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 Table of Contents  
Year : 2023  |  Volume : 7  |  Issue : 1  |  Page : 9-16

Global escalation in carbapenem-resistant Enterobacterales and carbapenem-resistant Acinetobacter baumannii infections: Serious threat to human health from the pink corner

Department of Microbiology, College of Medicine and Health Sciences, National University of Science and Technology, Sohar, Sultanate of Oman

Date of Submission02-Nov-2022
Date of Decision12-Jan-2023
Date of Acceptance04-Feb-2023
Date of Web Publication14-Mar-2023

Correspondence Address:
Mohan Bilikallahalli Sannathimmappa
Department of Microbiology, College of Medicine and Health Sciences, National University of Science and Technology, PO BOX: 391, PC: 321, Al Tareef, Sohar
Sultanate of Oman
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_366_22

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Rise in carbapenem-resistant Gram-negative bacterial infections, especially among immunocompromised patients in healthcare settings is an imminent threat as they are difficult to treat and result in a prolonged length of hospital stay, frequent treatment failures, increased economic burden on the patient and the nation, and a high rate of morbidity and mortality. Major carbapenemase-producing Gram-negative bacteria are carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Enterobacterales (CRE) such as Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., and others. These bacteria that contaminate health-care settings are the major causes of a wide range of hospital-associated infections including life-threatening septicemia, pneumonia, meningitis, bones and joint infections, and skin and soft-tissue infections. Carbapenems are regarded as last resort available antibiotics to treat multidrug-resistant Gram-negative bacterial infections that show resistance to most of the beta-lactam antibiotics in addition to fluoroquinolones, aminoglycosides, and trimethoprim-sulfamethoxazole. Emergence and spread of carbapenem-resistant Gram-negative pathogens such as CRE and CRAB is a matter of serious concern because of limited treatment options and grave consequences. The World Health Organization has given level one priority to these pathogens and the United States Centers of Disease Control and Prevention considers CRE and CRAB as one of the top five most priority pathogens of public health importance. Strict control measures by the government and public is critical to prevent emergence and dissemination of these dangerous pathogens. In this article, the authors have summarized the microbiological and epidemiological perspectives of CRE and CRAB with a special focus on diagnosis, prevention, and novel promising alternative treatment strategies.

Keywords: Acinetobacter, antimicrobial stewardship, carbapenemases, Enterobacterales, healthcare-associated infections, plasmids

How to cite this article:
Sannathimmappa MB. Global escalation in carbapenem-resistant Enterobacterales and carbapenem-resistant Acinetobacter baumannii infections: Serious threat to human health from the pink corner. Biomed Biotechnol Res J 2023;7:9-16

How to cite this URL:
Sannathimmappa MB. Global escalation in carbapenem-resistant Enterobacterales and carbapenem-resistant Acinetobacter baumannii infections: Serious threat to human health from the pink corner. Biomed Biotechnol Res J [serial online] 2023 [cited 2023 Mar 28];7:9-16. Available from: https://www.bmbtrj.org/text.asp?2023/7/1/9/371699

  Introduction Top

Drug resistance in Gram-negative bacteria is posing an imminent threat to human health as they are increasingly resistant to multiple commonly used antibiotics. Infections associated with these drug-resistant pathogens, especially in immunocompromised patients are of serious concern as they are difficult to treat, often become severely life-threatening, and may lead to frequent treatment failures, prolonged length of hospital stay, increased health-care cost, and high rate of deaths. They cause a wide range of infections including life-threatening meningitis, pneumonia, and septicemia in health-care settings.[1] The World Health Organization (WHO) identifies antimicrobial resistance (AMR) as a global health threat that requires urgent action from the governments as well as from the society.[2] It is estimated that AMR could lead to a daunting economic burden from 300 US dollars to more than 1 trillion dollars and the number of AMR-related deaths would surpass 10 million annually by 2050.[1],[3] The common Gram-negative bacteria that are frequently isolated from the clinical samples of hospitalized patient includes Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter spp., and others.[4] These Gram-negative bacteria possess several in-built mechanisms to show resistance to multiple antibiotics. Furthermore, they have a capability to acquire and transfer drug-resistant genes to other bacteria and make them drug-resistant by several mechanisms such as conjugation, transformation, transduction, and transposition. These phenomena have facilitated continued emergence and spread of novel drug-resistant pathogens.[1] Carbapenems are regarded as class of “last resort” antibiotics to treat infections caused by multidrug-resistant (MDR) Gram-negative pathogens that are resistant to most of the commonly used drugs such as penicillins, cephalosporins, fluoroquinolones, and aminoglycosides. Emergence and wide dissemination of carbapenem-resistant Gram-negative pathogens are a matter of serious concern due to limited therapeutic options and associated grave consequences.[5] WHO and the United States Centers of Disease Control and Prevention (CDC) considers carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant A. baumannii (CRAB) as one of the top five most priority pathogens of public health importance.[6],[7] [Figure 1] outlines different classes of multidrug resistant Gram-negative pathogens. Based on these criteria, almost all currently encountered carbapenem-resistant Gram-negative pathogens would be considered MDR, and a substantial subset of CRE and CRAB would be considered extensively drug resistant.[8] In this article, authors have reviewed the microbiological and epidemiological perspectives of CRE and CRAB with a special emphasis on their diagnosis, prevention, and promising alternative novel treatment strategies.
Figure 1: Classification of drug-resistant Gram-negative rods

