Emergence of ESBLs“Extended Spectrum B-Lactamases”

Dr Ahmed Abu SamraHoly Family Hospital

2008

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

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 .

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.

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.

Modes of resistance

The 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.

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.

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

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

Multi-resistant

Additionally 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

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.

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 .

Epidemiology of ESBL

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

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.

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

*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%

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

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.

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

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

Risk Factors for Colonization and Infection with ESBLs

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

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.

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.

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

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.

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

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.

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.

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

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.

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 .

Infection Control

This 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.

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.

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

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 .

*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

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

ESBL effect with gram-ve neonatal septicemia

outcomeCases with isolates

producing ESBL)%(

Cases with isolates not producing

ESBL)%(

survival38.764.2

death61.235.7

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.

The end • Use antibiotics wisely• treat infection not colonisation.• Prevent spread of Infection • Wash hands thoroughly

• Thank you

Diversity of ESBL Types

*

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.

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.

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

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 .

OXA

*The simultaneous production of carbapenem-hydrolyzing metaloenzyme and an aztreonam hydrolyzing OXA enzyme can readily lead to resistance to all B-lactam antibiotics

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

Others

VEB-1: resistance to non B-lactam antibiotics

BES-1GES.

TLA.

SFO.

IBC.

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