, Küsters U, Kolbert M, Hübner K, Pfennigwerth N, et al. Comparison of two commercial carbapenemase gene confirmatory assays in multiresistant Enterobacteriaceae and Acinetobacter baumannii-complex. PLoS One 2018;13:e0197839.
67Avlami A, Bekris S, Ganteris G, Kraniotaki E, Malamou-Lada E, Orfanidou M, et al. Detection of metallo-β-lactamase genes in clinical specimens by a commercial multiplex PCR system. J Microbiol Methods 2010;83:185-7.
68Southern TR, VanSchooneveld TC, Bannister DL, Brown TL, Crismon AS, Buss SN, et al. Implementation and performance of the BioFire FilmArray® blood culture identification panel with antimicrobial treatment recommendations for bloodstream infections at a Midwestern academic tertiary hospital. Diagn Microbiol Infect Dis 2015;81:96-101.
69Hill JT, Tran KD, Barton KL, Labreche MJ, Sharp SE. Evaluation of the nanosphere verigene BC-GN assay for direct identification of gram-negative bacilli and antibiotic resistance markers from positive blood cultures and potential impact for more-rapid antibiotic interventions. J Clin Microbiol 2014;52:3805-7.
70Antonelli A, Arena F, Giani T, Colavecchio OL, Valeva SV, Paule S, et al. Performance of the BD MAX™ instrument with check-direct CPE real-time PCR for the detection of carbapenemase genes from rectal swabs, in a setting with endemic dissemination of carbapenemase-producing Enterobacteriaceae. Diagn Microbiol Infect Dis 2016;86:30-4.
71Uddin F, McHugh TD, Roulston K, Platt G, Khan TA, Sohail M. Detection of carbapenemases, ampC and ESBL genes in Acinetobacter isolates from ICUs by DNA microarray. J Microbiol Methods 2018;155:19-23.
72García-Fernández S, Morosini MI, Marco F, Gijón D, Vergara A, Vila J, et al. Evaluation of the eazyplex® SuperBug CRE system for rapid detection of carbapenemases and ESBLs in clinical Enterobacteriaceae isolates recovered at two Spanish hospitals. J Antimicrob Chemother 2015;70:1047-50.
73Bir R, Mohapatra S, Kumar A, Tyagi S, Sood S, Das BK, et al. Comparative evaluation of in-house Carba NP test with other phenotypic tests for rapid detection of carbapenem-resistant Enterobacteriaceae. J Clin Lab Anal 2019;33:e22652.
74Kabir MH, Meunier D, Hopkins KL, Giske CG, Woodford N. A two-centre evaluation of RAPIDEC® CARBA NP for carbapenemase detection in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. J Antimicrob Chemother 2016;71:1213-6.
75Meier M, Hamprecht A. Rapid detection of carbapenemases directly from positive blood cultures by the β-CARBA test. Eur J Clin Microbiol Infect Dis 2019;38:259-64.
76Bogaerts P, Oueslati S, Meunier D, Nonhoff C, Yunus S, Massart M, et al. Multicentre evaluation of the BYG Carba v2.0 test, a simplified electrochemical assay for the rapid laboratory detection of carbapenemase-producing Enterobacteriaceae. Sci Rep 2017;7:9937.
77Dortet L, Tandé D, de Briel D, Bernabeu S, Lasserre C, Gregorowicz G, et al. MALDI-TOF for the rapid detection of carbapenemase-producing Enterobacteriaceae: Comparison of the commercialized MBT STAR®-Carba IVD kit with two in-house MALDI-TOF techniques and the RAPIDEC® CARBA NP. J Antimicrob Chemother 2018;73:2352-9.
78Boutal H, Vogel A, Bernabeu S, Devilliers K, Creton E, Cotellon G, et al. A multiplex lateral flow immunoassay for the rapid identification of NDM-, KPC-, IMP- and VIM-type and OXA-48-like carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother 2018;73:909-15.
79Pantel A, Monier J, Lavigne JP. Performance of the accelerate pheno™ system for identification and antimicrobial susceptibility testing of a panel of multidrug-resistant gram-negative bacilli directly from positive blood cultures. J Antimicrob Chemother 2018;73:1546-52.
80Veeraraghavan B, Pragasam AK, Bakthavatchalam YD, Anandan S, Ramasubramanian V, Swaminathan S, et al. 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.
