Bacterial Resistance to Antibiotics (page 2)
(This chapter has 4 pages)
© Kenneth Todar, PhD
The first signs of antibiotic resistance
There has probably been a gene pool in nature for resistance to
antibiotic as long as there has been for antibiotic production,
for most microbes that are antibiotic producers are resistant to their
own antibiotic. In retrospect, it is not surprising that resistance to
penicillin in some strains of staphylococci was
recognized almost immediately after introduction of the drug in 1946.
after their introduction in the late 1940s, resistance to
streptomycin, chloramphenicol and tetracycline was noted. By 1953,
during a Shigella outbreak in Japan, a strain of the dysentery
bacillus (Shigella dysenteriae)
was isolated which was
multiple drug resistant, exhibiting resistance to chloramphenicol,
tetracycline, streptomycin and the sulfonamides. Over the years, and
continuing into the present almost every known bacterial pathogen has
developed resistance to one or more antibiotics in clinical use.
Evidence also began to accumulate that bacteria could pass
genes for drug
resistance between strains and even between species. For example,
antibiotic-resistance genes of staphylococci are carried on
plasmids that can be exchanged with Bacillus,
providing the means for acquiring additional genes and gene
Some are carried on transposons, segments of DNA that can exist either
the chromosome or in plasmids. In any case, it is clear that
genes for antibiotic resistance can be exchanged between strains and
species of bacteria by means of the processes of horizontal gene
Multiple drug resistant organisms
Multiple drug resistant organisms are resistant to treatment with
several, often unrelated, antimicrobial agents as described above in Shigella. Some of the most
important types of multiple drug resistant
that have been encountered include:
MRSA - methicillin/oxacillin-resistant Staphylococcus aureus
VRE - vancomycin-resistant enterococci
ESBLs - extended-spectrum beta-lactamases (which are resistant to
cephalosporins and monobactams)
PRSP - penicillin-resistant
MRSA and VRE are the most commonly encountered multiple drug resistant
organisms in patients residing in non-hospital healthcare facilities,
such as nursing homes and other long-term care facilities. PRSP are
more common in patients seeking care in outpatient settings such as
physicians' offices and clinics, especially in pediatric settings.
ESBLs are most often encountered in the hospital (intensive care)
setting, but MRSA and VRE also have a significant nosocomial ecology.
Methicillin-Resistant Staph Aureus.
MRSA refers to
aureus", which are strains of the bacterium that are resistant
to the action of
methicillin, and related beta-lactam antibiotics (e.g. penicillin and
have evolved resistance not only to beta-lactam
antibiotics, but to several classes of antibiotics. Some MRSA are
resistant to all but one or two antibiotics, notably
vancomycin-resistant. But there have been several reports of VRSA
(Vancomycin-Resistant Staph Aureus) that are troublesome in the ongoing
battle against staph infections.
MRSA are often sub-categorized as Hospital-Associated MRSA (HA-MRSA) or
(CA-MRSA), depending upon the
circumstances of acquiring disease. Based on current data, these
are distinct strains of the bacterial species.
HA-MRSA occurs most frequently among patients who undergo invasive
medical procedures or who have weakened immune systems and are being
treated in hospitals and healthcare facilities such as nursing homes
and dialysis centers. MRSA in healthcare settings commonly causes
serious and potentially life threatening infections, such as
bloodstream infections, surgical site infections or pneumonia.
In the case of HA- MRSA, patients who already have an MRSA infection or
who carry the bacteria on their bodies but do not have symptoms
(colonized) are the most common sources of transmission. The main mode
of transmission to other patients is through human hands, especially
healthcare workers' hands. Hands may become contaminated with MRSA
bacteria by contact with infected or colonized patients. If appropriate
hand hygiene such as washing with soap and water or using an
alcohol-based hand sanitizer is not performed, the bacteria can be
spread when the healthcare worker touches other patients.
MRSA infections that occur in otherwise healthy people who have not
been recently (within the past year) hospitalized or had a medical
procedure (such as dialysis, surgery, catheters) are categorized as
community-associated (CA-MRSA) infections. These infections are usually
skin infections, such as abscesses, boils, and other pus-filled
About 75 percent of CA-MRSA infections are localized to skin and soft
tissue and usually can be treated effectively. However, CA-MRSA strains
display enhanced virulence, spread more rapidly and cause more severe
traditional HA-MRSA infections, and can affect vital organs leading to
widespread infection (sepsis), toxic shock syndrome and pneumonia. It
is not known why some healthy people develop CA-MRSA skin infections
that are treatable whereas others infected with the same strain develop
severe, fatal infections.
Studies have shown that rates of CA-MRSA infection are growing fast.
