Last Updated on January 15, 2020 by Sagar Aryal
Carbapenem-Resistant Gram-Negative Bacteria
The Carbapenem-Resistant Gram-Negative bacteria are a group of bacteria that have developed resistance against Carbapenem Antibiotics a last resort drug of administration for most gram-negative bacterial infections that have developed resistance against all possible antibiotics. These include the Carbapenemase Producing Organisms( CPOs) and Carbapenem-Resistant Enterobacteriaceae (CREs).
Carbapenem-Resistant Enterobacteriaceae (CREs) are a group of Gram-Negative bacteria, from the family of Enterobacteriaceae, which have developed resistance to one or more of the Carbapenem Antibiotics. Enterobacteriaceae is large groups of gram-negative bacteria family that couples harmful and harmless bacteria which include: Klebsiella, Shigella, E.coli, Yersinia pestis, Proteus, Serratia, Citrobacter.
And there are some opportunistic bacteria that have the ability to produce a Carbapenemase enzyme called Carbapenemase Producing Organisms (CPOs) or Superbugs (developed resistance to most antibiotics hence difficult to treat). These include Pseudomonas, Acinetobacter.
CREs and CPOs have several similar characteristics in morphology and their acquisition of resistance.
What are Carbapenems?
Carbapenems are a class of β-lactam antibiotic agents with very high effectiveness against severe and high-risk bacterial infections, which is normally a Drug of Last Resort (DoLR) antibiotic for Multi-Drug Bacterial infections. The mechanism of Carbapenem is to inhibit β-lactamase enzyme penicillinase, by binding to the Penicillin-binding proteins preventing bacterial cell wall synthesis. CPOs or CREs produces an enzyme known as Carbapenemase, which inactivates the mechanism of Carbapenem antibiotic, therefore becoming resistant to the antibiotic.
Carbapenems, among the beta-lactams, are the most effective against Gram-positive and Gram-negative bacteria presenting a broad spectrum of antibacterial activity. Their unique molecular structure is due to the presence of a carbapenem together with the beta-lactam ring. This combination confers exceptional stability against most beta-lactamases (enzymes that inactivate beta-lactams) including ampicillin and carbenicillin (AmpC) and the extended-spectrum beta-lactamases (ESBLs).
These Carbapenem-Resistant Gram-Negative bacteria (Superbugs) include:
1. Acinetobacter baumannii
2. Klebsiella pneumoniae
3. Pseudomonas aeruginosa
Figure 1: Carbapenem-Resistant Gram-Negative Bacteria
1. Acinetobacter baumannii: CPO
It’s short coccobacilli, gram-negative bacteria. Morphological and biochemical characterization indicates that they are catalase-positive, oxidase-negative, non-motile, non- fermenting
This bacteria has a low risk of infection but it is an opportunistic bacteria posing high risks for immuno-compromised patients like:
- Surgery patients with open wounds
- Weakened immune systems
- Patients using invasive devices catheters
- Chronic lung disease
- Patients with a prolonged hospital stay
Acinetobacter baumannii infections are highly prevalent in hospital settings as opportunistic infections; 60-70% of these bacteria have developed resistance to many antibiotics, including carbapenems. A. baumannii is usually introduced into a hospital by a colonized patient. Due to its ability to survive on artificial surfaces and resist desiccation, it can remain and possibly infect new patients for some time (www.futurelearn.com/courses/role-of-diagnostics-in-the-amr-response)
2. Klebsiella pneumoniae: CPE/CRE
Its Gram-negative, large, bacilli, non-motile lactose fermenting, facultative anaerobic bacteria that can cause pneumonia, bloodstream and urinary tract infections and meningitis. They are normal flora in the human skin, mouth, and intestines and can also be found in human feces.
Increasingly, Klebsiella bacteria have developed antimicrobial resistance, most recently to carbapenems. Klebsiella infections commonly occur among sick patients who are receiving treatment for other conditions in healthcare facilities. Patients whose care requires devices like ventilators (breathing machines) or intravenous (vein) catheters and patients who are taking long courses of certain antibiotics are most at risk for Klebsiella infection (www.cdc.gov/hai/organisms/klebsiella/klebsiella).
3. Pseudomonas aeruginosa: CPO
Pseudomonas infection is caused by strains of Gram-negative bacteria found widely in the environment. It is an opportunistic infection that causes disease in plants and animals, and humans.
Severe Pseudomonas infections usually occur in people in the hospital and/or with weakened immune systems e.g. cancer patients, on chemotherapy, suffering from HIV/AIDS, etc. Cystic fibrosis patients are especially at risk. Patients in hospitals, especially those on respirators, those with devices such as catheters, and patients with wounds from surgery or from burns are potentially at risk for serious, life-threatening infections.
