Some Klebsiella and E. coli strains are collectively called “Carbapenem-resistant Enterobacteriaceae” (CRE) because they have developed resistance to a former last-resort antibiotic, carbapenem. They mainly occur in long-term care facilities. Nevertheless, the Center for Disease Control regards them as an urgent threat because of their insensitivity to multiple antibiotics, and because of concerns that they may spread into the community.

1. Urgent Antibiotic-Resistant Threats: Klebsiella and E. coli
Most of us have heard that over the last 60 - 80 years, antibiotics removed the threat of many
infectious diseases. Regrettably, many of us have also heard the alarming stories that some of these
diseases may become untreatable again
because of increasing resistance to
antibiotics. Will the so-called post-antibiotic
era arrive soon? Is it possible for the days of
nightmare to return when effective
antibiotics are no longer available to keep us
out of harm’s way? In some instances, this is
already happening, for example in the case of
Carbapenem-resistant Enterobacteriaceae, a
group of bacteria.
The Centers of Disease Control (CDC) categorizes the top 18 threats posed by drug-resistant
microorganisms into three classes: urgent threats, serious threats, and concerning threats. There
are only three examples of urgent threats: Clostridium difficile, carbapenem-resistant
Enterobacteriaceae (mainly Klebsiella pneumoniae and E .coli), and Neisseria gonorrhoeae. The
best-known hazardous organism, methicillin-resistant Staphylococcus aureus (MRSA), is now
classified as a serious but not urgent threat. Carbapenem-resistant Enterobacteriaceae (CRE) have
become resistant to nearly all the antibiotics we have today. Almost half of hospital patients who
get bloodstream infections from CRE bacteria die from the infection.
Let us look at the issue of CRE more closely.
o Firstly, we will deal with some basic information, the definition and description of
carbapenem-resistant organisms.
o We will follow by discussing how bacteria develop resistance against antibiotics.
o We will then examine how CRE spread and the diseases they cause.
o Finally, we will consider protocols for treatment and prevention.
What is Carbapenem?
Carbapenems, like penicillin, contain a chemical structure called the beta-lactam ring that binds to,
and kills an enzyme involved in bacterial cell wall synthesis. A bacterium cannot survive without an
intact cell wall.
The first antibiotic containing a beta-lactam ring was penicillin, but many other versions of beta-
lactam antibiotics were developed and entered medical practice. In time, more and more organisms
became resistant to the antibiotics in use, mainly by evolving ways to inactivate the antibiotic. This
necessitated the introduction of newer and newer antibiotics whose structures made them less
susceptible to the effects of the inactivating enzymes of the bacterium. Carbapenems have a
Some Klebsiella and E. coli strains are collectively
called “Carbapenem-resistant Enterobacteriaceae”
(CRE) because they have developed resistance to a
former last-resort antibiotic, carbapenem. They mainly
occur in long-term care facilities. Nevertheless, the
Center for Disease Control regards them as an urgent
threat because of their insensitivity to multiple
antibiotics, and because of concerns that they may
spread into the community.

2. structure that renders them resistant to breakdown by enzymes that attack most beta-lactam ring
structures.
Thus, carbapenems became antibiotics of last resort for many infections, such as those by
Escherichia coli (E. coli) and Klebsiella pneumoniae. Unfortunately, as the title of this article
indicates, many strains have developed resistance to carbapenems.
What are Enterobacteriaceae?
Enterobacteriaceae are a large family of bacteria that contain many harmless organisms, as well as
several pathogens. E. coli and Klebsiella pneumoniae are the two main species belonging to this
family that cause widespread problems. Both are normally present in the human gut, but if they
colonize other organs, they can cause serious infections.
What diseases does Klebsiella pneumoniae (K. pneumoniae) cause?
K. pneumoniae has long been recognized as a risk factor for pneumonia, especially in
immunocompromised individuals. It can also cause urinary and biliary tract infections, as well as
wound site infections. The range of diseases caused by K. pneumoniae is wide, with a number of
conditions being serious or life threatening, such as meningitis and septicemia (blood poisoning).
Which diseases does E. coli cause?
Most strains of E. coli are harmless, but some cause food poisoning. The harmless strains are part of
the normal bacterial components of the gut. E. coli is the most common cause of complicated
urinary tract infections (so called uropathogenic E. coli), although there is a multitude of other
organisms that are also risk factors for such infections. Some E. coli strains can produce a toxin
(Shiga toxin or verotoxin) that destroys red blood cells and causes a hemolytic-uremic syndrome
(destruction of red blood cells and kidney failure). In May 2011, there was an outbreak in Germany
caused by an E. coli strain that produces a different sort of toxin. In addition, E. coli can cause
meningitis in newborns.
Thus, carbapenem-resistant Enterobacteriaceae represent two different organisms that cause a
number of different diseases. In clinical practice, the feature in common between these bacteria
that concerns a doctor is the difficulty in treating them because of their resistance to multiple
antibiotics.
How do organisms become resistant to carbapenem antibiotics?
Bacteria can become resistant to carbapenem (and to antibiotics in general) by a number of
mechanisms:
----By acquiring the ability to transport the antibiotic out of the cell
----By changing the outer membrane structure in a way that the prevents the antibiotic from
penetrating the bacterial cell
----By gaining enzymes that break down carbapenems. Several classes of such enzymes exist.
These arise in the following ways:

3. ----- Through mutations in pre-existing enzymes
----- By increased production of existing enzymes that inactivate the antibiotic
----- By uptake of DNA that codes for enzymes that inactivate the antibiotic. This DNA is usually
located on mobile elements (pieces of DNA such as plasmids that are able to propagate themselves
and move from one bacterial cell to another). Mobile elements represent the fastest way for
antibiotic resistance to spread among bacteria. Plasmids can sometimes carry multiple genes each
coding for an activity that can disarm a different class of antibiotic.
It seems there is an amazing capacity for bacteria to find many different ways to disable or expel
antibiotics! However, we have to remember that antibiotics are naturally occurring compounds
that are environmental toxins for bacteria, and bacteria have been able to develop strategies to
combat them over millions of years of evolution. When a new antibiotic is at first introduced in
medicine, it kills most of the bacteria, since they are sensitive to it. Unfortunately, a few of the
bacteria are not killed because they are resistant to the antibiotic. These can grow and multiply
until they largely replace the population of sensitive bacteria.
How do the CRE diseases spread?
Contaminated food
The food industry can be the source of drug-resistant E. coli organisms. The cause of the German
outbreak in 2011 (see above) was, in all probability, fenugreek seeds imported from Egypt.
Animals
Animals are also sources of antibiotic resistant organisms, both through handling and through
consumption.
Hospital and long-term care settings
However alarming epidemics like the German one can be, we have to remember that the majority of
CRE infections occur in hospital or long-term care settings. Patients in the greatest danger of
contracting CRE are those with weakened immune systems, or people who use invasive devices
such as catheters or are on mechanical ventilation. Many patients who contract CRE are suffering
from other diseases, which may partially account for the high mortality rate mentioned in the
introduction. CRE can spread through accidental transfer by workers touching contaminated
surfaces and equipment. Reuse of duodenoscopes (an endoscope for examining the duodenum) has
lead to transmission of infections in some facilities.
Symptoms and diagnosis
The symptoms vary according to the organs affected but often include fever and pain. These
symptoms are not unique to CRE bacteria, but can be due to infections by many other organisms.
The CRE organism must be identified using diagnostic tools. These are laboratory culture and
molecular methods. The latter do not just identify the organism, but may also reveal the
mechanism of resistance.
Incidence
According to a study released in October 2015 on data collected in seven states, the incidence of
CRE is close to 3 per 100,000 in the population, compared to 25 per 100,000 for MRSA. Urine

4. samples were the most frequent sources of the CRE organisms. Although most people affected by
CRE are hospitalized or long-term care patients and those with invasive devices, a sizeable fraction
of CRE-infected patients stayed in hospital for only a short time. Eight percent of the people
diagnosed with CRE did not receive any treatment before the development of the disease. This
raises concern about CRE spreading from the hospital environment into the community.
As mentioned previously, in some facilities patients were diagnosed with CRE infection after
undergoing exploratory procedures using endoscopes. Unfortunately, cleaning endoscopes
thoroughly is a challenge: there are reports of bacteria found on them after automatic disinfection.
To prevent contamination, some hospitals are now using gas sterilization.
Treatment
Some newer antibiotics, for example phosphomycin and tigecycline, can treat diseases caused by
multiresistant bacteria. Not all patients respond well to treatment with them, as is evident from the
high mortality rate. This is not just because patients in long-term care tend to be in poor general
health. A given antibiotic may not work efficiently enough for all varieties of the disease. For
example, tigecycline is not an efficient therapy for bloodstream infections because the antibiotic
quickly diffuses into the tissues, resulting in too low a plasma concentration.
Prevention
Protocols for prevention, including the isolation of infected patients and updated protocols for
cleaning surfaces, are in place in some hospitals. Since the organisms are transmitted through
contact, it is crucial to decontaminate surfaces. Study of the properties of different surfaces is also
important; for example, while stainless steel supports bacterial growth, copper surfaces destroy the
organisms. The latest guidelines from the CDC emphasize good hand hygiene, contact precautions,
and education of staff, among other suggestions.
Careful hand washing is also important outside the hospital, and washing of uncooked vegetables
and meat are crucial to fend off infection. Food poisoning is possible from these sources.
If you have procedures necessitating the use of a duodenoscope, for example endoscopic retrograde
cholangiopancreatography (ERCP), talk to the healthcare professionals about concerns.
Summary
CRE is a group of microorganisms (Klebsiella and E. coli) that has acquired resistance to
carbapenem, the former last-resort antibiotic, as well as to many other antibiotics. This makes
treatment problematic and results in high mortality rates. Klebsiella and E. coli cause varied
diseases, such as urinary tract infections, pneumonia, and blood stream infections. The large
majority of cases occur in patients with invasive devices or in long-term care, although there are
concerns about the diseases spreading into the community. Improvements in hygiene, including
better surface cleaning, and care in using invasive devices are important for preventing the spread
of CRE organisms.
New antibiotics are also likely to be available soon. The emerging threat of multiresistant
microorganisms has stimulated renewed interest in the development of new types of antibiotic and