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  Carbapenem-Resistant Enterobacterales Top

Carbapenems are class of beta-lactam antibiotics in which the sulfur atom in the thiazolidine ring of the penicillin molecule is replaced by a carbon atom.[9] [Figure 2] depicts the core structure of carbapenems. This class of antibiotics with unique molecular structure confer exceptional stability against β-lactamases, including extended-spectrum β-lactamases (ESBLs).[9] The MDR Gram-negative rods, often referred to as superbugs are notoriously known to produce extended-spectrum β-lactamases and develop resistance to nearly all penicillins and cephalosporins.[10],[11] Enterobacteraciae is the largest family of Gram-negative bacteria of medical importance and it includes common pathogens such as E. coli, K. pneumoniae, Enterobacter spp., Citrobacter spp., Proteus spp., and others. These are prevalent in hospital environment and are associated with wide range of healthcare-associated infections (HAIs).[1]
Figure 2: Core structure of a carbapenems

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Carbapenems such as imipenem, meropenem, ertapenem, and others are regarded as last resort antibiotics to fight against MDR Gram-negative pathogens.[12] Therefore, development of resistance to carbapenems makes treatment potentially difficult and may lead to frequent treatment failures. The broad definition of “CRE” remains ambiguous. However, CDC defines CRE as Enterobacterales that show resistance to at least one of the carbapenem antibiotics or produce a carbapenemase that make them resistant to carbapenems.[7] The prevalence of CRE has been growing worldwide and considerable increase in HAIs by these pathogens in recent years, especially in immunocompromised patients poses higher risk of increased mortality.[13],[14],[15],[16] As per 2019 CDC report, in the United States alone, >1100 CRE-related deaths have occurred and >130 million US dollars was spent to treat CRE infections in 2017. The global prevalence of infection and deaths due to CRE is assumed to be much more than the estimated due to lacunae in accurate identification and reporting, especially from the third-world countries.[7] A 5-year retrospective study from December 2011 to December 2016 in Thailand reported a significant increase in CRE infections from 3.37/100,000 patient days in 2011 to 32.49/100,000 patient days in 2016.[17] The most notable factors contributing to the development of resistance to carbapenems are overuse of antibiotics in humans, agriculture, and livestock in addition to inadequate infection control practices, and non-adherence to strict antibiotic policy.[18],[19] An international cohort study conducted in 10 countries reported the significant difference in mortality due to CRE bloodstream infection in patients who received appropriate treatment (39%) and patients received inappropriate treatment (61%).[20] Among CREs, highest frequency of carbapenem resistance was noted in K. pneumoniae worldwide, though the percentage varies across different geographic locations. A study conducted in New York reported 25% of K. pneumoniae clinical isolates in a US network of long-term acute care hospital (LTACH) settings as carbapenem-resistant K. pneumoniae (CRKP).[21] Another study reported significant difference in death rate among patients infected with carbapenem-resistant K. pneumoniae (42.14%) and carbapenem-susceptible K. pneumoniae (21.16%) (CSKP).[22]

The spread of carbapenemase-encoding genes within Enterobacterales occurs either because of horizontal transfer through extra-nuclear genetic elements such as plasmids and transposons or by clonal expansion.[9],[23] CRE may also emerge by noncarbapenemase mechanism by the production of ESBLs and/or AmpC cephalosporinases (AmpC) combined with altered membrane permeability due to chromosomal mutation.[24] Therefore, carbapenemase producing and non-carbapenemase producing CRE are referred to as CP-CRE and non-CP-CRE, respectively. In the United States, approximately 30% CRE carry a carbapenemase.[24]

