What is Carbapenem-Resistant Enterobacterales?
Antibiotic resistance is an increasing concern. Resistance has been noted for all current antibiotics, and the emergence of pathogens resistant to multiple drugs is becoming a widespread issue. The concern escalates as there are fewer new antibiotics being made to fight against the ones which have become resistant.
Certain bacteria, known as Gram-negative bacteria, have developed strong resistance due to structural changes and the presence of enzymes capable of breaking down antibiotics, collectively called beta-lactamases. These enzymes include extended-spectrum beta-lactamases (ESBL) which can break down penicillins, certain types of cephalosporins, and monobactams. Other types include AmpC beta-lactamases which can break down most penicillins, many cephalosporins, and most combinations of beta-lactam beta-lactamase. Finally, there are carbapenemases that can break down carbapenems and a wide range of other beta-lactams. These enzymes causing resistance complicate the choice of antibiotics for treatment.
A specific type of bacteria called Carbapenemase-producing Enterobacterales (CRE) are of great concern. These bacteria either have an enzyme called a carbapenemase, which can break down antibiotics in the carbapenem class, or exhibit resistance to a carbapenem that doesn’t usually resist. Carbapenems are powerful antibiotics that are normally used to treat pathogens resistant to multiple drugs. They are similar to penicillins but include a pyrroline ring, an added feature that protects them from some bacterial enzymes. Given these bacteria are developing resistance against carbapenems, it poses serious concerns for patient care and hospital management.
Specialized knowledge is required for diagnosing, treating, and preventing infections from such superbugs. Keeping up with the rapidly evolving topic of antibiotic resistance is crucial to provide the best patient care. Great antibiotic stewardship practices are vital to reduce the rates of these superbugs in our communities. These bacteria employ various mechanisms for drug resistance, with the most common one being the production of carbapenemase enzymes. Other resistance mechanisms include increased action of efflux pumps and specific blocking of pores in the bacterial cell’s outer layer, reducing the antibiotics’ ability to penetrate and thus making them ineffective.
What Causes Carbapenem-Resistant Enterobacterales?
Beta-lactamases are enzymes that break down different types of antibiotics, making bacteria resistant to these drugs. These enzymes can be sorted into different groups using a system called the Ambler classification.
One key family of these enzymes is known as carbapenemases. These enzymes break down a powerful type of antibiotics called carbapenems. There are three main classes of carbapenemases—A, B, and D.
Class A carbapenemases specifically include ones like Klebsiella pneumoniae carbapenemase (KPC). These enzymes have a molecule called serine at their active sites. They can break down different kinds of antibiotics including penicillins, cephalosporins, carbapenems, and aztreonam. KPC is the most common type of enzyme in this class, especially found in the United States.
Class B carbapenemases, also known as metallo-beta-lactamases, have molecules that bind to the metallic element zinc. Examples of these enzymes are New Delhi metallo-lactamase (NDM), Imipenem-resistant Pseudomonas (IMP), and Verona integron-encoded metallo-lactamase (VIM). These can break down nearly all types of antibiotics but not aztreonam. What’s unique about this class is, their genes are often found on plasmids, mobile pieces of DNA that can move between bacteria, facilitating the spread of resistance. Identifying these enzymes can be complicated due to their genetic variety.
Finally, class D carbapenemases, like Oxacillin-hydrolyzing carbapenemase (OXA), also contain serine at their active sites. They differ from class A because they are less effective at breaking down carbapenems and penicillins, show no activity against some advanced cephalosporins, and are not blocked by older beta-lactamase inhibitors. However, most of these enzymes can be inhibited by a newer beta-lactamase inhibitor called avibactam. The most common enzyme from class D is OXA-48, typically found in Klebsiella pneumoniae.
Risk Factors and Frequency for Carbapenem-Resistant Enterobacterales
The KPC enzyme is the most common among bacteria that resist carbapenem antibiotics (CRE). This is particularly common in certain areas like the United States, Mexico, Portugal, Italy, Israel, and Greece. However, other varieties of these enzymes are found in different regions. Oxa-48-like ones are common in areas like the Middle East, North Africa, and much of Europe, while NDM enzymes are prevalent in South Asia, the Mediterranean, and some European countries like Romania, Denmark, and Poland. IMP enzymes are commonly found in the Asia-Pacific region, like Australia, China, and Japan, while Turkey frequently sees Oxa-48-like enzymes. This geographical distribution can change due to population movements.