Clinical features of Carbapenem-Resistant Gram-Negative Bacteria
- CNS infections
- Septic Arthritis
- Ophthalmic infections
- Intra-abdominal infections
- Skin and soft-tissue infections
- Urinary tract infections (UTIs)
- Lower Respiratory Tract Infections
Resistance transfer mechanism of carbapenem-resistant Gram-Negative Bacteria
These bacteria can acquire genes encoding multiple antibiotic resistance mechanisms, including extended-spectrum -lactamases (ESBLs), AmpCs, and carbapenemases. Lactam drugs are often the primary therapeutic option for serious infections, and carbapenems, in particular, are often considered agents of last resort. Thus, the emergence and spread of carbapenem-resistant Enterobacteriaceae (CRE) and Carbapenemase- Producing Organisms are a significant clinical and public health concern. CREs and CROs are often resistant to all -lactam drugs and frequently carry mechanisms conferring resistance to other antimicrobial classes, further limiting treatment options (Joseph D. Lutgring, Brandi M. Limbagob, The Journal of Microbiology, 2016).
Bacteria have tendencies of exchanging or transferring their genetic material and one of them including antibiotic resistance genes when the right conditions are provided. This transfer mechanism is known as Horizontal Gene Transfer (HGT). The genes that promote horizontal gene transfer, contribute to antibiotic resistance allowing new variants to arise without a mutation in that variant. Horizontal gene transfer takes place in two forms: a DNA plasmid or a transposon. A transposon, also know as a jumping gene, is a genetic material that can jump or move from one position to another and in this case, they move from one organism to another, incorporating new DNA into another organism, therefore, altering its DNA sequence. Plasmids, however, do not become incorporated into the DNA of the host organism.
There are three mechanisms in which horizontal gene transfer occurs:
a. Transformation – uptake of genetic material from a dead organism
b. Transduction – allowing bacterial DNA to move between cells.
c. Conjugation – transfer of genetic material between two living organisms.
Figure 2: Mechanisms of Transformation, Transduction, and Conjugation (sciencing.com)
- Transformation occurs between different species of bacteria including some recipient species that were not previously known to be competent for natural transformation.
- Transduction may be playing an important role in generating novel methicillin-resistant Staphylococcus aureus (MRSA) strains, although the details of transferring the SCCmec element are not yet fully understood.
- Resistance genes are probably moving to plasmids from chromosomes more rapidly than in the past.
- Resistance genes are aggregating upon plasmids. The linkage of numerous resistance genes on individual plasmids may underlie the persistence of resistance to specific antimicrobials even when the use of those antimicrobials is discontinued.
Horizontal gene transfer contributes to the spread of antibiotic resistance through the exchange of genetic material across genera, which increases the potential for a harmful, antibiotic-resistant bacteria to develop. This is the major mechanism through which Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa develop resistance to antibiotics.
Other mechanisms that promote resistance include:
- the altered function of membrane-associated proteins such as porins
- Activation of drug Efflux pump
- Production of enzymes (e.g., carbapenemase) that are capable of hydrolyzing carbapenems
- Non-coding small RNAs
- Biofilm formation
Diagnosis of Carbapenem-Resistant Gram-Negative Bacteria
Diagnosis of these Superbugs are crucial in three ways:
- To screen for carriers to enable infection prevention and control measures
- To identify infected individuals to guide treatment
- For active surveillance of resistant Hospital Associated infections to enable alerts of outbreaks and to provide data for treatment guidelines and development/optimization of AMR control strategies
Samples: Blood, Urine, and sputum
Diagnosis of the Carbapenem-Resistant Gram-Negative Bacterial infections usually involves demonstrating the organism’s resistance to multiple antibiotics, including carbapenem, and by PCR tests
Detection can be done using:
- Culture-based techniques for antibiotic sensitivity testing
- Molecular testing, by using automated molecular techniques like PCR which are fast and sensitive.
Treatment of CPOs and CREs
Polymyxins (colistin, polymyxin B) have been first-line antibiotics against carbapenem-resistant Bacterial infections. New anti-CRB antibiotics (ceftazidime-avibactam, meropenem-vaborbactam, plazomicin) improve outcomes in CRB-infected patients and reduce toxicity compared with polymyxins. Ceftazidime-avibactam, meropenem-vaborbactam, and plazomicin demonstrated excellent anti-CRB activity in vitro and in animal studies, and they have been shown to be superior to polymyxins or other best available regimens in treating CRB-infected patients (Cornelius J. C., Brian A. P., Deanna B., and Hong M. N.).