Three major mechanisms are attributed to the non-susceptibility of Enterobacterales to carbapenems: reduced uptake due to altered porin channels, overexpression of efflux pumps resulting in increased expulsion of the drug from the bacterial cell, and enzymatic destruction of the carbapenems by carbapenemases.[25] These enzymes break down carbapenem antibiotics and prevent them from killing the Enterobacterales. As per the Amber classification system, there are four classes of beta-lactamases. Based on molecular structures, carbapenemases that confer resistance in Enterobacterales are categorized within three classes of Amber classification namely class A, B, and D.[9],[26] [Table 1] depicts the classification and characteristics of major carbapenemases in Enterobacterales. The predominant carbapenemases seen in Enterobacterales include K. pneumoniae carbapenemase (KPC), metallo-β-lactamases (MBLs) such as New Delhi-metallo-β-lactamases (NDM), Oxacillinase (OXA)-48-like β-lactamases, Verona integron-encoded metallo-β-lactamases (VIM), and active-in-imipenem family of carbapenemases.[27] It is worth mentioning that subset of Enterobacterales have shown carbapenem resistance, especially in K. pneumoniae by non-carbapenemase mechanism. In these noncarbapenemase-producing Enterobacterales, carbapenem resistance was noticed due to the production of extended-spectrum β-lactamases (ESBLs) and or AmpC enzymes in combination with decreased intracellular uptake resulting from mutation in outer membrane porin proteins (OmpK35, OmpK36) or overexpression of efflux pumps.[28]
Table 1: Classification and characteristics of major carbapenemases in Enterobacterales

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Class A and B possess a serine residue at the active site that facilitates β-lactam ring opening and is thus nomenclated as serine-β-lactamases (SBLs). Class B carbapenemases possess zinc ions at the active site that facilitates bond hydrolysis and hence they are termed MBLs. Serine-β-lactamase producing Gram-negative rods are susceptible to β-lactamase inhibitors such as clavulanic acid, tazobactam, and sulbactam. While MBLs are non-susceptible to β-lactamase inhibitors but are susceptible to metal ion chelators such as dipicolinic acid or EDTA. However, none of the metal ion chelators are licensed for human use.[9],[29],[30]

Global distribution of carbapenemase varies. In the United States, the most prevalent type is KPC (class A), however, sporadic outbreaks of other classes namely VIM, NDM, IMP (class B), and OXA-48 (class D) have also been reported.[31] KPC-producing CRE is predominant also in specific European countries namely Italy and Greece.[8] The first KPC enzyme was detected in 1996 in the United States from a K. pneumoniae. Since then, several KPC enzyme producing strains of Klebsiella species are disseminated worldwide.[32] So far 13 KPC variants have been identified, out of which KPC2 and KPC3 were the most frequently found strains and are encoded by blaKPC. The blaKPC genes are plasmid borne and hence, inter-species horizontal transmission may occur rapidly. These strains often show resistance to other commonly used antibiotics such as fluoroquinolones and aminoglycosides due to coexistence of additional resistance mechanisms. Thus, pose serious challenge to the therapy.[33]

Imipenem-hydrolyzing-β-lactamase (IMI) producing strains usually show resistance to imipenem but show susceptibility toward extended-spectrum cephalosporins and intermediate resistance to ertapenem. IMI-1 carbapenemases are chromosomally encoded, often show unusual antimicrobial profile, and the panels of genes to detect them is usually not included in diagnostic laboratories.[34] The genotypes of blaGES gene that encode for GES-β-lactamase show point mutation resulting in the replacement of glycine by serine. GES strains are less frequently reported, however, there is a steady increase in the frequency of their isolation.[35]

MBLs that belong to class B carbapenemases are encoded by plasmid borne genes, molecularly diverse, and capable of inactivating majority of β-lactams, however, they are susceptible to monobactams.[36] MBL-producing CRE are more frequently isolated in the Indian Subcontinent and in specific European countries such as Spain, Hungary, Denmark, and Romania.[37] NDMs are reported to confer resistance to β-lactams including carbapenems in several enteric pathogens including E. coli and K. pneumoniae. It is worth mentioning that NDM strains show susceptibility toward aztreonam and the strains that co-express MBLs and SBLs are capable of hydrolyzing even aztreonam.[9]

