Lecture by Dr. Edsel Salvana during the 23rd PHICS Convention last May 18, 2017 at the Crowne Plaza

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

2. 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.

3. Drug Resistance Crisis
 Rapid increase in multi-
drug resistant strains of
gram-positive and gram
negative organisms
http://www.idsociety.org/10x20.htm

4. WHO 2014 Antimicrobial Resistance Global Report on Surveillance

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

7. + bacteria of global concern
 Pseudomonas aeurginosa – MBL, panresistance
 Acinetobacter baumanii – MBL, panresistance

14. 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

15. 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.

16. “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

17. “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

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

19. 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

20. 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

21. From Carmeli 2009 presentation

22. Antimicrobial Resistance Surveillance
Reference Laboratory. RITM , DOH 2015

23. Antimicrobial Resistance Surveillance
Reference Laboratory. RITM , DOH 2015

24. Antimicrobial Resistance Surveillance
Reference Laboratory. RITM , DOH 2015

25. Antimicrobial Resistance Surveillance
Reference Laboratory. RITM , DOH 2015

26. Klebsiella pneumoniae
Antimicrobial Resistance Surveillance
Reference Laboratory. RITM , DOH 2015

27. Antimicrobial Resistance Surveillance
Reference Laboratory. RITM , DOH 2015

28. Antimicrobial Resistance Surveillance
Reference Laboratory. RITM , DOH 2015

31. 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

32. 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

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

34. 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

35. 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

36. 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

39. 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

40. Antimicrobial Resistance Surveillance
Reference Laboratory. RITM , DOH 2015

42. 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