Dr.T.V.Rao MD 1

ESBL PRODUCING BACTERIATherapeutic Options

Dr.T.V.Rao MD

Dr.T.V.Rao MD 2

Beginning of ESBL Producers• ESBL producing organisms were first described in the

1980s and first reported in the UK in 2000 affecting in Klebsiella spp; Gram negative / “coliform” organisms. Resistance is genetically encoded and may be passed from one species to another; even between species.

• They also confer resistance to penicillin's and are often linked with resistance mechanisms to other classes of antimicrobials thus limiting the range of options available for their treatment.

Dr.T.V.Rao MD 3

Drug Resistance associated with ESBL and AmpC

• ESBL and AmpC are enzymes produced by certain Gram negative bacteria that confer resistance to 3rd

generation or “extended spectrum” cephalosporin's e.g. ceftazidime and cefotaxime

Dr.T.V.Rao MD 4

Is ESBL a life Threating or Just Coloniser ???

Infections with extended-spectrum beta-lactamase (ESBL) producing Gram negative bacilli can be serious and life-threatening. Examples include bloodstream infection, meningitis, peritonitis and hospital-acquired pneumonia.• At the other extreme, ESBL-producing organisms may be

associated with colonization rather than true infection.• A common example is urinary tract colonization,

especially associated with indwelling urinary catheters

Dr.T.V.Rao MD 5

ESBL’s can be Life threating• Bloodstream infection with ESBL-

producing Gram negative bacilli is typically associated with a portal of entry such as a central venous catheter, urinary tract infection, pneumonia or an intra-abdominal infection. Meningitis due to ESBL-producing organisms usually follows neurosurgical procedures

Dr.T.V.Rao MD 6

Resistant bacteria ( coliforms ) colonised in the large Intestine

• These resistance mechanisms affect the facultatively anaerobic Gram negative organisms (“coliforms”). These organisms are found in very high numbers colonizing the large intestine and are most commonly implicated in infections of the gastrointestinal, hepato-biliary and genitor-urinary systems.

Dr.T.V.Rao MD 7

ESBL and Urinary Tract Infections

• The majority of ESBL and AmpC related infections are of the urinary tract.

Dr.T.V.Rao MD 8

ESBL detection in Laboratory• ESBLs were detected using the disc

approximation and double-disc synergy methods and confirmed with cefotaxime and ceftazidime Etest ESBL strips (AB Biodisk). For the disc approximation test, clavulanate diffusion from an amoxicillin–clavulanate (AMC30) disc was used to test for synergy with cefotaxime, ceftazidime, cefuroxime, cefepime and cefixime (Oxoid) as described by (Sonnevend et al., 2006).

Dr.T.V.Rao MD 9

Performing Double disc Synergy test

• For the double-disc synergy test, a ceftazidime disc (30 μg) was placed 30 mm away from a disc containing amoxicillin–clavulanate (60/10 μg). ESBL production was considered positive when an enhanced zone of inhibition was visible between the β-lactam and β-lactamase inhibitor-containing discs (Cormican et al., 1996; Livermore & Yuan, 1996).

Dr.T.V.Rao MD 10

Performing E-test for ESBL Detection

• the Etest, ESBL strips containing ceftazidime and ceftazidime–clavulanate and strips containing cefotaxime and cefotaxime–clavulanate were used to determine the MIC ratio according to the manufacturer's instructions (AB Bio disk). Cultures were incubated aerobically at 37 °C for 18–24 h.

Dr.T.V.Rao MD 11

ESBL infection occurs due to Poor Hygienic Practices in the Hospitals

• These organisms are part of the faecal flora and as such are of particular relevance to urinary catheters and faecally contaminated items. Transmission occurs due to poor hand hygiene and contaminated fomites in the clinical setting. Hand hygiene is of paramount importance and alcohol hand gel is very effective against ESBL and AmpC producing organisms. Adherence to good infection control practice regarding urinary catheter care and personal hygiene are vital.

Dr.T.V.Rao MD 12

Shall we use Cephalosporin's in ESBL Producers or Not ???