5. alternative treatments. These will take time to come into use, however. Until then – and forever
after - we have to rely on responsible use of antibiotics.
Update: In a recent (March 2016) issue of Science, the “Insights” section presented further
warnings on the spread of extremely antibiotic resistant CRE. Colistin, an antibiotic that was
developed about half a century ago but was not widely used because of its toxicity, has recently
been reemployed as an emergency measure to fight multiresistant CRE organisms. However,
organisms resistant to colistin itself have already appeared. The “Insights” review refers to recent
studies showing that colistin resistance, the so-called mcr-1 gene, can be carried on plasmids, which
is not good news because this mechanism greatly facilitates its spread.
RESOURCES
Biggest Threats. Centers for Disease Control and Prevention.
http://www.cdc.gov/drugresistance/biggest_threats.html. Updated August 26, 2015. Accessed
March 5, 2015.
Witze A, Morello L, Turner M. Scientific advice: Crisis counselors. Volcanic eruptions, oil spills and
bacterial outbreaks all land in the laps of government science advisers, and put them to the test.
Nature 2014; 512: 360-363
Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. Molecular mechanisms of antibiotic
resistance. Nat. Rev. Microbiol. 2015; 13: 42-51.
Davis CP. CRE bacteria infection: Symptoms and treatment. MedicieNet.com.
http://www.medicinenet.com/cre_infection/article.htm. Accessed March 21, 2016.
Pullen LC. Carbapenem-Resistant Enterobacteriaceae: Emerging Threat. Medscape.com.
http://www.medscape.com/viewarticle/852198. Published October 06, 2015. Accessed March 23,
2016.
Sprenger M, Fukuda K.: New mechanisms, new worries. Science 2016; 351: 1263-1264

6. alternative treatments. These will take time to come into use, however. Until then – and forever
after - we have to rely on responsible use of antibiotics.
Update: In a recent (March 2016) issue of Science, the “Insights” section presented further
warnings on the spread of extremely antibiotic resistant CRE. Colistin, an antibiotic that was
developed about half a century ago but was not widely used because of its toxicity, has recently
been reemployed as an emergency measure to fight multiresistant CRE organisms. However,
organisms resistant to colistin itself have already appeared. The “Insights” review refers to recent
studies showing that colistin resistance, the so-called mcr-1 gene, can be carried on plasmids, which
is not good news because this mechanism greatly facilitates its spread.
RESOURCES
Biggest Threats. Centers for Disease Control and Prevention.
http://www.cdc.gov/drugresistance/biggest_threats.html. Updated August 26, 2015. Accessed
March 5, 2015.
Witze A, Morello L, Turner M. Scientific advice: Crisis counselors. Volcanic eruptions, oil spills and
bacterial outbreaks all land in the laps of government science advisers, and put them to the test.
Nature 2014; 512: 360-363
Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. Molecular mechanisms of antibiotic
resistance. Nat. Rev. Microbiol. 2015; 13: 42-51.
Davis CP. CRE bacteria infection: Symptoms and treatment. MedicieNet.com.
http://www.medicinenet.com/cre_infection/article.htm. Accessed March 21, 2016.
Pullen LC. Carbapenem-Resistant Enterobacteriaceae: Emerging Threat. Medscape.com.
http://www.medscape.com/viewarticle/852198. Published October 06, 2015. Accessed March 23,
2016.
Sprenger M, Fukuda K.: New mechanisms, new worries. Science 2016; 351: 1263-1264