Class D carbapenemases include oxacillinases which can efficiently hydrolyze oxacillin. OXA-2 was the first oxacillinase detected. OXA-48 was the most prevalent type, while OXA-23, OXA-24/40, and OXA-58 were the other less frequently detected oxacillinases. OXA-48-producing carbapenemases are relatively common in European countries, especially in the Mediterranean region. The first case of OXA-48-producing Enterobacterales is K. pneumoniae, and was isolated in Turkey in 2001.[38] The highest epidemiological level of OXA-48 is found in Turkey.[37] Recent study from Turkey, reported 90% of CRE as OXA-48-like producers.[39] Reports suggest that OXA-48-like enzymes have spread globally to Middle East, Africa, and Asia.[40],[41],[42],[43],[44],[45] The major concern of these strains is non-availability of inhibitors for them. In a recent study conducted during 2014 to 2016 in Egypt, reported blaOXA-48 (58.62%) as the predominant carbapenemase gene followed by blaNDM (27.58%), blaVIM-3 (10.3%), and blaKPC-2 (6.89%) recovered from Gram-negative pathogens in neutropenic pediatric cancer patients.[46] Another study conducted in Iran between 2015 and 2016 revealed blaOXA-48 as the most prevalent carbapenemase gene (72%), followed by blaNDM (31%) among carbapenemase producing K. pneumoniae strains isolated from various clinical samples.[47] A study conducted in Oman during 2014 to 2017, reported K. pneumoniae and E. coli as the most common Enterobacterales showing carbapenem-resistance. Whole genome sequencing and multi-locus sequence typing identified genes encoding for MBLs in 68/149 isolates, OXA-48-like enzymes in 60/149 isolates, and KPC in 6/149 isolates. Among CRE genes, blaNDM-1 (45; 30.2%) and blaOXA-48 (29; 19.5%) were the most frequent. The most common sequence types identified were E. coli ST410 (21.1%) and ST38 (18.4%), and K. pneumoniae ST147 (16%) and ST231 (8.6%).[48]

  Carbapenem-Resistant Acinetobacter Top

A. baumannii possess extensive genetic resistance islands and has tremendous capability to resist harsh environmental conditions. It frequently contaminates the healthcare facilities including medical devices and frequently causes severe infections, especially immunocompromised patients treated at hospitals. It has a remarkable ability to acquire drug-resistance and rapid surge in strains resistant to almost all relevant antimicrobials has limited the therapeutic option. Furthermore, mounting resistance to last resort antibiotics such as carbapenems because of inappropriate use of antibiotics, poses clinicians a serious challenge to treat infections caused by CRAB.[49],[50] The first case CRAB was identified in 1991 and ever since the first identification, there is a surge in CRAB strains globally.[51],[52],[53] Hospital outbreaks of CRAM have been reported from many countries including the USA, Canada, Europe, Middle East, Australia, South America, and Asia.[54],[55] A study from North America witnessed rapid rise in CRAB strains from 1% in 2003 to 58% in 2008.[52] Similar study from Europe reported 70% of the invasive strains of A. baumannii isolated in hospitals to be carbapenem resistant.[56] Carbapenem resistance in Acinetobacter spp. is either because of acquisition of resistance genes encoding for production of carbapenemases or chromosomal mutation resulting in alteration in efflux pumps, outer membrane proteins and penicillin-binding proteins.[57],[58],[59],[60],[61] However, carbapenemase production by plasmid encoded oxacillinase genes is the main mechanism associated with non-susceptibility of A. baumannii strains towards carbapenems.[57],[60] Of these, Oxa-23 is the most widespread carbapenem-resistant determinant noticed in most countries, while Oxa-24 and Oxa-58 were found to be dominant in some specific locations.[54] Two specific clones designated as global clone 1 (GS1) and Global clone 2 (GS2) are responsible for most of these outbreaks.[54],[61] Other carbapenem-resistant genes such as those encoding for metallo-ß-lactamases (bla VIM, bla IMP and bla NDM) or class A carbapenemases (bla KPC and bla GES-11) are less frequently seen in A. baumannii.[54],[62],[63]

  Diagnostic Tests for Identification of Carbapenem-Resistant Enterobacterales and Carbapenem-Resistant Acinetobacter baumannii Top

The Food and Drug Administration (FDA) approved several commercial tests for rapid detection of carbapenem resistance among Enterobacterales and Acinetobacter spp. Broadly, tests are divided into two categories: Novel conventional phenotypic tests that detect the activity of carbapenemase enzymes in vitro and molecular tests that detect the carbapenemase genes.[64] According to CLSI guidelines, carbapenemase production in Enterobacterales is suspected if the minimum inhibitory concentration (MIC) to meropenem or imipenem is 2–4 μg/ml and for ertapenem 2 μg/ml.[65] [Figure 3] outlines the common diagnostic tests available for the detection of CRE strains.
Figure 3: Common diagnostic tests available for detection of CRE strains. CRE: Carbapenem-resistant Enterobacterales

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Conventional phenotypic tests to detect carbapenemase enzyme activity:

