Management Strategies and Outcomes of MDRO Infections

Edsel Maurice T. Salvana, MD, DTM&H, FPCP, FIDSA

Objectives To describe the increasing burden of Gram negative

MDROs globally and in the Philippines

To discuss evidence-based and best practices in managing MDROs and its effects on outcomes.

Drug Resistance Crisis Rapid increase in multi-

drug resistant strains of gram-positive and gram negative organisms

http://www.idsociety.org/10x20.htm

WHO 2014 Antimicrobial Resistance Global Report on Surveillance

http://www.idsociety.org/10x20.htm

+ bacteria of global concern Pseudomonas aeurginosa – MBL, panresistance

Acinetobacter baumanii – MBL, panresistance

Recognizing ESBLs ESBL – extended spectrum B-lactamase

Implies resistance to extended-spectrum (3rd

generation) cephalosporins such as ceftazidime and ceftriaxone, or monobactams

Many, many types

Epidemic levels in recent years, particularly in Enterobacteriaceae such as Klebsiella spp. and E. coli

ESBL Risk factors

Colodner R, Rock W, Chazan B, Keller N, Guy N, Sakran W, Raz R. Risk factors for the development of extended-spectrum beta-lactamase-producing bacteria in nonhospitalized patients. Eur J Clin Microbiol Infect Dis. 2004 Mar;23(3):163-7.

“Classic” ESBLs Derived from classic plasmid B-lactamases most

commonly TEM (E. coli) and SHV (Klebsiella); or acquired plasmids from other species (CTX-M)

TEM and SHV are prototypical B-lactamases that hydrolyze penicillins (but not extended-spectrum cephalosporins) and are inhibited by clavulanic acid, sulbactam and tazobactam

“Classic” ESBLs Mutations produce ESBLs which typically confers

resistance to extended-spectrum cephalosporins with oxymino-side chain (ceftriaxone, ceftazidime) and aztreonam

Cephamycins (cefoxitin, cefotetan, cefmetazole) retain activity

Clavulanic acid restores activity, but not reliable for clinical use

http://upload.wikimedia.org/wikipedia/commons/3/32/ESBL_Stokes.jpg

Rule of thumb If you see resistance in an Enterobacteriaceae

(especially E. coli and Klebsiella) to ANY 3rd

generation cephalosporin, SUSPECT ESBL

Drug of choice for ESBL is a CARBAPENEM

Tigecycline has some activity, and Cefepime may retain activity at lower MICs

ESBLs Piperacillin-tazobactam may come back susceptible,

but is associated with increased risk of clinical failure

Ciprofloxacin in ESBL bacteria is associated with excess mortality even if susceptible

From Carmeli 2009 presentation

Antimicrobial Resistance Surveillance

Reference Laboratory. RITM , DOH 2015

Antimicrobial Resistance Surveillance

Reference Laboratory. RITM , DOH 2015

Antimicrobial Resistance Surveillance

Reference Laboratory. RITM , DOH 2015

Antimicrobial Resistance Surveillance

Reference Laboratory. RITM , DOH 2015

Klebsiella pneumoniae

Antimicrobial Resistance Surveillance

Reference Laboratory. RITM , DOH 2015

Antimicrobial Resistance Surveillance

Reference Laboratory. RITM , DOH 2015

Antimicrobial Resistance Surveillance

Reference Laboratory. RITM , DOH 2015

Carbapenem Resistance Two main mechanisms: production of a β-lactamase (a

cephalosporinase or an ESBL) with a very low level of carbapenem-hydrolyzing activity combined with decreased permeability due to porin loss or alteration OR carbapenem-hydrolyzing β-lactamases

Increasing prevalence of carbapenemase production in Enterobacteriaceae (CRE)

Kuzon et al., 2011

Carbapenemases – hydrolyzing enzymes metallo-β-lactamases (IMP, VIM, NDM)

plasmid-mediated clavulanic acid-inhibited β-lactamases (NmcA, IMI, SME, GES, and KPC)

expanded-spectrum oxacillinase (OXA-48)

KPC and MBL (NDM-1) carbapenemases were originally found in Klebsiella but are now also in E. coli, Enterobacter, Pseudomonas and Acinetobacter

KPC emerged in the United States in 2001

MBL – particularly NDM-1 emerged in 2008

Kuzon et al., 2011

http://www.cdc.gov/hai/organisms/cre/definition.html#dif

Caveats to CREs All approved B-lactams locally are ineffective

Always include ertapanem susceptibility – most sensitive for KPCs, some may still show susceptibility to meropenem or imipenem but high rate of failure

For patients with carbapenem resistance but susceptible to other B-lactams – CAUTION – for KPCs and MBLs, high risk of failure.

For OXA-48 type may be susceptible to 3G cephalosporins and aztreonam

http://www.cdc.gov/hai/organisms/cre/defini

tion.html#dif

Drug of choice for CRE colistin/polymxyin B plus carbapenem – emerging

colistin resistance (mcr)

some data adding rifampicin to colistin beneficial

some activity for tigecycline

increasing infusion time for carbapenems increases time above the MIC for non-carbapenemase mechanisms

aztreonam inhibits MBL

IV fosfomycin used in Europe (no activity against MBL)

Newer agents in the US or in trials: ceftazidime-avibactam combinations, plazomicin, and eravacycline

Prevention of CRE emergence Use carbapenems judicially

Need more alternatives for ESBLs other than carbapenem – locally available: ceftolozane-tazobactam and tigcycline

Need more agents active against CRE’s

What about Pseudomonas? ESBLs and CREs showing up in Pseudomonas

Multiple resistance mechanisms can co-exist, with seeming pan-resistance that can be overcome with combinations

Most B-lactams near 20% resistance – need double-coverage empirically to maximize activity

Antimicrobial Resistance Surveillance

Reference Laboratory. RITM , DOH 2015

Summary Antimicrobial resistance is a crisis of global

proportions

We are running out of antibiotic options

Good antimicrobial stewardship starts with appropriate diagnosis, susceptibility data, treatment at appropriate dose and duration

Increasing drug resistance in common infections necessitates familiarity with current antimicrobial resistance patterns

Prevention measures such as hand hygiene and infection control are key to containing the spread of drug-resistant bacteria