esbl producing bacteria - management

MANAGEMENT OF INFECTIONS CAUSED BY ESBL PRODUCING BACTERIA : 

MANAGEMENT OF INFECTIONS CAUSED BY ESBL PRODUCING BACTERIA Dr.H.R.V.RAJKUMAR CONSULTANT MICROBIOLOGIST KAMINENI HOSPITALS

ESBLs INCLUDE : 

ESBLs INCLUDE Enzymes that mediate resistance to Penicillins, 3rd generation Cephalosporins, Aztreonam. But not to Cephamycins (Cefoxitin & Cefotetan) and Carbapenems. Most of these are derived from point mutations of older TEM and SHV beta-lactamases that normally confer high level resistance to early Penicillins and 1st generation Cephalosporins. Commonly produced by E.coli and Klebsiella but may also occur in Enterobacter, Salmonella, Proteus, Citrobacter, Morganella, Serratia, Shigella etc.

NEWER ESBLs INCLUDE : 

NEWER ESBLs INCLUDE These are not mutated from TEM and SHV. CTX-M types – Evolved separately, at least some of them via the escape and mutation of chromosomal beta-lactamases of Kluyvera spp. Over 35 types are known. Spread into community. VEB-1: Acinetobacter boumanni – Vietnam/France. PER-1: Pseudomonas and Acinetobacter – Turkey OXA-2 & OXA-10 mutants: Pseudomonas – Turkey.

ESBLs ARE CLINICALLY IMPORTANT : 

ESBLs ARE CLINICALLY IMPORTANT They destroy Cephalosporins, workhorse hospital antibiotics, given as first-line agents to many severely ill patients. Delayed recognition and inappropriate treatment with Cephalosporins → Increased mortality. ESBL-mediated resistance is not always obvious in vitro to all Cephalosporins. Many ESBL producers are multi-resistant to non-beta-lactam antibiotics – Quinolones, Aminoglycosides, Co-trimoxazole.

Slide 5: 

ESBL Co-resistance Aminoglycosides Fluoroquinolones Tetracyclines Sulfamethoxazole-Trimethoprim Chloramphenicol

EPIDEMIOLOGY : 

EPIDEMIOLOGY Prevalence Probably underestimated. Significant proportion of laboratories do not perform tests specifically designed to detect ESBLs. Increasing Considerable geographical variation. Risk factors Central venous or arterial catheter, gastrostomy or jejunostomy tube, urinary catheter Emergency intra-abdominal surgery GI colonization Prolonged ICU or hospital stay Prior antibiotics (including 3rd gen cephalosporins) Number and duration of antibiotics probably most important factors Prior nursing home stay Severity of illness Mechanical ventilation

SO IT IS IMPORTANT FOR ALL LABORATORIES TO DETECT AND REPORT ESBL PRODUCING ORGANISMS TO PREVENT TREATMENT FAILURE AND REDUCE MORTALITY : 

SO IT IS IMPORTANT FOR ALL LABORATORIES TO DETECT AND REPORT ESBL PRODUCING ORGANISMS TO PREVENT TREATMENT FAILURE AND REDUCE MORTALITY

ESBL DETECTION METHODS : 

ESBL DETECTION METHODS Double disc synergy test Inhibitor potentiated disc diffusion test. Broth micro dilution method. E test.

Slide 11: 

E test for ESBLs Cefotaxime Cefotaxime + clavulanate

TREATMENT OPTIONS : 

TREATMENT OPTIONS CEPHAMYCINS (Cefoxitin and Cefotetan) – Though Cephamycins are resistant to most ESBLs they should be used carefully, because they develop resistance quickly due to reduced expression of OMPs. Further Cephamycins are hydrolyzed by other type of beta-lactamases called Amp C.

TREATMENT OPTIONS : 

TREATMENT OPTIONS Beta lactamase inhibitor combinations. BLI acts as a suicide substrate that forms a stable intermediate, rendering the ESBL enzyme inactive. Clavulanic acid, Tazobactam, Sulbactam.

