1. Dr. Sandeep Budhiraja,
MD, DNB, MRCP (UK),
Director, Internal Medicine,
Max Healthcare

2. There is probably no chemotherapeutic
drug to which in suitable circumstances
the bacteria cannot react by in some way
acquiring ‘fastness’ [resistance].”
—Alexander Fleming, 1946

4. Increasing Resistance: A Serious &
Global Problem
 “Increasing levels of resistance to antibiotics
routinely used against bacteria responsible for
nosocomial infections remains a serious and
growing global problem”
Impact of Resistance
Infections with resistant organisms results in
Higher Higher Prolonged
morbidity mortality hospitalization
Masterton RG. Int J Antimicrob Agents. 2009 Feb;33(2):105-10

6. Bad Bugs
It behooves us
to use
antibiotics
judiciously
and
appropriately.

7. Bad Bugs
Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumonia (producing
ESBL’s & Carbapenemases )
Acinetobacter baumanii
Pseudomonas aeruginosa
Enterobacter spp.

8. ESBLs (Extended spectrum β-lactamases):
The main culprit
 ESBL: enzyme produce by bacteria to
destroy all cephalosporins, penicillins
& aztreonem
 Mainly found in Gram –ve bacteria
Rajni et al. Indian J Pract Doctor 2008 : 4 Walsh TR. JAC.2007; 59:799-820

9. ESBL: How is it spread?

10. Frequency distribution of ESBL-positive isolates
in the Asia-Pacific (AP) region during SMART: 2009
Hawser et al., AAC Aug 2009: 3280 - 3284

11. In India, bacteria are now producing multiple types of β-lactamases
Bush. Rev Inf Dis 1987;10:681; Bush et al. Antimicrob Agents Chemother
1995;39:12; Bush. Curr Opin Investig Drugs 2002;3:1284

12. Classical beta-lactamases:
Resistance to:
•TEM-1
1970s •Penicillins
•TEM-2
•1st gen cephalosporins
•SHV-1
ESBLs:
Resistance to:
•TEM-3….180
•Above
•SHV-2……… 1983
•2nd & 3rd gen cephalosporins
•CTX-M………
•OXA Resistance to:
•Amp-C 1990s
•Above
•BL+BLIs
Metallo beta lactamases
•IMP Resistance to:
•VIM-1… •Above
•GIM-1..
1991- 2009 •Carbapenems
•NDM-1

13. Global distribution of CTX-M

15. AmpC β-lactamase
Klebsiella In India Co-production of
E. Coli ESBL+AmpC by
spp.
Enterobacteriaceae = 40%
Delhi, 2003 - -
Chennai, 2003 24.1% 37.%
Aligarh, 2003 - - AmpC also masks detection of
ESBLs in Lab: Making the co-
Chennai, 2005 20.8% 16.6% production even more
Delhi, 2008 56.7% 70% difficult to identify
Rajni et al. Indian J Pract Doctor 2008 : 4

16. ESBL, OXA: Co-production
Multicenter study in 6 Indian cities in 2007
ESBL, OXA: Co-production
In India bacteria are frequently co-producing OXA along with ESBL (CTX-M-15)
Which are Resistant to penicillinsWalsh TR genJ cephalosporins
& 3rd et al. Antimicrob Chemother 2007; 59:799–820
cephamycins & BLIs (Cefepime is sensitive)

17. Classification of Carbapenem-hydrolyzing
beta-lactams (Carbapenemases)
 Class A: IMI, KPC, NMC, SME
 Class B: VIM, IMP, GIM, SPM
 Class C: OXA-23-like, OXA-24-like, OXA-49,
OXA-51-like, OXA-58
Livermoe DM. Clin Microbiol Infect 2008; 14 (Suppl 1): 3-10

18.  Increasingly being reported
 KPC is the most prevalent. Found in USA, Israel,
Turkey, China, India, UK & Nordic countries.
 KPC invariably found in K.pneumoniae, although it can
cross boundaries.
 OXA-48: mainly found in K.pneumoniae and is now
reported from Turkey, China, India, and UK.
 MBLs have been mainly found in Pseudomonas
aeruginosa, but are increasingly been reported in
Enterobacteriaceae, particularly from Greece and Turkey.
 VIM-1/VIM-4 clusters are mainly found in
K.pneumoniae.

