Specific Multi-drug Resistance

MRSA-VRSA-ESBL-KPC

ByDr. Sayan Chakraborty

2nd Year PGT- MD Tropical MedicineSchool of Tropical Medicine, Kolkata

E-mail: dr.sayan@gmail.com

WHO Theme 2011

Antibiogram - Blood

Staph aureus today!!

Most common cause of skin and soft tissue infections

MC cause of cellulitis, osteomyelitis, septic arthritis, surgical wounds

MC cause of nosocomial infectionsMC cause of health care associated endocarditis

(52%) and in IDUs (57%) Common cause of bacteremia, foodborne

disease, implant infection, abscess etc

[2002]

MRSA

• 1959: First clinical use of methicillin

• 1960: First description of MRSA

• Resistant to penicillinase-resistant penicillins and all cephalosporins except ceftaroline

Worldwide prevalence of MRSA

Mechanism of Methicillin Resistance

Horizontal transfer of genomic island SCCmec

Contains gene mecA

Produces PBP2a protein responsible for resistance

Factors that Facilitate TransmissionCrowding

Frequent ContactCrowding

Factors that Facilitate Transmission

Frequent ContactCrowding

Compromised Skin

Factors that Facilitate Transmission

Frequent Contact

Contaminated Surfacesand Shared Items

Crowding

Factors that Facilitate Transmission

Compromised Skin

Frequent Contact

Cleanliness

Crowding

Contaminated Surfacesand Shared ItemsCompromised Skin

Factors that Facilitate Transmission

Contaminated Surfacesand Shared Items

Frequent Contact

Cleanliness

Crowding

Compromised Skin

Factors that Facilitate Transmission

Antimicrobial Use

Susceptible groups

DiabeticsImmunocompromised (HIV, Cancer,

Transplant, lupus)Extended hospital stayIndwelling catheters/ prosthetic devicesElderlyDialysis patientsIDUsH/o MRSA

Lab Diagnosis of MRSA

The Clinical and Laboratory Standards Institute (CLSI), CDC recommends:Broth microdilution testingCefoxitin disk screen testLatex agglutination test for PBP2aPlate containing 6 μg/ml of oxacillin in Mueller-

Hinton agar supplemented with 4% NaCl

New FDA-approved selective chromogenic agars can also be used for MRSA detection

Interpretive Criteria (MIC)

Test Susceptible Resistant

Oxacillin MIC ≤ 2 μg/ml ≥ 4 μg/ml

Cefoxitin MIC ≤ 4 μg/ml ≥ 8 μg/ml

Cefoxitin Disk Diffusion

≥ 22 mm ≤ 21 mm

Treatment of MRSA

Oral therapy for Skin and soft tissue infections:Clindamycin 300-450 mg tidTMP-SMX (1 or 2 ds tablets bid)Minocycline or Doxycycline 100 mg q12hLinezolid 600 mg bidTedizolid 200 mg once dailyAlternative: Tigecycline

Treatment of MRSAParenteral therapy for Serious infections (complicated skin infections, bacteremia, endocarditis):Drug of choice:Vancomycin 15-20 mg/kg q8-12h (max 2 g)Daptomycin 6 mg/kg q24hAlternatives:Linezolid 600 mg q12h PO or IVCeftaroline 600 mg IV q12hTigecyclineNew drug: Teixobactin (Gram +ve coverage)

Therapy for special settings• Prosthetic valve endocarditis: Vancomycin (30 mg/kg q24h, max 2g) or Daptomycin 6 mg/kg q24h + Gentamicin 1 mg/kg q8h + Rifampin 300 mg q8h for ≥ 6 weeks

• Hematogenous osteomyelitis or Septic arthritis:Children: 4 week course of therapyAdults: More prolonged course

• Prosthetic joint infections: Rifampin + Ciprofloxacin especially when the device cannot be removed

VISA / VRSA

• 1997: Vancomycin intermediate Staph aureus reported from Japan

• 2002: Vancomycin resistant Staph aureus isolated

Mechanism of ResistanceVISA:oAbnormally thick cell walloVancomycin trapped by abnormal peptidoglycan

cross-linkingoUnable to gain access to its target siteVRSA:oHorizontal conjugal transfer of vanA gene from

vancomycin resistant strain of Enterococcus faecalis

ovanA gene produces dipeptide D-Ala-D-Lac in place of D-Ala-D-Ala to which the drug cannot bind

Lab diagnosis of VRSACLSI-CDC recommends:Reference broth microdilutionAgar dilutionEtest®MicroScan® overnight and Synergies plus™BD Phoenix™ systemVitek2™ systemDisk diffusionVancomycin screen agar plate [brain heart

infusion (BHI) agar containing 6 µg/ml of vancomycin]

Interpretive Criteria (MIC)

Staph aureus MIC (µg/mL)VSSA 0.5 - 2VISA 4 - 8VRSA ≥ 16

Treatment of VRSA/VISA

Drug of Choice:Daptomycin 6 mg/kg q24h

Alternatives:Ceftaroline 600 mg IV q12hLinezolid 600 mg IV or PO q12hTedizolid 200 mg IV or PO once dailyDalbavancin - two IV doses : 1000 mg followed in 1 week by

500 mg

Other drugs for VISA: Quinipristin/Dalfopristine; Telavancin

Antibiogram - Urine

ESBL• 1980s: 3rd generation

cephalosporin introduced in Ampicillin resistant E. coli and K. pneumoniae

• 1983: K. ozaenae with plasmid mediated resistance to broad spectrum cephalosporins