Problems associated with using beta-lactams with or without BLIs : 

Problems associated with using beta-lactams with or without BLIs Inoculum effect If the inoculum of the testing organism is increased by 100 fold, MIC increases very much dramatically. Inoculum CTX CTZ AZT 5 x 105 cfu 2 1 0.5 5 x 107 cfu 256 32 32

Problems associated with using beta-lactams with or without BLIs : 

Problems associated with using beta-lactams with or without BLIs Clinical importance of Inoculum effect When bacterial killing and destruction of the antibiotic occur simultaneously, liberated enzyme from the dead cells reduces the external concentration of the antibiotic. The larger the inoculum effect is - the more susceptible the drug is to hydrolysis by the organism’s beta-lactamases.

Problems associated with using beta-lactams with or without BLIs : 

Problems associated with using beta-lactams with or without BLIs Clinical importance of Inoculum effect Higher inocula occur in endocarditis, meningitis, septic arthritis, osteomyelitis, abscesses and other deep seated infections. When treated with BLI combinations the patient initially shows improvement but later deteriorates rapidly, owing to faster destruction of the antibiotic by the enzyme released from the dead bacteria.

Problems associated with using beta-lactams with or without BLIs : 

Problems associated with using beta-lactams with or without BLIs BLI combinations are not useful when bacteria produce ESBLs along with other types of beta-lactamases like Amp C. Amp C beta-lactamases Chromosomal, Class C beta-lactamases Produced by several enterobacteriaceae and Pseudomonas Confers resistance to most beta-lactams including BLI combinations. Treatment of choice – 4th generation cephalosporins like Cefepime or Carbapenems. (Cefepime – Think about inoculum effect)

Problems associated with using beta-lactams with or without BLIs : 

Problems associated with using beta-lactams with or without BLIs Plasmid mediated Amp C Transfer of genes from chromosomes to plasmids Occurs in E.coli, Klebsiella, Citrobacter, Enterobacter, Proteus etc. MIR-1, CMY-2, BIL-1, FOX-1, MOX-1, CMY-3 Detection of plasmid mediated Amp C is difficult by routine tests because it is not inducible. So all the labs should detect both ESBLs and Amp C. We have bacteria producing 3-6 types of beta lactamases including BL of different classes.

TREATMENT OPTIONS : 

TREATMENT OPTIONS Carbapenems Meropenem, Imipenem+Cilastatin, Ertapenem Highly resistant to ESBLs – due to the trans-6 hydroxy ethyl group. They have significant PAE even against Pseudomonas Resistance mechanisms Production of Metallo carbapenamases (Class B beta-lactamases) by some-Acinetobacter and Pseudomonas strains Efflux pumps Changes in OMPs Aztreonam is the drug of choice in treating infections caused by carbapenamase producing bacteria.

CONCLUSIONS : 

CONCLUSIONS Carbapenems (Imipenem, Meropenem) are consistently active and are the treatment of choice in severe infections due to ESBL producers. Susceptibilities of ESBL producers to BLI combinations vary with the isolate and its amount of enzyme, and are not always consistent between similar tests. These combinations are probably best avoided in severe infections due to ESBL producers.

CONCLUSIONS : 

CONCLUSIONS Non beta-lactams: Many ESBL producers, including community isolates with CTX-M enzymes are multi-resistant to fluoroquinolones and aminoglycosides, but susceptibilities vary, and these are good options where a strain is susceptible.

PREVENTION – INFECTION CONTROL : 

PREVENTION – INFECTION CONTROL Antibiotic selection pressure for resistance plasmid dissemination and genetic mutation important in spread of resistance. Clonal strain transmission reported as primary mechanism for ESBL outbreaks indicating that patient-to-patient spread is significant problem Contact precautions (gloves, gowns) important Notification by institutions when transferring patients may help limit spread (inter-hospital transfer of ESBL producing organisms has been described) Restrict use of antibiotics, especially cephalosporins.