19. Mechanism Organisms involved Affected Not affected
Simple beta- Almost all GNBs Ampicillin, 2/3rd gen ceph,
lactamases Carbenicillin BL+BLI, Monobatam,
Carbapenem
ESBLs E.coli, Klebsiella, Above + 2/3rd Carbapanem,
Other Enterobacteriacae gen Ceph, Cephamycins,
family members Monobactam Tigecycline,
BL+BLIs ?
Amp C & OXA SPICE bugs Above + Cefepime,
BL + BLI Carbapenem,
Cephamycins Tigecycline
Metallo beta- S. Maltophilia, Above + Colistin,
lactamases Pseudomonas, E.coli Carbapenems Tigecycline
Acinetobacter,Klebsiella,
Enterobacter

20.  In February 2009 a patient feeling unwell, with
restlessness, nausea and vomiting was submitted to
hospital in London.
 One week prior to admission he had been discharged
from a hospital in Curaçao where he had spent two
weeks after becoming ill while on holiday; he had had no
other admissions to hospital since 2007.
 A urinary catheter had been in situ for three weeks at the
time of admission in the UK. He received medical
treatment for acute renal failure, the urinary catheter was
removed on day 2 of admission, no antibiotic treatment
was given and he was discharged home on day 3 under
the care of his general practitioner.
 A catheter urine specimen collected on admission grew
K. pneumoniae resistant to all penicillins, cephalosporins,
ertapenem and ciprofloxacin.
N. Virgincar et al. / Journal of Hospital Infection 78 (2011) 293e296

22.  The isolates were initially detected by Vitek 2
(AST-N054) using 2009 Clinical Laboratory
Standards Institute (CLSI) breakpoints, which
reported ertapenem as resistant, but
meropenem as susceptible.
 However, Vitek 2’s advanced expert system
(AES) interpreted meropenem as intermediate-
resistant and inferred presence of
carbapenemase.
N. Virgincar et al. / Journal of Hospital Infection 78 (2011) 293e296

23.  In a June 2010 update, CLSI lowered the
susceptibility breakpoints to <1 mg/L for
imipenem and meropenem and < 0.25 mg/L for
ertapenem to better identify carbapenemase-
producing Enterobacteriaceae.
 The EUCAST susceptibility breakpoints are still
< 2 mg/L for imipenem and meropenem and <
0.5 mg/L for ertapenem.
 Both committees recommend performing
phenotypic tests to detect carbapenemase
production for infection control purposes.

24. What are KPCs
 Klebsiella pneumoniae carbapenemase’ (KPC)
enzymes are an international clinical and
public health concern.
 They belong to molecular class A
carbapenemases which also include SME
(Serratia marcescens enzyme), NMC/IMI
(non-metallo- carbapenemase/imipenem
hydrolysing b-lactamase) and GES (Guiana
extended spectrum) enzymes.
Emerging Infectious Diseases;www.cdc.gov/eid;Vol. 17, No. 10, October 2011

25.  Carbapenem-resistant Enterobacteriaceae have been
reported worldwide as a consequence largely of
acquisition of carbapenemase genes
 The first carbapenemase producer in
Enterobacteriaceae (NmcA) was identified in 1993
and since then, a large variety of carbapenemases
has been identified in Enterobacteriaceae belonging
to 3 classes of β-lactamases: the Ambler class A, B,
and D β-lactamases.
 In addition, rare chromosome encoded
cephalosporinases (Ambler class C) produced by
Enterobacteriaceae may possess slight extended
activity toward carbapenems, but their clinical role
remains unknown.
Emerging Infectious Diseases;www.cdc.gov/eid;Vol. 17, No. 10, October 2011

