CREs in South Africa

MBBCh PhD FCP(SA) FRCP FCCP

Director Multidisciplinary ICU Johannesburg Hospital

G.A.Richards

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

•  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

Extended spectrum β –lactamases: Enterobacteriaceae (KEEPS MSC)

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

0

20

40

60

80

100

120

140

Pre-2012 2012-2013 2013-2014

Total CRE

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)

Seru

m A

ntib

iotic

Con

cent

ratio

n

0

2

4

6

8

10

0 1 2 3 4 5 6 7 8 Time (hours)

(mcg

/mL)

9 10 11 12

Dose

MIC

Use Antibiotics Correctly: PK/PD

AUIC >120 For efficacy

Peak to MIC ratio

T > MIC

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 (<25 g/l) increases ff markedly (eg ceftriaxone, flucloxacillin, teicoplanin, ertapenem & daptomycin)

Udy Intensive Care Med 2013

ARC & clinical failure

•  Prospective, single-center observational study •  Greater mortality, lower cure with CLCR ≥

150ml/min in VAP treated with dori & imi •  Separate PK/PD modeling suggested daily dori

doses (up to 2g 8 hrly) might be required for adequate drug exposure

Claus J Crit Care 2013 Kollef Crit Care 2012 Roberts Crit Care Med 2013

Targeting of Higher MICs with Infusion & Increasing Dose

*Probability of attaining 35% T > MIC based on Monte Carlo simulation. In vivo

Bhavnani AAC 2005

0

20

40

60

80

100

MIC, µg/mL

Target Attainment

%

0.06 0.12 0.25 0.5 1 2 4 8 16

500mg tds over 4-h 500mg tds over 1h

35%

78%

100% 95%

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<0.043) – Higher PK/PD target attainment

100% fT[MIC] on day 1 (97 vs 70%, p<0.001) & day 3 (97 vs 68%, p<0.001)

•  No difference in 14 or 30-day survival

Abdul-Aziz Intensive Care Med 2015

Dose and Efficacy of Tigecycline vs Imipenem for HAP

•  Subjects randomized to 150mg & 75mg 12hrly or 200mg & 100mg 12rly vs 1g imipenem 8hrly

•  Clinical cure with 100mg (17/20; 85.0%) was numerically superior to 75mg (16/23, 69.6%) and imipenem (18/24, 75.0%) – No new safety signals – Higher AUIC ratio may be necessary to achieve

clinical cure with HAP

Ramirez J et al. Antimicrob Ag Chemother 2013;57(4):1756-62

HAP: hospital-acquired pneumonia AUIC: AUC/MIC AUC: area under concentration-time curve MIC: minimum inhibitory concentration

GNB: Doses and Administration: Normal Renal Function

► Meropenem 2g q8 over 3 hours ► Imipenem 1g q6 -8 over 3hrs ► Doripenem 1g q8 over 4 hrs ► Ertapenem 1g BD ► Cefepime 2g stat 6g daily over 24hrs* ► Ceftazidime 2g stat & 6g over 24hrs* ► Pip–tazo 4.5g stat & 18g daily*► Tigecycline 200mg stat and 100mg BD ►  *Temperature < 25º

Bariran N et al. J Antimicrob Chemother 2003;51:651-8 Brink AJ et al. Int J Antimicrob Agents 2009;33:432-6 Georges B et al. Br J Clin Pharmacol 2012;73(4):588-96 Kollef MH et al. Crit Care 2012;16(6):R218 Richardson BL et al. J Antimicrob Chemother 1981;8(Suppl B):233-6 Mathew M et al. J Clin Pharm Ther 1994;19(6):397-9 Nicasio AM et al. J Crit Care 2010;25(1):69-77 Bauer AAC 2013

GNB: Gram negative bacteria BD: twice daily

Concentration Dependent: Aminoglycosides

•  In animal studies efficacy correlates with Cmax/MIC ratio (8-10) and AUIC(80-100)

•  To achieve this MIC must be ≤ 2µg/ml, tobramycin/gentamycin dose: Age < 30: 6 mg/kg

30-60: 5mg/kg >60: 4mg/kg

•  Nephrotoxicity less with once daily dosing

Turnidge J. Infect Dis Clin North Am 2003;17:503-28

MIC: minimum inhibitory concentration AUIC: AUC/MIC AUC: area under concentration-time curve

Colistin: Appropriate Dose

Administered as Colistin methane sulphonate

Makes bolus necessary to achieve therapeutic effect apidly Effective against GNB except: Proteus sp, Burkholderia cepacia, Providencia , Serratia marcescens, Morganella sp.

