CREs in South Africa

G.A.Richards

MBBCh PhD FCP(SA) FRCP FCCP

Director Multidisciplinary ICU Johannesburg Hospital

The Problem

ESCAPE Pathogens •  •  •  •  •  • 

Enterococcus Staph aureus Clostridium difficile Enterobacteriaceae Acinetobacter Pseudomonas

XDR and MDR organisms •  In 2008 we stated “the die was cast” for emergence of XDR and PDR organisms in SA •  Based on suboptimal AB management; excessive duration, use of multiple often inappropriate/unnecessary agents, and virtual absence of de-escalation •  Prescribers ignore AB “stewardship” Brink SAMJ 2008

PISA study: Number of Antibiotics Used

Paruk, Richards SAMJ 2013

Extended spectrum β –lactamases: Enterobacteriaceae (KEEPS MSC) •  New drugs were developed to counter emerging ẞ-lactamase enzymes eg piperacillin, 3rd & 4th GC, clavulanate, tazobactam •  ESBLs emerged which hydrolyse them •  Mostly also resistant to non ẞ-lactams •  Only carbapenems reliably effective

Paterson et al. Clin Infect Dis 2000;30:473-478 Lautenbach et al. Clin Infect Dis 2001;33:1288-1294 Babini & Livermore. J Antimicrob Chemother 2000;45: 183-189

The new nightmare:CREs Carbapenemases belong to different Ambler classes • Class A: K. pneumoniae carbapenemases (KPC) & Guinea ESBLs (GES) • Class B: Metallo-beta-lactamases (MBL); Verona integron-encoded MBLs (VIM) and New Delhi Metallo-β-lactamases (NDM-1) • Class C: AmpC, FOX, CMY, LAT, ACC, DHA • Class D: OXA-type: OXA-48 and derivatives Bradford CID 2004 Segal South Afr J Epidemiol Infect 2006 Elliott CID 2006 Brink J Clin Micro 2012

History of CRE in South Africa 140 120 100

Total CRE

80 60 40 20 0 Pre-2012

2012-2013

2013-2014 Ampath NRL Data April 2010 – March 2014

Citations in PubMed from 1960-2011 using either terms ‘colistin’ or ‘colistin resistance’

Biswas S et al. Expert Rev Anti Infect Ther 2012;10(8):917-34

Pseudomonas aeruginosa: Complex resistance •  Intrinsic resistance Porin plus efflux systems – Increase MICs for most B-lactams, including meropenem, plus non β-lactams like FQ •  Extrinsic resistance – All β-lactamases: including carbapenemases VIM†, NDM†, SPM†, IMP†, GIM†, SIM†, KPC, GES) †

Metallo-β-lactamases (MBL)

Limitation of CREs: Antibiotic Stewardship 1.  Limit use 2.  Drug – narrowest spectrum? 3.  Dose: PK/PD principles (T>MIC, AUIC, Peak to MIC ratio), weight, ARC, Vd 4.  Duration: short as possible 5.  Delivery route: oral/IV 6.  De-escalation

Limit Use: Overuse of Carbapenems 2172 episodes of HCA bacteraemia: Prior isolation of an ESBL OR 5.9 (3.02- 11.5) Renal transplant: OR 4.3 (1.96- 9.63) Urinary source: OR 4.2 (2.22-7.84) Shock: OR 2.4 (1.35- 4.1) Previous cephalosporin use [OR 2.6 (1.54, 4.51)] Previous carbapenem use [OR 2.5 (1.24, 5.05)] Were significantly associated with ESBL E.coli and Klebs spp. Martınez Journal of Antimicrobial Chemotherapy (2006)

Serum Antibiotic Concentration (mcg/mL)

Use Antibiotics Correctly: PK/PD 10

Peak to MIC ratio

8

AUIC >120 For efficacy

6 4

T > MIC

2

MIC

0 0

1

2

3

4

5

Time (hours)

Dose

6

7

8

9 10 11 12

Optimal Pharmacokinetics: Time Dependent Antibiotics: T> MIC •  •  •  • 

Optimal time above MIC is: >50% for penicillins >60% for cephalosporins >40% for Carbapenems Lodise In Antimicrobial Resistance: Problem Pathogens and Clinical Countermeasures. Eds Owens, Lautenbach Informa Healthcare 2008: Craig CID 1997; De Ryke AAC 2007; Drusano CID 2003; Ong Diag Microbiol Infect Dis 2007 ; Craig. Diagn Microbiol Infect Dis 1996

Why are Serum levels lower in Critically Ill Patients? •  •  •  • 

Volume of Distribution Albumin ARC Fluid losses (open abdomen/ orthopaedic surgery etc)

Protein binding •  Free fraction (ff) responsible for efficacy/ toxicity •  Increased ff also increases renal elimination & Vd with ẞ-lactams, A-glycosides & glycopeptides •  If drug > 90% protein bound & mainly renally eliminated , low albumin ( MIC based on Monte Carlo simulation. In vivo

MIC, µg/mL

Bhavnani AAC 2005

Continuous Infusion vs Intermittent in Severe Sepsis (BLISS) •  N=140: CI had: –  Higher clinical cure (56 vs 34%, p = 0.011) –  Higher median ventilator-free days (22 vs 14 days p 14 or 21 days should be routinely screened

Control of CRE: Regional/ Facility interventions to stop transmission •  •  •  •  •  • 

Hand hygiene Contact Precautions/contact screening Education Patient and Staff Cohorting Rapid notification Liquid chlorhexidine (2%)/impregnated wipes daily to all patients regardless of colonization •  Antimicrobial stewardship CRE: carbapenem-resistant Enterobacteriaceae

CDC: National Center for Emerging and Zoonotic Infectious Diseases, Guidance for Control of CRE 2012 (http://www.cdc.gov/hai/organisms/cre/cre-toolkit/ - accessed on 12/4/13; Climo MW et al. NEJM 2013;368:533-42