Download - Emergence of ESBLs “ Extended Spectrum B-Lactamases ” Dr Ahmed Abu Samra Holy Family Hospital 2008
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Emergence of ESBLs“Extended Spectrum B-Lactamases”
Dr Ahmed Abu SamraHoly Family Hospital
2008
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Introduction*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes) capable of hydrolyzing the extended spectrum CS was published.
* TEM-1 and SHV-1 * The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001
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What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics have a β-lactam ring in their structure.
• The effectiveness of these antibiotics relies on their ability to reach the PBP [penicillin binding protein] on the bacterial cell wall intact and their ability to bind to it and to disrupt cell wall synthesis destruction of bacteria .
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Modes of resistance• There are 2 main modes of bacterial
resistance to β-lactams.1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the β-lactam ring.
2. The second mode of β-lactam resistance is due to possession of altered penicillin-binding proteins.
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Modes of resistance• The first mode : If the bacteria produces the
enzymes β-lactamase or penicillinase, these enzymes will break open the β-lactam ring of the antibiotic, rendering the antibiotic ineffective.
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Modes of resistanceThe genes encoding these enzymes may
be inherently present on the bacterial 1. chromosome 2. or may be acquired via plasmid transfer
β-lactamase gene expression may be induced by exposure to beta-lactams.
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Modes of resistance• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and inactivating a wide variety of ß-Lactams, including third-generation cephalosporins, penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ß-Lactamase enzymes commonly found in the Enterobacteriaceae family.
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Resistance • ESBLs are generally well inhibited by ß-
Lactamase inhibitors and usually retain sensitivity to the =
• carbapenems ertapenem, imipenem, meropenem• cephamycins cefoxitin• beta-lactamase inhibitors clavulanic acid, sulbactam• However these antibiotics may be inactive due to other resistance mechanisms
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Mode of resistance• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic material between the same bacterial clone as well as different clones.
• i.e. genetic material can be transferred from an E. coli to a Klebsiella or to another Klebsiella
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Multi-resistantAdditionally these plasmids often carry genes for
resistance to other classes of antibiotics• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multi-resistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections
Increased mortality related to delays in receiving effective antibiotic
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Mode of resistance • The second mode of β-lactam resistance is due
to possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance include methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae.
• Altered PBPs do not necessarily rule out all treatment options with β-lactam antibiotics.
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Definition of ESBLs
*The ESBLs are B-lactamases capable of conferring bacterial resistance to the penicillins, 1st,2nd,3rd GCS, and aztreonam (but not the cephamycins or carbapenemes) by hydrolysis of these antibcs, and which are inhibited by b-lactamase inhibitors such as clavulanic acid.
*The most common ESBL producing organisms are Klebsiella pneumonia, E.coli
and other K.spp .
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Epidemiology of ESBL
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Europe *Although the initial reports were from Germany and
England, the vast majority of reports in the first decade were from France.
*1986 :first large outbreak; 54 pts in ICU were infected and spread to 4 other wards then occurred
*By the early 1990s, 25-35% of nosocomially acquired K.pneumonia isolates in France were ESBL producers.
*The proportion fell from 19.7% in 1996 to 7.9% in 2000.
*Outbreak of infection with ESBL producing organisms have now been reported from every European country
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Europe
* Large study from >100 ICUs found that the prevalence of ESBLs in Klebsiella ranged from as low as 3% in Sweden to as high as 34% in Portuglal.
* A survey done in turkey revealed that 58% of 193 Klebsiella spp isolated from ICUs harbored ESBLs.
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North America* 1989 :significant infections with TEM-10
producing K.pneumonia were noted. *NNIS from 1998 to 2002 reveal that:
1 -6.1% of K.pneumonia isolates from 110 ICUs were resistant to 3rd GCSs.
2 -In at least 10% of ICUs resistance exceeded 25%.
3 -In non-ICUs inpt areas: 5.7% 4 -outpt areas just 1.8% were ceftazideme
resistant
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*Africa and middle east : -documented in many countries.
- no national surveillance has published- 36.1% of K.pnemonia isolates collected in
single south Africa hospital in 1999 were ESBLs
* Australia: -The 1st isolates detected were collected
between 1986-1988.- Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%
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Asia* IN 1988, isolates of K.pneumonia from China
which contained SHV-2 were reported. *In a major teaching hospital in Beijing, 27% of
E.coli and K.pneumonia blood Cx isolates between 1997-99 were ESBL producers.
