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