• 1989: 1st “substantial review” of ESBLs

ESBL Resistance PatternESBL causes hydrolysis ofPenicillins1st-, 2nd- and 3rd gen cephalosporins4th gen cephalosporins (some instances)Monobactams like AztreonamFluoroquinolonesTMP-SMXAminoglycosidesTetracyclines

ESBL producers• Klebsiella pneumoniae, oxytoca• E. coli• Pseudomonas aeruginosa• Acinetobacter baumanii• Enterobacter cloacae and aerogenes• Citrobacter freundii• Proteus• Serratia marcescens• Providencia• Morganella morganii

India > China > Rest of Asia, Latin America Europe > USA, Canada, Australia

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Types of ESBL enzymes

SHV:

• 1st B-lactamase found in K. ozaenae Germany 1983

• Frequently found isolate• SHV refers to sulfhydryl variable

• Repl glycine by serine @ pos 238• most commonly found in K. pneumoniae

• SHV-2 accounts for extended spectrum properties

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Types of ESBL enzymes

TEM: • Most common, found in E. coli and K. pneumoniae• 100+ TEM types derived from TEM-1 & TEM-2• TEM-1

• 1st reported from E. coli isolate in pt named Temoneira• Hydrolyzes amp > carbenicillin, oxacillin, or cephalothin• Inhibited by clavulanic acid; inhibitor resistant TEM

present now• First true ESBL is TEM-3

• Plasmid-mediated B-lactamase CTX-1(cefotaxime)

Types of ESBL enzymes

CTX-M • greater activity against cefotaxime• normally found in Kluyvera species• mainly found in strains of Salmonella enterica serovar

Typhimurium and E. coli• Associated with resistance to fluoroquinolones, TMP-

SMX, aminoglycosides and tetracyclines• Increased incidence of uncomplicated cystitis due to

CTX-M producing E. coli among healthy ambulatory woman

• Fosfomycin and nitrofurantoin - most reliable

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B-lactamases other types

• AmpC• Hydrolyze 3rd gen cephalosporins • Induction of resistance during therapy• Active against cephamycins (cefoxitin, cefotetan)• Resistant to inhibition by clavulanic acid/b-lactamase inh• May not exhibit resistance to FQs, TMP-SMX,

aminoglycosides, tetracyclines

• Carbapapenemases• Metallo-B-lactamases & serine carbapenemases

• KPC-2, KPC-3, SME-2 most frequently isolated in US• Metallo-B-lactamases most prevalent in Europe

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ESBL Other Types

• OXA• Hydrolyze Oxacillin• Predominately occur in Pseudomonas aeruginosa and

Acinetobacter baumaniiconfers greater resistance to cefotaxime and cefepime than it does resistance to ceftazidime• PER

• Hydrolyze pcn and ceph• VEB-1

• High level resistance to ceftaz, cefotaxime, & aztr• GES, BES, TLA, SFO, & IBC

Detection of ESBLs

Disc method: Double disc method Combination Disc method

Automated methods:• AS: Microscan, Vitek2, Phoenix• Phenotypic tests: Etest, DDS• Molecular tests: PCR, IsoElectric Focusing (IEF)

Treatment

Most reliable drugs are: Carbapenems Amikacin Cefepime Piperacillin- Tazobactam Polymyxins (colistin and polymyxin B) Tigecycline

Drugs with limited clinical data: Fluoroquinolones TMP-SMX Other aminoglycosides

Antibiogram - Sputum

KPC 2001: First

reported from North Carolina

an Ambler class A beta-lactamase

Encoded by the gene blaKPC

Resistance similar to ESBLs along with Carbapenems

Worldwide distribution

Carbapenem Resistant Enterobacteriaceae

Revised Ambler Classification: Class A

carbapenemase: KPC, SME, IMI, GES

Class B metallo-beta lactamase: NDM-1, VIM, IMP

Class D Beta lactamase: OXA-48

Mechanism of Resistance to Carbapenems

• Cleave beta lactam ring• Ambler classification

Carbapenemase

• Active transport• Augmented drug efflux

Efflux

• Prevent entry• Huge rise of MIC

Loss of membrane

porins

Mechanism of Antibiotic resistance

Lab DiagnosisCLSI-CDC recommends: Disk diffusion or MIC testing Phenotyping by Modified Hodge test

Other tests include: Inhibition testing by boronic acid (class A), EDTA

(class B) or dipicolinic acid (class B) Nested arbitary PCR (ARB-PCR) Matrix-assisted laser desorption ionization-

time of flight mass spectrometry (MALDI-TOF MS)

TreatmentRecommended: Polymyxins (Polymyxin B or Colistin) Tigecycline (low conc in blood and urine)

Other options: Fosfomycin Nitrofurantoin Aminogycosides

Newer drugs under development:• Beta lactamase inhibitorNXL104• Polymyxin derivatives NAB739 and NAB740• Tetracycline PTK-0796• Aminoglycoside ACHN-490

Urine C/S – Take that!!!!

Prevention of Resistance in CCU

Creation of institution based strategy for combating drug resistance

Re-evaluation of antibiotic therapy after 48 hours of initiation

Adequate duration of therapy

CLINICAL SCENARIO

Scenario 1

• 40 year old female patient presented with uncontrolled T2DM admitted for evaluation. Although asymptomatic, her urine C/S shows ESBL E.coli .

What to do????

Scenario 2

• 50 year old male admitted at CCU for acute exacerbation of COPD along with fever. Empirically, he was started with Inj Meropenem (keeping in mind of his antibiotic history). Sputum C/S was sent before starting antibiotic, which in 3 days showed Klebsiella pneumoniae sensitive to Ciprofloxacin, Polymixin B, Colistin and Tigecycline (all with MIC values 0.5) and resistant to Meropenem.

Opinion????

Thank you……

All is not lost till… the fight goes on….