One study of children in south Texas found that cases of CA-MRSA had a
14-fold increase between 1999 and 2001.
CA-MRSA skin infections have been identified among certain populations
that share close quarters or experience more skin-to-skin contact.
Examples are team athletes, military recruits, and prisoners. However,
more and more CA-MRSA infections are being seen in the general
community as well, especially in certain geographic regions.
Also, CA-MRSA are infecting much younger people. In a study of
Minnesotans published in The Journal of the American Medical
Association, the average age of people with MRSA in a hospital or
healthcare facility was 68. But the average age of a person with
CA-MRSA was only 23.
More people in the U.S. now die from MRSA infection than from AIDS.
aureus was responsible for an estimated 94,000 life-threatening
infections and 18,650 deaths in 2005, as reported by CDC in the Oct.
17, 2007 issue of The Journal of the American Medical Association. The
national estimate is more than double the invasive MRSA prevalence
reported five years earlier. That same year, roughly 16,000 people in
the U.S. died from AIDS, according to CDC. While most invasive
MRSA infections could be traced to a hospital stay or some other health
care exposure, about 15% of invasive infections occurred in people with
no known health care risk. Two-thirds of the 85% of MRSA infections
that could be traced to hospital stays or other health care exposures
occurred among people who were no longer hospitalized. People over age
65 were four times more likely than the general population to get an
MRSA infection. Incidence rates among blacks were twice that of the
general population, and rates were lowest among children over the age
of 4 and teens.
(ESBL) - producing Gram-negative
bacteria Extended-spectrum beta-lactamases (ESBLs) are
lactamases that have recently been
found in the Enterobacteriaceae.
ESBLs are capable of
hydrolyzing penicillins, many narrow spectrum
cephalosporins, many extended-spectrum cephalosporins,
oxyimino-cephalosporins (cefotaxime, ceftazidime), and monobactams
(aztreonam). Beta-lactamase inhibitors (e.g. clavulanic acid) generally
inhibit ESBL producing strains. ESBL producing isolates are most
commonly Klebsiella ssp,
predominantly Klebsiella pneumoniae,
and E. coli, but they have
been found throughout the Enterobacteriaeae.
Because ESBL enzymes are plasmid mediated, the genes encoding these
enzymes are easily transferable among
different bacteria. Most of these plasmids not only contain DNA
encoding ESBL enzymes but also carry genes conferring resistance to
several non-ß-Lactam antibiotics. Consequently, most
ESBL isolates are resistant to many classes of antibiotics. The most
frequent coresistances found in ESBL-producing organisms are
aminoglycosides, fluoroquinolones, tetracyclines, chloramphenicol, and
sulfamethoxazole-trimethoprim. Treatment of these multiple
organisms is a therapeutic challenge.
ESBL producing strains have been isolated from abscesses, blood,
catheter tips, lung, peritoneal fluid, sputum, and throat cultures.
apparently have a world-wide distribution. Rates of isolation vary
greatly worldwide and within geographic areas and are
rapidly changing over time. In the United States, between 1990 to 1993,
survey of the intensive care units of 400 hospitals recorded an
increase from 3.6% to 14.4% in ESBL producing strains of Klebsiella. In
1994, the CDC reported that 8% of Klebsiella
spp from a few large
centers produced ESBLs. In Europe, as of 1995, ESBLs occurred in
of Klebsiella ssp from
patients in ICUs, although they were found in patients up to
30%-40% frequency in
Known risk factors for colonization and/or infection with organisms
harboring ESBLs include admission to an intensive care unit, recent
surgery, instrumentation, prolonged hospital stay and antibiotic
exposure, especially to extended-spectrum beta-lactam antibiotics.
Use of extended-spectrum antibiotics exerts a selective pressure for
emergence of ESBL producing strains. The resistance plasmids can then
transferred to other bacteria, not necessarily of the same species,
conferring resistance to them.
The lower GI tract of colonized patients is the main
reservoir of these organisms. Gastrointestinal carriage can
persist for months. In some cities in the United States, nursing
homes may be an important reservoir of ESBL producing strains. Nursing
home patients are more likely to be treated empirically with
antibiotics, and thus on admission to a hospital to be more likely to
possess an ESBL producing strain. Patient to patient transmission of
ESBL producing organisms occurs via
the hands of hospital staff. It is known that ESBL
producing strains can survive in the hospital environment.
Nosocomial infections in patients occur through the
administration of extended spectrum beta-lactam antibiotics or via
transmission from other patients via health care workers, who become
colonized with resistant strains via exposure to
patients or other health care workers. Spread of ESBL producing strains
can be minimized by good infection
control practices, especially by good hand washing