81Wong D, van Duin D. Novel beta-lactamase inhibitors: Unlocking their potential in therapy. Drugs 2017;77:615-28.
82Coleman K. Diazabicyclooctanes (DBOs): A potent new class of non-β-lactam β-lactamase inhibitors. Curr Opin Microbiol 2011;14:550-5.
83Ehmann DE, Jahić H, Ross PL, Gu RF, Hu J, Kern G, et al. Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A 2012;109:11663-8.
84Papp-Wallace KM, Nguyen NQ, Jacobs MR, Bethel CR, Barnes MD, Kumar V, et al. Strategic approaches to overcome resistance against gram-negative pathogens using β-lactamase inhibitors and β-lactam enhancers: Activity of three novel diazabicyclooctanes WCK 5153, zidebactam (WCK 5107), and WCK 4234. J Med Chem 2018;61:4067-86.
85Moya B, Barcelo IM, Cabot G, Torrens G, Palwe S, Joshi P, et al. In vitro and in vivo activities of β-lactams in combination with the novel β-lactam enhancers zidebactam and WCK 5153 against multidrug-resistant metallo-β-lactamase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother 2019;63. pii: e00128-19.
86Dhillon S. Meropenem/vaborbactam: A review in complicated urinary tract infections. Drugs 2018;78:1259-70.
87Zasowski EJ, Rybak JM, Rybak MJ. The β-lactams strike back: Ceftazidime-avibactam. Pharmacotherapy 2015;35:755-70.
88Buckman SA, Krekel T, Muller AE, Mazuski JE. Ceftazidime-avibactam for the treatment of complicated intra-abdominal infections. Expert Opin Pharmacother 2016;17:2341-9.
89Hackel MA, Lomovskaya O, Dudley MN, Karlowsky JA, Sahm DF.In vitro activity of meropenem-vaborbactam against clinical isolates of KPC-positive Enterobacteriaceae. Antimicrob Agents Chemother 2018;62. pii: e01904-17.
90Lapuebla A, Abdallah M, Olafisoye O, Cortes C, Urban C, Quale J, et al. Activity of meropenem combined with RPX7009, a novel β-lactamase inhibitor, against gram-negative clinical isolates in New York city. Antimicrob Agents Chemother 2015;59:4856-60.
91Castanheira M, Huband MD, Mendes RE, Flamm RK. Meropenem-vaborbactam tested against contemporary gram-negative isolates collected worldwide during 2014, including carbapenem-resistant, KPC-producing, multidrug-resistant, and extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother 2017;61. pii: e00567-17.
92Biedenbach DJ, Kazmierczak K, Bouchillon SK, Sahm DF, Bradford PA.In vitro activity of aztreonam-avibactam against a global collection of gram-negative pathogens from 2012 and 2013. Antimicrob Agents Chemother 2015;59:4239-48.
93Karlowsky JA, Kazmierczak KM, de Jonge BL, Hackel MA, Sahm DF, Bradford PA.In vitro activity of aztreonam-avibactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated by clinical laboratories in 40 countries from 2012 to 2015. Antimicrob Agents Chemother 2017;61. pii: e00472-17.
94Kazmierczak KM, Bradford PA, Stone GG, de Jonge BL, Sahm DF.In vitro activity of ceftazidime-avibactam and aztreonam-avibactam against OXA-48-carrying Enterobacteriaceae isolated as part of the international network for optimal resistance monitoring (INFORM) global surveillance program from 2012 to 2015. Antimicrob Agents Chemother 2018;62. pii: e00592-18.
95Chew KL, Tay MK, Cheng B, Lin RT, Octavia S, Teo JW. Aztreonam-avibactam combination restores susceptibility of aztreonam in dual-carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother 2018;62. pii: e00414-18.
96Sader HS, Castanheira M, Mendes RE, Flamm RK, Jones RN. Antimicrobial activity of high-proportion cefepime-tazobactam (WCK 4282) against a large number of gram-negative isolates collected worldwide in 2014. Antimicrob Agents Chemother 2017;61. pii: e02409-16.
97Livermore DM, Mushtaq S, Warner M, Turner SJ, Woodford N. Potential of high-dose cefepime/tazobactam against multiresistant gram-negative pathogens. J Antimicrob Chemother 2018;73:126-33.