PCR, a type of molecular testing, has been the most effective way to track and understand the spread of these antibiotic-resistant bacteria. This method can identify specific strains of CRE and map their distribution worldwide. However, changes in the genes of these bacteria can sometimes complicate their identification.
- People usually get infections from CRE bacteria in hospitals or long-term care facilities.
- Most of these patients have been frequently exposed to healthcare environments for reasons unrelated to their CRE infection.
- If a CRE infection is detected, healthcare workers need to follow proper infection control procedures to stop it from spreading.
Signs and Symptoms of Carbapenem-Resistant Enterobacterales
Carbapenem-Resistant Enterobacteriaceae (CRE) is a type of infection that can occur in different parts of the body, including the urinary tract, lungs, abdomen, surgical sites, and bloodstream. This type of infection is particularly problematic in hospitals and long-term care facilities. The likelihood of bacterial resistance builds up with continued and varied use of antibiotics.
Healthcare providers should ask patients about their medical history, focusing on prior hospital stays, long-term care facility residency, and any previous use of antibiotics. These factors are essential in evaluating the risk of CRE infections. Other risk factors include the use of a urinary catheter and previous CRE colonization. To minimize the risk of spreading CRE, patients in hospitals or long-term care facilities who have had a previous CRE infection or colonization should be put in isolation.
It’s important to remember that resistance to carbapenem antibiotics does not make CRE more likely to cause disease. So, the initial symptoms of a CRE infection can be similar to infections caused by less resistant bacteria. If the initial treatment isn’t working, it might indicate a resistant infection like CRE. To confirm a CRE infection, the bacteria’s identity must be determined, and tests must be run to identify resistance to specific antibiotics or detect resistance genes. These tests can take several days, so if CRE is suspected, the medical professional should consider changing the initial treatment.
Testing for Carbapenem-Resistant Enterobacterales
Diagnosing bacterial infections based on their characteristics (also known as phenotypic diagnosis) involves growing the bacteria in a lab and identifying them. There are different methods to identify carbapenem-resistant bacteria, such as the disk diffusion method, E-test or automatic susceptibility testing. These methods can measure the least amount of antibiotics (like carbapenems) that stop the growth of the bacteria, which provides an indication of their resistance to carbapenem antibiotics. One downside of this process is that it takes multiple days and doesn’t provide a lot of details on how the bacteria has developed drug resistance.
Even if the results indicate that carbapenem antibiotics can be effective, the bacteria could still be producing enzymes (carbapenemase) that can breakdown carbapenem antibiotics. If this is suspected, the bacteria should be further tested.
Another test used often is the chromogenic media test. This test involves a type of gel which changes color when enzymes produced by drug-resistant bacteria are present. The Carba NP test is another cost-friendly recommended test for identifying bacteria resistant to carbapenem antibiotics. This test only takes a few minutes to 2 hours and it has a high degree of accuracy. There’s also a more advanced technology known as Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF). This method uses lasers to weigh the bacteria’s proteins, making it possible to identify if the bacteria can breakdown carbapenems. However, this technology can be expensive, isn’t accessible everywhere, and is quite new.
There used to be a test called the modified Hodge test, which measured the level of carbapenem antibiotics left in the gel after the bacteria have grown. But this test has not been very effective and can often give false results, so it is no longer generally recommended.
An alternative way to identify drug-resistant bacteria is through molecular tests, which look directly at the bacteria’s DNA. These tests take a few hours and can identify the techniques that the bacteria use to resist antibiotics. On the downside, this method only identifies the presence of drug resistance genes and doesn’t measure how effective antibiotics can be. Early detection of antibiotic-resistant bacteria is very important to choose the best treatments and minimize the chances of spreading the infection.
PCR and microarray are the two most common techniques used for molecular tests. There are many commercially available kits for performing these tests. However, these tests can be expensive and may not always identify all the genetic changes that make bacteria resistant to drugs.
The choice of testing method depends on the resources available in the lab and the urgency to get a diagnosis. Usually, identifying drug resistance characteristics suggests the bacteria are carbapenem-resistant, but additional tests like the Carba NP test or DNA tests are done for more information. In serious conditions, both types of tests can be done simultaneously to get immediate results and choose appropriate treatments as soon as possible.