*National survey have indicated that the rates of ESBL production by K.pneumonia have been as low as 5% in Japan and 20-50 % elsewhere in Asia
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Molecular Epidemiology of ESBLs *>50 studies have targeted the molecular typing
methods in the study of ESBL epidemiology,3000pt.
*Mostly K.pneumonia was addressed *Klebseillae has the well noted adaptation to the
hospital environment, survive longer on hands and environmental surfaces, facilitating cross infection within hospital.
*A no. of outbreaks have been described with dissemination of a single clone of genotypically identical organism.
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Molecular epidemiology *Recent reports have described the clonal
dissemination of 5 diff ESBL producing Klebsiellae strains in the same unit at the same time.
*Additionally, members of a single epidemic strain may carry diff plasmids
*furthermore, genotypically nonrelated strains may produce the same ESBL due to plasmid transfer from species to another.
*The same strain at the same unit may be mediated by diff plasmid via the effect of
antibiotic pressure or plasmid transfer
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Molecular epidemiology* Transfer from hospital to hospital, from city to
city, and from country to country has been documented. A notable clone has been SHV-4 K. which has spread to multiple hospitals in France and Belgium.
*ICU are often the epicenter for ESBL production in hospitals, in one large outbreak, more than 40% off all the hospital ESBLs were from pts in intensive care units.
*Other units: burn, neurosurgical, obs and gyn, hematology and oncology, and geriatric units
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Risk Factors for Colonization and Infection with ESBLs
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Risk Factors• Seriously ill pts with prolonged hospital stay and in
whom invasive medical devices are present for prolonged duration.
• In one study, the median length of hospital stay prior to isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was applied in 69% of pts and central venous catheters were found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor
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Community acquired infections• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from non-hospitalized pts in France in 1993 revealed no truly community acquired infections.
• In the last 3 years there have been several reports of true community acquired infections or colonization with E.coli from Spain, Israel, UK, Canada and Tanzania.
* The cause of this sudden upsurge isn't yet clear, but associations with foodstuffs, animal consumption of antibiotics and frequent pt contact with health care facilities need to be explored.
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Modes of spread within hospitals
• It seems that the most significant reservoir of the microorganism is the GIT of colonized pts and that transmission occurs mostly via the hands of nursing staff.
• Hand carriage has been documented by most investigators.
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Modes of spread within hospitals
• In these instances, the hand isolates were genotypically identical to isolates which caused infection in pts.
• The use of artificial nails promotes long term carriage and has been associated with at least one outbreak
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Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs, glass thermometers, and bronchoscopes. These isolates were resembling the infecting strains.
• For every pt with ESBL infection, at least one other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care workers, but its rare and seldom prolonged except for Salmonella spp.
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Infection control interventions appropriate to controlling spread of ESBL-producing organisms within a hospital
• Identify patients infected with ESBL-producing organisms by use of appropriate detection methods in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs plated onto selective media
• Perform molecular epidemiologic analysis of strains from infected or colonized patients (for example, by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if numerous strain types are demonstrated
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Infection control…
*Although common environmental sources of infection have rarely been discovered, when they are recognized their impact on arresting the outbreak of infection can be dramatic.
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Infection control…In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were colonized with ESBLs. their Disinfection curtailed the outbreak.
Contact isolation: by the use of gloves and gowns when contact colonized pts can lead to significant reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in order to adequately control this outbreak.
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Infection control…• Selective Digestive
Decontamination:
- 3 groups successfully used SDD with polymyxin,neomycin, and nalidixic acid, colistin and tobramycin, or norfloxacin to interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR to aminoglycosides
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Infection control…
• A recent study has utilized a nasal spray with povidine-iodine as a means of decolonizing the upper respiratory tract.
• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led to management of an outbreak.
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Infection Control…
• *Close attention to practices that may lead to breakdown in good infection control.
• *Change in antibiotic policy may play a greater role in this setting.
*In 2 institutions in Texas, the use of ceftazidime declined by 27% and 71% respectively, while the use of piperacillin-tazobactam increased by
14% and 40% respectively .
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Infection ControlThis resulted in a significant decline (50% and 32%,respectively)in ceftazidime-resistant K.pneumonia .
Furthermore, the rate of piperacillin-Tazobactam resistant Klebsiella declined by 36% and 47% respectively, despite the significant increase in use of piperacillin-tazobactam.
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Treatment of ESBLs *Resistance to many B-lactam antibiotics
*Furthermore,however,they carry resistance to aminoglycoside and tri-sulfa.