Dr.T.V.Rao MD 13

Does the ESBL’s have different sensitivities to different Cephalosporin's

• How frequently are ESBL producing organisms “susceptible” to third generation cephalosporin's? The answer to this question depends on which breakpoints are used. Differences between different organizations are quite considerable.

Dr.T.V.Rao MD 14

CLSI and EUCAST guidelines differ

• The CLSI (Clinical and Laboratory Standards Institute) denotes third and fourth generation cephalosporin susceptibility as a minimal inhibitory concentration (MIC) ≤ 8 μg/mL whereas EUCAST denotes a cephalosporin MIC of ≤ 1

Dr.T.V.Rao MD 15

Review studies show Cephalosporin resistance in ESBL’s to evaluated Individually

• The review of studies which have evaluated collections of ESBL producing organisms using standard CLSI disk diffusion or MIC breakpoints,13-49% of isolates were cefotaxime “susceptible”, 36-79% ceftriaxone “susceptible”, 11-52% ceftazidime “susceptible” and 10-67% aztreonam “susceptible

Dr.T.V.Rao MD 16

Why Cephalosporin Resistance differ Individually

• The reasons for this apparent susceptibility to some cephalosporin's is the result of varying degrees of hydrolysis of cephalosporin's by different β-lactamases and enhance penetration through the bacterial outer membrane of some cephalosporin's compared to others.

Dr.T.V.Rao MD 17

Enzymatic mechanisms of Resistance Make Difference

• Regardless, extended-spectrum cephalosporin MICs of 2-8 μg/mL are 4-8 dilutions higher than those seen in the same strain producing only the parent TEM-1, TEM-2 or SHV-1 β-lactamase (0.03-0.25 μg/mL)

Dr.T.V.Rao MD 18

Use of Cephamycins in ESBL Producers

• Cephamycins (for example, cefoxitin and cefotetan) are also stable to hydrolysis by ESBLs. Various other cephalosporins are sometimes partially stable to hydrolysis by certain ESBLs, but in general are not recommended for treatment of ESBL-producing organisms.

Dr.T.V.Rao MD 19

Considering other Drug Options• In vitro, the

carbapenems (including imipenem, meropenem, doripenem and ertapenem) have the most consistent activity against ESBL producing organisms, given their stability to hydrolysis by ESBLs.

Dr.T.V.Rao MD 20

Available options in Treating ESBL Producers

• Infections with ESBL-producing organisms can be life threatening. In vitro studies would suggest that Carbapenems or non-beta-lactam antibiotics should be optimal therapy for ESBL-producers since they are not hydrolysed by ESBLs

• Non-beta-lactam antibiotics such as fluoroquinolones, aminoglycosides, tigecycline and polymyxins round out the armamentarium against ESBL-producers

Dr.T.V.Rao MD 21

Newer Options in Dealing with ESBL Infected Patients

• Colistin and polymyxin B also have activity against most ESBL producing strains but dosing regimens are not well-established for these antibiotics, especially in critically ill individuals with renal failure. There are case reports of success with colistin or polymyxin B for treating serious infections with multiply resistant Gram negative infections.

Dr.T.V.Rao MD 22

ESBL’s increases Morbidity and Mortality

• ESBL-producing organisms have the capability to be associated with infections that have high underlying mortality. Inadequate treatment of such infections may increase the mortality still further. At the present time, Carbapenems are regarded as the treatment of choice for serious infections due to ESBL producers

Dr.T.V.Rao MD 23

Poor Infection Control Measures in the Hospital raises Multidrug resistant Pathogens

• However, the spread of carbapenemase producing organisms (mainly as a result of poor infection control) threatens the long-term utility of this drug class.

Dr.T.V.Rao MD 24

Updating Laboratory• All the

Laboratories are requested to Update the Antibiograms interpretation as per current CLSI guidelines.

Dr.T.V.Rao MD 25

Use of WHONET Strengthens our Microbiology Laboratory

Reporting

Dr.T.V.Rao MD 26

Hand Washing Can Still Reduce Spread of ESBL Producers

Dr.T.V.Rao MD 27

• The Programme Created by Dr T.V.Rao MD for Clinical and

Laboratory Professionals• Email

• doctortvrao@gmail.com