  • Carba NP test: Colorimetric microtube assay utilized for the detection of carbapenemase production in Enterobacterales and Acinetobacter spp. It is highly sensitive and specific (>90%) for the detection of certain carbapenemases such as KPC, NDM, VIM, and IMP, but has low sensitivity (11%) for detecting OXA-48 carbapenemases.[65] RAPIDEC® Carba NP test is a ready-to-use test available commercially[9]
  • Modified carbapenem inactivation method (mCIM): Like Carba NP test, this is also utilized for the detection of carbapenemase production in Enterobacterales and Pseudomonas. However, it has several advantages over carba NP test. First, the test is simple, easily interpretable, and utilizes reagents and media readily available, unlike Carba NP which requires special reagents. Second, it is possible to differentiate between serine carbapenemases from metallo beta-lactamases by using EDTA-mCIM and mCIM simultaneously[65]
  • Bioluminescence-based carbapenem susceptibility detection assay: This test, recently developed by Vincent et al. allows the detection of CRE within 2–3 h directly from the culture growth with a high sensitivity and specificity of 99% and 98%, respectively.[66]
  • Immunochromatographic assays: These rapid tests-based monoclonal antibodies can detect VIM, NDM, KPC, and OXA-48 carbapenemases within 5–10 min directly in the bacterial colonies[67]
  • Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a newer technique utilized for the detection of carbapenemases. In this technique, freshly grown bacterial growth is mixed with carbapenems and incubated for 2–4 h at 35-37°C. After incubation, the suspension is centrifuged, and the supernatant is examined by mass spectrometry. In case of carbapenemase hydrolysis, the degraded product and sodium salt of carbapenem molecule are visible in spectrometry[68]
  • Spectrophotometry: In this technique, bacterial crude extract obtained after sonication is mixed with buffered imipenem solution and the hydrolysis of the beta-lactam ring is measured using a spectrophotometer.[69]

  Molecular Methods for Detection of Carbapenemase Genes Top

Over the past several years, several nucleic acid amplification (NAATs) tests for detection of carbapenemase genes have been presented in the literature. However, only few of them were approved by the FDA, United States and Conformite Europeene Mark for clinical diagnostic testing. [Table 2] depicts FDA approved tests for detection of CP-CRE.
Table 2: Food and drug administration approved molecular tests for detection of carbapenemase-producing-carbapenem-resistant Enterobacterales

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NAATs have several advantages compared to conventional phenotypic culture-based tests: rapid results within few hours; accurate identification of specific carbapenemase genes; some tests can be directly done on clinical specimen without the need of bacterial culture.[64],[77] NAATs too have disadvantages. First, they detect only those enzymes specified by primers and probes and this may lead to false negative results if resistance is mediated by a novel carbapenemase variant or carbapenem resistance conferred by mechanisms other than the production of carbapenemases.[64]

  Treatment for Carbapenem-Resistant Enterobacterales and Carbapenem-Resistant Acinetobacter baumannii Top

Treating CRAB and CRE remains challenging for clinicians due to limited therapeutic options and also, CRE encompasses a wide range of organisms with different resistance mechanisms and variable global and local epidemiology. Hence, there is an urgent need for developing novel and effective anti-CRE therapies. Currently, tigecycline and polymyxins (colistin and polymyxin B) are considered as drugs of choice for CREs. In addition, fosfomycin and aminoglycosides are occasionally used to treat CREs. Previous studies have reported >90% CRE strains showing susceptibility toward tigecycline and colistin.[21],[49] However, more frequent use of these drugs to treat CRE in recent years resulted in gradual growing resistance to these drugs. In-line with this, a recent study in Thailand reported increased resistance among CRKP with only 47% showing susceptibility toward tigecycline.[78]

Preventive measures

A steady increase in resistance to tigecycline and polymyxins needs to be considered very seriously as there were no other newer drugs in the pipeline or approved for use. Therefore, giving paramount importance to develop newer treatment strategies and preventive measures to control the emergence and spread of all MDR pathogens including CRE and CRAB is highly warranted. [Figure 4] illustrates standard infection control measures one must adopt to control emergence and spread of dangerous MDR pathogens.
Figure 4: Standard infection control measures to combat antimicrobial resistance

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  Novel Strategies to Combat Drug-Resistance Menace Top

Despite good infection control practices and antibiotic stewardship, a steady rise in AMR with emergence and spread of novel strains is witnessed worldwide, especially in third-world countries. To combat drug-resistance menace, researchers looking forward for better alternative strategies.[79] [Figure 5] outlines promising alternative strategies that are under different stages of clinical trials and some of these might become available for future clinical practice.
Figure 5: Promising novel alternative strategies to combat antimicrobial resistance

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Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2]


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