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

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

“Increasing levels of resistance to antibiotics routinely used against bacteria responsible for nosocomial infections remains a serious and growing global problem”

Masterton RG. Int J Antimicrob Agents. 2009 Feb;33(2):105-10

Impact of ResistanceInfections with resistant organisms results in

Higher morbidity

Higher mortality

Prolonged hospitalization

Increasing Resistance: A Serious & Global Problem

It behooves us It behooves us to use to use

antibiotics antibiotics judiciously judiciously

and and appropriately.appropriately.

Bad Bugs

Enterococcus faecium

Staphylococcus aureus

Klebsiella pneumonia (producing ESBL’s & Carbapenemases )

Acinetobacter baumanii

Pseudomonas aeruginosa

Enterobacter spp.

Bad Bugs

ESBL: enzyme produce by ESBL: enzyme produce by bacteria to destroy all bacteria to destroy all cephalosporins, penicillins & cephalosporins, penicillins & aztreonemaztreonem

Mainly found in Gram –ve Mainly found in Gram –ve bacteriabacteria

Rajni et al. Indian J Pract Doctor 2008 : 4 Walsh TR. JAC.2007; 59:799-820

ESBLs (Extended spectrum β-lactamases): The main culprit

ESBL: How is it spread?

Hawser et al., AAC Aug 2009: 3280 - 3284

Frequency distribution of ESBL-positive isolates in the Asia-Pacific (AP) region during SMART: 2009

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

Classical beta-lactamases:•TEM-1•TEM-2•SHV-1

Resistance to:•Penicillins

•1st gen cephalosporins

1991- 2009

ESBLs:•TEM-3….180•SHV-2………•CTX-M………

Resistance to:•Above

•2nd & 3rd gen cephalosporins1983

1970s

•OXA•Amp-C

Resistance to:•Above

•BL+BLIs

Metallo beta lactamases•IMP

•VIM-1…•GIM-1..•NDM-1

Resistance to:•Above

•Carbapenems

1990s

Global distribution of CTX-M

Klebsiella Klebsiella spp.spp. E. Coli E. Coli

Delhi, 2003Delhi, 2003 -- --

Chennai, 2003 Chennai, 2003 24.1%24.1% 37.%37.%

Aligarh, 2003 Aligarh, 2003 -- --

Chennai, 2005 Chennai, 2005 20.8%20.8% 16.6%16.6%

Delhi, 2008Delhi, 2008 56.7%56.7% 70%70%

Rajni et al. Indian J Pract Doctor 2008 : 4

In India Co-production of ESBL+AmpC by

Enterobacteriaceae = 40%

AmpC also masks detection of ESBLs in Lab: Making the co-

production even more difficult to identify

AmpC -lactamase

Multicenter study in 6 Indian cities in 2007

Walsh TR et al. J Antimicrob Chemother 2007; 59:799–820

In India bacteria are frequently co-producing OXA along with ESBL (CTX-M-15)

Which are Resistant to penicillins & 3Resistant to penicillins & 3rdrd gen cephalosporins gen cephalosporins cephamycins & cephamycins & BLIsBLIs (Cefepime is sensitive) (Cefepime is sensitive)

ESBL, OXA: Co-production

ESBL, OXA: Co-production

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

Classification of Carbapenem-hydrolyzing beta-lactams (Carbapenemases)

Livermoe DM. Clin Microbiol Infect 2008; 14 (Suppl 1): 3-10

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.

Mechanism Organisms involved Affected Not affected

Simple beta- lactamases

Almost all GNBs Ampicillin, Carbenicillin

2/3rd gen ceph,

BL+BLI, Monobatam,

Carbapenem

ESBLs E.coli, Klebsiella,

Other Enterobacteriacae family members

Above + 2/3rd gen Ceph, Monobactam

Carbapanem,

Cephamycins,

Tigecycline,

BL+BLIs ?

Amp C & OXA SPICE bugs Above +

BL + BLI

Cephamycins

Cefepime,

Carbapenem,

Tigecycline

Metallo beta- lactamases

S. Maltophilia, Pseudomonas, E.coli

Acinetobacter,Klebsiella,

Enterobacter

Above + Carbapenems

Colistin,

Tigecycline

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

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

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.

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.

What are KPCs

Emerging Infectious Diseases;www.cdc.gov/eid;Vol. 17, No. 10, October 2011

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

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

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.

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

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

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

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): 481–484Clin Infect Dis. 2011 February 15; 52(4): 481–484.

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

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

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

Pharmacotherapy Rounds 2012 | Lee, G

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.

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.

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

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.

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

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.

Consultant in Infectious Diseases and Clinical Mycology, Apollo Hospital, Chennai.

.•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

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

Pharmacotherapy Rounds 2012 | Lee, G

Pharmacotherapy Rounds 2012 | Lee, G

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

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)

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