98Moya B, Barcelo IM, Bhagwat S, Patel M, Bou G, Papp-Wallace KM, et al. Potent β-lactam enhancer activity of zidebactam and WCK 5153 against Acinetobacter baumannii, including carbapenemase-producing clinical isolates. Antimicrob Agents Chemother 2017;61. pii: e01238-17.
99Stone GG, Newell P, Bradford PA.In vitro activity of ceftazidime-avibactam against isolates from patients in a phase 3 clinical trial for treatment of complicated intra-abdominal infections. Antimicrob Agents Chemother 2018;62. pii: e01820-16.
100Stone GG, Bradford PA, Yates K, Newell P.In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a phase 3 clinical trial programme for the treatment of complicated urinary tract infections. J Antimicrob Chemother 2017;72:1396-9.
101Stone GG, Bradford PA, Newell P, Wardman A.In vitro activity of ceftazidime-avibactam against isolates in a phase 3 open-label clinical trial for complicated intra-abdominal and urinary tract infections caused by ceftazidime-nonsusceptible gram-negative pathogens. Antimicrob Agents Chemother 2017;61. pii: e01820-16.
102Nichols WW, de Jonge BL, Kazmierczak KM, Karlowsky JA, Sahm DF.In vitro susceptibility of global surveillance isolates of Pseudomonas aeruginosa to ceftazidime-avibactam (INFORM 2012 to 2014). Antimicrob Agents Chemother 2016;60:4743-9.
103Hackel M, Kazmierczak KM, Hoban DJ, Biedenbach DJ, Bouchillon SK, de Jonge BL, et al. Assessment of the in vitro activity of ceftazidime-avibactam against multidrug-resistant Klebsiella spp. Collected in the INFORM global surveillance study, 2012 to 2014. Antimicrob Agents Chemother 2016;60:4677-83.
104Kazmierczak KM, Biedenbach DJ, Hackel M, Rabine S, de Jonge BL, Bouchillon SK, et al. Global dissemination of blaKPC into bacterial species beyond Klebsiella pneumoniae and in vitro susceptibility to ceftazidime-avibactam and aztreonam-avibactam. Antimicrob Agents Chemother 2016;60:4490-500.
105Yu F, Lv J, Niu S, Du H, Tang YW, Bonomo RA, et al. In vitro activity of ceftazidime-avibactam against carbapenem-resistant and hypervirulent Klebsiella pneumoniae isolates. Antimicrob Agents Chemother 2018;62. pii: e01031-18.
106Yin D, Wu S, Yang Y, Shi Q, Dong D, Zhu D, et al. Results from the china antimicrobial surveillance network (CHINET) in 2017 of the in vitro activities of ceftazidime-avibactam and ceftolozane-tazobactam against clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother 2019;63. pii: e02431-18.
107Jean SS, Lu MC, Shi ZY, Tseng SH, Wu TS, Lu PL, et al. In vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, and other comparable agents against clinically important gram-negative bacilli: Results from the 2017 surveillance of multicenter antimicrobial resistance in Taiwan (SMART). Infect Drug Resist 2018;11:1983-92.
108Zhou M, Chen J, Liu Y, Hu Y, Liu Y, Lu J, et al. In vitro activities of ceftaroline/Avibactam, ceftazidime/Avibactam, and other comparators against pathogens from various complicated infections in China. Clin Infect Dis 2018;67:S206-16.
109Karlowsky JA, Adam HJ, Baxter MR, Lagacé-Wiens PR, Walkty AJ, Hoban DJ, et al. In vitro activity of ceftaroline-avibactam against gram-negative and gram-positive pathogens isolated from patients in Canadian hospitals from 2010 to 2012: Results from the CANWARD surveillance study. Antimicrob Agents Chemother 2013;57:5600-11.
110Pfaller MA, Huband MD, Mendes RE, Flamm RK, Castanheira M.In vitro activity of meropenem/vaborbactam and characterisation of carbapenem resistance mechanisms among carbapenem-resistant Enterobacteriaceae from the 2015 meropenem/vaborbactam surveillance programme. Int J Antimicrob Agents 2018;52:144-50.
111Sader HS, Castanheira M, Shortridge D, Mendes RE, Flamm RK. Antimicrobial activity of ceftazidime-avibactam tested against multidrug-resistant Enterobacteriaceae and Pseudomonas aeruginosa isolates from U.S. medical centers, 2013 to 2016. Antimicrob Agents Chemother 2017;61. pii: e01045-17.