26.  KPC-type enzymes in carbapenem-resistant Klebsiella
pneumoniae strains were first reported in 2001 in North
Carolina.* *Antimicrob. Agents Chemother. 2001, 45:1151-1161.
 The first case of KPC-producing K. pneumoniae outside
the United States occurred in France, where a patient
who had been hospitalized in New York carried the
strain with him.** *Antimicrob. Agents Chemother. 2005, 49:4423-4424.
 A highly epidemic carbapenem-resistant clone of KPC-
3-producing Klebsiella pneumoniae emerged in Israel in
2006, causing a nationwide outbreak. This clone was
genetically related to outbreak strains from the United
States isolated in 2000 but differed in KPC-carrying
plasmids. The threat of the global spread of
hyperepidemic, extensively drug-resistant bacterial
strains should be recognized and confronted.***
***ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 2009, p. 818-820

27.  KPC confers resistance to all ß-lactams
including extended-spectrum cephalosporins
and carbapenems.
 Gene (blaKPC ) that encodes these enzymes are
located on plasmids-mobile genetic elements.
-increases risk transfer.
 Most commonly in Klebsiella pneumoniae or
Escherichia coli.
 2007 data from CDC regarding health care
associated infections – indicated that 8% of all
Klebsiella isolates were carbapenem resistant,
compared with fewer than 1% in 2000.

30. First KPC isolated in North Carolina
in 2000
2002 – First outbreak of KPC in New
York
2005- cases of KPC in France
2006- First KPC producing P.
Aeruginosa found in Columbia
2006- First KPC producing P.
Aeruginosa found in Columbia
2007 – First KPC outbreak in Israel
2010 - blakpc-11 discovered

31.  Multidrug resistant and even pan drug resistant(i.e.
resistant to all available classes)KPC producing
bacteria may be the source of therapeutic dead ends ,
since novel anti gram negative molecules are not
expected in the near future. Careful and conservative
use of antibiotics combined with good control practices
is therefore mandatory.
Lancet Infectious Diseases 2009;9:Pg 228-36

32. A novel acquired carbapenemase, New Delhi metallo-beta-lactamase 1
(NDM-1), has recently been described in the United Kingdom and Sweden,
mostly in patients who had received care on the Indian subcontinent.
As per a survey among 29 European countries (the European Union
Member States, Iceland and Norway from 2008 to 2010,out of 77 reported
MBL cases from 13 countries.
Klebsiella pneumoniae was the most frequently reported species with
54%.
European Centre for Disease Prevention and Control-Date 18 November 2010

34.  By virtue of its epicentre in the huge population of
India, the number of individuals affected by NDM-1–
producing K. pneumoniae may already exceed that of
KPC-producing K. Pneumoniae.
Clin Infect Dis. 2011 February 15; 52(4): 481–484.

35.  KPC-producing organisms have been associated
with increased length of stay, costs, frequent
treatment failures, and death
 Mortality rates of >50% have been reported
 Mixed reports of whether previous carbapenem
use is associated with the development of
infections caused by KPC producing bacteria
Pharmacotherapy Rounds 2012 | Lee, G

36.  easy plasmid transmission (KPC,NDM-1)
 environmental contamination may be
common, unrecognized
 lack of good screening media
 difficult algorithms for detecting or
confirming resistance
 few treatment options
 lack of data res: effective infection control

37.  Advanced Age
 Severity of Illness
 Previous antibiotic treatment
 Organ or stem-cell transplantation
 Mechanical ventilation
 Long hospitalizations

38. Pharmacotherapy Rounds 2012 | Lee, G

41.  Due to the rise in carbapenem resistance, all the
isolates of K. pneumoniae and E. coli were screened
for carbapenemase and Amp C production from
2009 to determine the mechanism of resistance. A
total of 423 isolates (167 E. coli and 256 K.
pneumoniae) were screened. More than half of the
total 256 isolates of K. pneumoniae (130 isolates,
51%) were MHT positive thus carbapenemase
producers. Of these, carbapenemase producers
in K. pneumoniae, 103 (79%) were MBL producers .
Indian Journal of Med Res 2012 Jun;135(6):907-12.