Treatment Options for Carbapenem-Resistant Enterobacterales
Treating CRE (Carbapenem-resistant Enterobacteriaceae), a family of germs that are hard to kill because they’re resistant to a lot of antibiotics, is a complex process. The treatment methods depend on various factors, such as where the infection is in the body, the specific type of germ causing the infection, and the germ’s resistance to different drugs. Doctors also need to conduct in vitro susceptibility testing, which involves exposing the germ in a lab to different types of antibiotics to see which ones are most effective.
The type of antibiotics chosen for treatment might include carbapenems, cefiderocol (a type of drug that attracts and destroys bacteria), polymyxins, aminoglycosides, tigecycline, fluoroquinolones, trimethoprim-sulfamethoxazole, and beta-lactam/beta-lactamase inhibitors (antibiotics that stop the bacteria from destroying the antibiotic). In complicated cases, doctors might also need to consult with an infectious disease specialist or microbiologist.
For a simple bladder infection or cystitis, a dose of aminoglycosides, or a fluoroquinolone (a powerful type of antibiotic) could be recommended if it appears these would work based on the susceptibility testing. If a patient has a complicated urinary tract infection, antibiotics that are effective to this strain, should be used per the testing recommendations.
For infections that have spread outside the urinary tract, a wider range of antibiotics may be used and the choice again is determined by susceptibility testing results. Certain broad-scope antibiotics known as carbapenems might also be considered if the germ is a form of Enterobacterales that produces an enzyme that breaks down the antibiotic (carbapenem-producing Enterobacterales).
In some cases, tigecycline and eravacycline may be used as alternative treatments in patients where beta-lactam antibiotics (a common class of antibiotics) are not effective. However, these are usually not recommended as the sole treatment for severe infections or urinary infections, as they do not reach high levels in the blood or urine.
What else can Carbapenem-Resistant Enterobacterales be?
The reasons why an antibiotic called Carbapenem might not work as effectively, or resistance might happen, are:
- The bacteria starts producing an enzyme called Carbapenemase
- The decline in the production of porin, a protein that helps antibiotics to enter bacteria
- The bacteria’s efflux pump, which usually throws out harmful substances, starts working harder, throwing out more antibiotics
What to expect with Carbapenem-Resistant Enterobacterales
The outcome for a patient with an infection greatly depends on how severe the infection is. Having access to effective antibiotics plays a significant role in their recovery. However, if such medicines are not available or hard to reach, the patient’s health can worsen. Effective antibiotics are usually newer and expensive, which can make them less accessible for the treatment.
Possible Complications When Diagnosed with Carbapenem-Resistant Enterobacterales
Antibiotic resistance can cause serious health issues, side effects from medical treatments, and in some cases, death. One of the challenges when dealing with infections caused by bacteria resistant to carbapenem antibiotics (CRE) is recognizing when they have become resistant to different treatment options. The commonly seen resistance methods in CRE to antibiotics such as aminoglycosides, fosfomycin, and beta-lactamase inhibitors can become even more complicated.
For instance, a single mutation in a certain part of the bacterial gene can make all aminoglycosides, a type of antibiotics, ineffective. This resistance may typically occur when aminoglycosides are used for treatment and is most common in certain types of CRE, although it can be found in many other types as well.
Resistance to fosfomycin, another antibiotic, is frequently seen in E.coli, but many other types of bacteria, including those producing extended-spectrum beta-lactamases (ESBL) and CRE, usually don’t show resistance. However, when resistance does happen, it can make treatment more difficult.
One of the drugs often used for treating certain types of CRE is ceftazidime-avibactam, but resistance can sometimes develop to this drug as well, through specific mutations in certain bacterial genes.
Common Complications:
- Severe illnesses
- Adverse effects secondary to medical treatments
- Death
- Development of resistance to commonly used antibiotics
- Difficulties in treatment due to resistance
Preventing Carbapenem-Resistant Enterobacterales
If you have an infection caused by carbapenem-resistant Enterobacteriaceae (CRE), this is considered an urgent health problem and it’s important that you understand the risks associated with this condition. CRE are germs that are highly resistant to antibiotics. You should also be aware that once you’ve had a CRE infection, it’s likely the germs could continue to live in your body without causing any symptoms. This is known as being colonized by CRE, which can complicate your medical treatment.
Being colonized with CRE increases the chance that the germs may be passed on to others, and also makes you more likely to get other infections in the future. To prevent further spreading of CRE and to reduce the risk of future infections, it’s important to follow infection prevention practices. For example, if you have a CRE infection or are colonized with CRE, you should follow contact isolation procedures. This involves limiting direct contact with others to prevent the spread of germs. Your healthcare team will provide additional guidance on this.