112Thomson KS, AbdelGhani S, Snyder JW, Thomson GK. Activity of cefepime-zidebactam against multidrug-resistant (MDR) gram-negative pathogens. Antibiotics (Basel) 2019;8. pii: E32.
113Karlowsky JA, Hackel MA, Tsuji M, Yamano Y, Echols R, Sahm DF.In vitro activity of cefiderocol, a siderophore cephalosporin, against gram-negative bacilli isolated by clinical laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015. Int J Antimicrob Agents 2019;53:456-66.
114Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF.In vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 study). Antimicrob Agents Chemother 2017;61. pii: e00093-17.
115Seifert H, Stefanik D, Sutcliffe JA, Higgins PG. In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents 2018;51:62-4.
116Abdallah M, Olafisoye O, Cortes C, Urban C, Landman D, Quale J. Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from new york city. Antimicrob Agents Chemother 2015;59:1802-5.
117Livermore DM, Mushtaq S, Warner M, Woodford N.In vitro activity of eravacycline against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother 2016;60:3840-4.
118Sutcliffe JA, O'Brien W, Fyfe C, Grossman TH. Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother 2013;57:5548-58.
119Castanheira M, Davis AP, Mendes RE, Serio AW, Krause KM, Flamm RK.In vitro activity of plazomicin against gram-negative and gram-positive isolates collected from U.S. Hospitals and comparative activities of aminoglycosides against carbapenem-resistant Enterobacteriaceae and isolates carrying carbapenemase genes. Antimicrob Agents Chemother 2018;62. pii: e00313-18.
120Walkty A, Karlowsky JA, Baxter MR, Adam HJ, Zhanel GG.In vitro activity of plazomicin against gram-negative and gram-positive bacterial pathogens isolated from patients in Canadian hospitals from 2013 to 2017 as part of the CANWARD surveillance study. Antimicrob Agents Chemother 2019;63. pii: e02068-18.
121Zhang Y, Kashikar A, Bush K.In vitro activity of plazomicin against β-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE). J Antimicrob Chemother 2017;72:2792-5.
122Galani I, Souli M, Daikos GL, Chrysouli Z, Poulakou G, Psichogiou M, et al. Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. J Chemother 2012;24:191-4.
123Galani I, Nafplioti K, Adamou P, Karaiskos I, Giamarellou H, Souli M, et al. Nationwide epidemiology of carbapenem resistant Klebsiella pneumoniae isolates from Greek hospitals, with regards to plazomicin and aminoglycoside resistance. BMC Infect Dis 2019;19:167.
124Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: Results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis 2016;62:1380-9.
125Qin X, Tran BG, Kim MJ, Wang L, Nguyen DA, Chen Q, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents 2017;49:579-88.
126Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis 2016;63:754-62.
127Torres A, Zhong N, Pachl J, Timsit JF, Kollef M, Chen Z, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): A randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis 2018;18:285-95.
128Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): A randomised, pathogen-directed, phase 3 study. Lancet Infect Dis 2016;16:661-73.
129Kaye KS, Bhowmick T, Metallidis S, Bleasdale SC, Sagan OS, Stus V, et al. Effect of meropenem-vaborbactam vs. piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: The TANGO I randomized clinical trial. JAMA 2018;319:788-99.
130Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, Mathers AJ, Bassetti M, Vazquez J, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: The TANGO II randomized clinical trial. Infect Dis Ther 2018;7:439-55.
131Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother 2016;60:6234-43.
132Sims M, Mariyanovski V, McLeroth P, Akers W, Lee YC, Brown ML, et al. Prospective, randomized, double-blind, phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother 2017;72:2616-26.
133Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JC, Ariyasu M, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: A phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2018;18:1319-28.
134Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, et al. Assessing the efficacy and safety of eravacycline vs. ertapenem in complicated intra-abdominal infections in the investigating gram-negative infections treated with eravacycline (IGNITE 1) trial: A randomized clinical trial. JAMA Surg 2017;152:224-32.
135Solomkin JS, Gardovskis J, Lawrence K, Montravers P, Sway A, Evans D, et al. IGNITE4: Results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs. meropenem in the treatment of complicated intra-abdominal infections. Clin Infect Dis 2018.