42.  ESBL producing E. coli increased from 40 per
cent in 2002 to 61 per cent in 2009, similarly
there was a significant (P<0.05) rise in
resistance to cefotaxime (75 to 97%),
piperacillin-tazobactum (55- 84%) and
carbapenem (2.4-52%) in K. pneumoniae. A
significant (P<0.05) association was observed
between resistance and consumption of
carbapenem and piperacillin and tazobactum
consumption in K. Pneumonia.
Indian Journal of Med Res 2012 Jun;135(6):907-12.

43.  Resistance to carbapenems is of great concern as
carbapenems are considered to be antibiotics of
last resort to combat infections by multidrug
resistant bacteria, especially in ICUs and high
risk wards. While carbapenem resistance in
Pseudomonas and Acinetobacter spp is well
known, resistance among Enterobacteriaceae is
increasing. Carbapenem resistance in
Enterobacteriaceae has increased from 0% in 2006
to 8% in Jan – Aug 2009 in ICU blood cultures.
This is worrisome
*Journal of Association of Physicians of India , March 2010 | Volume 58

44.  August 2009 to November 2009 (3 months!!!)
 Single tertiary care hospital in Mumbai.
 24 carbapenem resistant Enterobacteriaceae 22 were NDM
producers.(90%!!)
 10 were Klebsiella spp, 9 were E Coli, 2 were Enterobacter spp
and 1was Morganella morganii.

45. Distribution of number of NDM mediated versus total number of carbapenem
resistant isolates

46.  Carbapenemases producing Enterobacteriaceae isolates
seem to be increasing in number in the last few years in
India
 The above study showed a high incidence of blaNDM among K.
pneumoniae by PCR.
 Among the carbapenem-resistant Enterobacteriaceae
isolates, NDM-1 was detected in 75% (27/36) of K.
pneumoniae by PCR.
 Deshpande et al. reported a similar finding from a tertiary
care hospital in Mumbai, in which majority of blaNDM
producing isolates were K. pneumoniae.
 Carbapenem -resistant organisms were isolated mainly from
urine samples up to 42% (n = 21), followed by wound
discharge (18%) and respiratory secretions (16%). 80%
(17/21) of urine isolates were positive for blaNDM , which is
similar to the finding of Deshpande et al.

48. •We Indians are the leaders in antibiotic resistance.
.
•Most of the Government hospitals in India are not worried about
resistance.
•Our country, India, is the world leader in antibiotic resistance, in no other
country antibiotics been misused to such an extent.
•Indian medical community has to be ashamed
of the NDM-1 (“New Delhi Metallo-1”) gene
Consultant in Infectious Diseases and Clinical Mycology, Apollo Hospital, Chennai.

51. MIC90 for Enterobacteriaceae from Chennai
and Haryana, India and the UK

52. Pharmacotherapy Rounds 2012 | Lee, G

53. Pharmacotherapy Rounds 2012 | Lee, G

54.  Conduct surveillance study on the
susceptibility patterns of KPCs
 Minimize the use of Carbapenems
 Adopt adequate infection control policies and
guidelines
 Rationalize the antibiotic use in clinical settings
 Review and update hospital antibiogram from
time to time
 Follow the guidelines as set by the Antibiotic
policy of the Government of India 2011

55.  active screening identified colonized patients
who would otherwise have been missed in
NYC ICUs
(Calfee, Infect Control Hosp Epidemiol 2008)
 “bundle” (active surveillance, contact isolation,
flagging, environment cleaning)
(Ben-David, Infect Control Hosp Epidemiol 2010; Borer, Infect Control
Hosp Epidemiol 2011)
 nationwide control in Israel
(Schwaber, Clin Infect Dis 2011)

56. But what actually matters is…….
•Good infection control policies
•Hand-hygiene
•Judicious use of antibiotics
•Antibiotic protocols
•Restricted use of antibiotics
•Know your local flora
•Audits
•Strict enforcement of drug
laws
Otherwise we will be creating more “Superbugs” in future