Plachouras D et al. Antimicrob Agents Chemother 2009;53(8):3430-6

CMS

Colistin

CMS: colistin methane suphonate GNB: Gram negative bacteria

Colistin: Appropriate Dose

Plachouras D et al. Antimicrob Agents Chemother 2009;53(8):3430-6

Colistin: Appropriate Dose

Load with 12 MU •  > 60 kg: 3MU 8hrly/ 4.5MU BD Renal impairment: Load with 12MU, Then: •  Cr Cl 20 – 50: 1 – 2 MU 8hrly •  10 – 20: 1 MU every 12 -18 hrs •  CRRT- full dose; Intermittent HD 1MU 12hrly & 1MU

post dialysis •  Never use Colistin as monotherapy

MU: million units BD: twice daily Cr Cl: creatinine clearance Rif: rifampicin Dalfino L et al. Clin Infect Dis 2012;54(12):1720-6

CRE Therapy: Combinations Reduce mortality in KPC bacteremia

205 patients with KPC bacteremia

M C

Daikos GL et al. Antimicrob Agents Chemother 2014;58: 2322

Mortality: BSI due to KPC-KP

Multivariate analysis of factors associated with death

P value Odds Ratio (95% CI)

Shock 0.008 7.17 (1.65–31.03)

Inadequate initial treatment 0.003 4.17 (1.61–10.76)

High APACHE III score <0.001 1.04 (1.02–1.07)

Post-antibiogram therapy with tigecycline + colistin + meropenem 0.01 0.11 (0.02–0.69)

Tumbarello M, et al. Clin Infect Dis 2012;55(7):943–50

Outcome of 36 patients with KPC- KP BSI according to the MICs for meropenem.

No. (%) of patients

Meropenem MIC

Total Non

survivors

Survivors

MIC≤2 5 0 5 (100)

MIC=4 10 2 (20) 8 (80)

MIC=8 4 1 (25) 3 (75)

MIC≥16 17 6 (35.2) 11 (64.7)

Total 36 9 (25) 27 (75)

Tumbarello M, et al. Clin Infect Dis 2012;55(7):943–50

CRE Therapy

•  Colistin plus HD carbapenem [Imipenem 1gram 8hrly or mero 2g 8hrly (provided MIC <32µg/ml)] – ± HD tigecycline 200 stat then 100 bid or

rifampicin 600mg bid or gentamicin (mg/kg dose) – NB: If Colistin MIC> 2 substitute for another drug – NB: If Tigecycline MIC > 4 substitute

Petrosillo Exp Rev Anti Infective Therapy

Management of KPC Bacteremia

MIC meropenem <16 MIC meropenem >16 TIGECYCLINE + GENTAMICIN

+ RIFAMPICIN

Colistin-R

Tigecycline-R Replace with RIFAMPICIN 10mg/Kg/BD

MEROPENEM + TIGECYCLINE + RIFAMPICIN

Double Carbapenem Therapy

Ceccarelli G et al. AAC 2014

Fosfomycin in Combination with other Antibiotics?

•  GNB develop resistance rapidly in vitro & in vivo when administered as monotherapy

•  Interpretative criteria of resistance are quite different among international organisms

Use high doses: 4-6 g every 6 hours

Therapy of XDR Acinetobacter

•  Colistin + rifampicin reduces bacterial load; no difference in mortality. Systematic review: lack of clinical efficacy more hepatotoxicity

•  Tigecycline may be an option if MIC is ≤1mg/l & organism is resistant to other agents (BIII)

•  Consider sulbactam or colistin + 2nd agent (TGC, rif, fosfomycin) for clinical failures

Tumbarello Clin Infect Dis 2012 Petrosillo Expert Rev Anti Infect Ther 2013 Al-Shaer Ann Pharmacother 2014 Garnacho-Montero ICM 2015

CRE Screening

•  Current CRE screening criteria in SA include: – Prior hospitalisation for ≥ 1 week in last 6 mnths

Direct transfers from other countries –  Inter-ICU transfers validated by this small cohort.

•  Patients who are in ICU > 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

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

CRE: carbapenem-resistant Enterobacteriaceae