136Connolly LE, Riddle V, Cebrik D, Armstrong ES, Miller LG. A multicenter, randomized, double-blind, phase 2 study of the efficacy and safety of plazomicin compared with levofloxacin in the treatment of complicated urinary tract infection and acute pyelonephritis. Antimicrob Agents Chemother 2018;62. pii: e01989-17.
137Wagenlehner FM, Cloutier DJ, Komirenko AS, Cebrik DS, Krause KM, Keepers TR, et al. Once-daily plazomicin for complicated urinary tract infections. N Engl J Med 2019;380:729-40.
138McKinnell JA, Dwyer JP, Talbot GH, Connolly LE, Friedland I, Smith A, et al. Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae. N Engl J Med 2019;380:791-3.
139Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, et al. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria. Antimicrob Agents Chemother 2018;62:e01454-17.
140Tillotson GS. Trojan horse antibiotics–A novel way to circumvent gram-negative bacterial resistance?. Infect Dis: Research and Treatment 2016;9:IDRT-S31567.
141Kohira N, West J, Ito A, Ito-Horiyama T, Nakamura R, Sato T, et al. In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob Agents Chemother 2016;60:729-3.
142Leone S, Damiani G, Pezone I, Kelly ME, Cascella M, Alfieri A, et al. New antimicrobial options for the management of complicated intra-abdominal infections. Eur J Clin Microbiol Infect Dis 2019;38:819-27.
143Scott LJ. Eravacycline: A Review in Complicated Intra-Abdominal Infections. Drugs 2019;79:315-24.
144Olesky M, Morrissey I, Hawser S, Magnet S, Guemmaz A, Monti F. In vitro activity of eravacycline and comparators against resistant Gram-negative isolates collected in 2016 from patients in Europe. [abstract no. P0099]. In: 28th ECCMID. 2018.
145Livermore DM, Mushtaq S, Warner M, Woodford N. In vitro activity of eravacycline against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother 2016;60:3840-4.
146Zheng JX, Lin ZW, Sun X, Lin WH, Chen Z, Wu Y, et al. Overexpression of OqxAB and MacAB efflux pumps contributes to eravacycline resistance and heteroresistance in clinical isolates of Klebsiella pneumoniae. Emerg Microbes Infec 2018;7:1-1.
147Thabit AK, Monogue ML, Newman JV, Nicolau DP. Assessment of in vivo efficacy of eravacycline against Enterobacteriaceae exhibiting various resistance mechanisms: A dose-ranging study and pharmacokinetic/pharmacodynamic analysis. Int J Antimicrob Agents 2018;51:727-32.
148Zhao M, Lepak AJ, Marchillo K, VanHecker J, Andes DR. In vivo pharmacodynamic target assessment of eravacycline against Escherichia coli in a murine thigh infection model. Antimicrob Agents Chemother 2017;61:e00250-17.
149Petraitis V, Petraitiene R, Maung BB, Khan F, Alisauskaite I, Olesky M, et al. Pharmacokinetics and comprehensive analysis of the tissue distribution of eravacycline in rabbits. Antimicrob Agents Chemother 2018;62:e00275-18.
150Connors KP, Housman ST, Pope JS, Russomanno J, Salerno E, Shore E, et al. Phase I, open-label, safety and pharmacokinetic study to assess bronchopulmonary disposition of intravenous eravacycline in healthy men and women. Antimicrob Agents Chemother 2014;58:2113-8.
151European Medicines Agency. Xerava (Eravacycline): Summary of product characteristics. 2018. Available from: [Last accessed on 2018 Nov 01].
152Newman JV, Zhou J, Izmailyan S, Tsai L. Randomized, double-blind, placebo-controlled studies of the safety and pharmacokinetics of single and multiple ascending doses of eravacycline. Antimicrob Agents Chemother 2018;62:e01174-18.
153Peri AM, Doi Y, Potoski BA, Harris PN, Paterson DL, Righi E. Antimicrobial treatment challenges in the era of carbapenem resistance. Diagn Microbiol Infect Dis 2019.
154Theuretzbacher U, Paul M. Developing a new antibiotic for extensively drug-resistant pathogens: The case of plazomicin. Clin Microbiol Infect 2018;24:1231-3.
155Livermore DM. Current epidemiology and growing resistance of gram-negative pathogens. Korean J Intern Med 2012;27:128.