*Increasing reports of quinolone resistance will limit the role of these antibiotics in the future.
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Recommended Rx for ESBLs Infection typeRx of choice2nd line Rx
UTIQuinoloneAmox-clav acid
BacteremiacarbapenemQuinolone
Hospital acquired pneumonia
carbapenemquinolone
Intra-abdominal infection
carbapenemQuinolone+ metronidazole
meningitismeropnemIntrathecal polymyxinB
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Drawbacks… *The carbapenems (including imipenem,
meropnem, and ertapenem) have the most consistent activity against ESBL producing organisms
* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly rare.
- the epidemiology has yet to be studied - 8 pts with carbapenem resistance were identified
in a single intensive care unit .
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*All of them had previously been treated with imipenem.
* Since no other antibiotic options were available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement of infection control.
* Tigecycline or polymxins may be considered in Rx of carbapenem-
resistant klebseilla
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Outcome of ESBLs infections *Increased morbidity and mortality.
*Increased duration of hospital stay : Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with infection due to ESBLs had a median length of hospital stay postinfection of 29 days compared to 11days in non-B-lactamase infected pts.
*Increased costs
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ESBL effect with gram-ve neonatal septicemia
outcomeCases with isolates
producing ESBL)%(
Cases with isolates not producing
ESBL)%(survival38.764.2
death61.235.7
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Conclusion • The ESBL-producing organisms are a breed of multidrug-resistant
pathogens that are increasing rapidly and becoming a major problem in the area of infectious diseases.
• High rates of third-generation cephalosporin use have been impli-cated as a major cause of this problem.
• Problems associated with ESBLs include multidrug resistance, difficulty in detection and treatment, and increased mortality.
• Of all available anti-microbial agents, carbapenems are the most active and reliable treatment options for infections caused by ESBL isolates.
• However, overuse of carbapenems may lead to resistance of other gram-negative organisms.
• Therefore, restricting the use of third-generation cephalo-sporins, along with implementation of infection control measures, are the most effective means of con-trolling and decreasing the spread of ESBL isolates.
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The end • Use antibiotics wisely• treat infection not colonisation.• Prevent spread of Infection • Wash hands thoroughly
• Thank you
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Diversity of ESBL Types
*
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SHV* Sulfhydryl variable
*SHV-1 as the usual B-lactamase enzyme *In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by replacement of glycine by serine at the 238 position.
*This single mutation accounts for the extended spectrum properties of this enzyme=SHV-2
*Found in wide range of enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter
spp.
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TEM* TEM-1 first isolated from a pt in Greece
named TEMoneira. {E.coli} *Over 100 TEM type, the majority are ESBLs.
*TEM-12 for example came from a neonatal unit in UK which had been stricken by an outbreak of Klebsiella oxytoca producing TEM-1 and was treated with ceftazidime.
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CTX-M and Toho B-lactamases *The name CTX reflects the hydrolytic activity
of these B-lactamases against cefotaxime. *The same organism may harbor both CTX-m
type and SHV type more antbc resistance. *Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university) *The no. of CTX-M type is rapidly expanding,
they have now been detected world wide although for some years they were detected in certain geographic areas: South America, Eastern Europe , and Far East
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OXA* So named bcz of their oxacillin-hydrolyzing
abilities . *they predominantly occur in P.aeruginosa, but
have been detected in many other gram -ve bacteria.
*OXA-1 which is the commonest OXA enzymes has been found in 1-10% Of E.coli isolates.
*Originally discovered in Ankara. *Later OXA-18,19,28 discovered in France.
*Frank resistance to cefotaxime and sometimes ceftazideme and aztreonam .
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OXA
*The simultaneous production of carbapenem-hydrolyzing metaloenzyme and an aztreonam hydrolyzing OXA enzyme can readily lead to resistance to all B-lactam antibiotics
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PER *Share only around 25-27% homology with known
TEM and SHV type ESBLs *PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates. *In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1 *PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera. *Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected in Italy resistance to all B-lactam antibiotics
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OthersVEB-1: resistance to non B-lactam antibioticsBES-1GES.TLA.SFO.IBC.
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Infection Control When ESBLs are Not Endemic
*When empirical antibiotic therapy inactive against ESBL producers are used, this will increase the morbidity and mortality.
*The initial stages of the infection control program in a unit which has not been affected by ESBLs should include:
1-performance of rectal swabs for colonization 2-evaluation of the presence of a common
environmental source of infection. 3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized pts