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