Dr Gokul Bangalore: Over the years antibiotic resistant infections have emerged as a serious threat world over. The mortality is increasing phenomenally and a serious thought should be given to prevent or at least delay the rapid development of resistance. Alexander Fleming clearly said in his speech when he received the Nobel prize in 1950, for the discovery of Penicillin, that if these antibiotics fall into wrong hands and misused, there will be increasing development of antibiotic resistance in bacteria ultimately pushing the world into pre antibiotic era. How true. The world is facing this now. Antibiotics are a single class of drugs which are maximally misused,abused, indiscriminately used and over used. Antibiotic stewardship programs should have been in place at least 40 years back when a pattern of resistance started emerging. Now every individual who prescribe antibiotics should think globally act locally. However there are a number of reasons for the failure of antibiotic stewardship programs. That is a different issue and addressed seriously.Gokul Bangalore: Dr. B. N. Gokul. MBBS, MD (Bangalore), Cert. HIC & ID (Sweden). Former: Professor of Microbiology, NIMHANS, Bangalore,

1. Times Of MDR & PDR Pathogens
Rational use of Antibiotics
Dr. B.N. Gokul

2. Antimicrobial resistance in GNB
Gaynes R et al;CID:41:848-54; 2005

3. Sensitivity of cephalosporins
26
59 60
78
0
25
50
75
100
1989 1995 1997 2001 2003 2002
Progressive increase in resistance to 3rd
generation Cephalosporins like Ceftazidime
& Cefotaxime
India
EGAST study group, Hosp Today 2004 Jones RN. Int J Antimicrob Agents 2002 Mathai D. Diagn MicrobiolInfect Dis. 2002
Mathur P. Indian J Med Res 2002 Jain A,. Med Microbiol 2003. Mohanty S. Indian J Med Sci 2004
Nandivada LS, FEMS Microbiol Lett. 1989 Expert Group on Antibiotic Susceptibility tests (EGAST). Ind Intern Med 1995
Abigail S. Ind J Med Res 1995 Hansotia JB. Ind J Med Res 1997

4. 49
26
82
60 60
68
86.6
66.75
0
25
50
75
100
1989
1993
1997
2000
2001
2002
2002
2003
2004
Prevalence of ESBLs
EGAST study group, Hosp Today 2004 Jones RN. Int J Antimicrob Agents 2002 Mathai D. Diagn MicrobiolInfect Dis. 2002
Mathur P. Indian J Med Res 2002 Jain A,. Med Microbiol 2003. Mohanty S. Indian J Med Sci 2004
Nandivada LS, FEMS Microbiol Lett. 1989 Expert Group on Antibiotic Susceptibility tests (EGAST). Ind Intern Med 1995
Abigail S. Ind J Med Res 1995 Hansotia JB. Ind J Med Res 1997
India

5. Community Acq. & Other Infections
• Tuberculosis
• Malaria
• Salmonella
• Candida
• MRSA / VRSA
• C. difficile

9. Selection Pressure
• Hospital / community
• Agriculture
• Animal feeds
• Veterinary
• Fisheries
• Forestry

11. Can we escape from
“ESKAPE”?
Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumonia (producing ESBL’s
& Carbapenemases )
Acinetobacter baumanii
Pseudomonas aeruginosa
Enterobacter spp.

13. Now, India has its own superbug on the world map:
“New Delhi Metallo--lactamase producing bacteria”
• Emerging since 2006
• Most isolates with resistant to
ALL standard IV antibiotics
– Possible options:
• Polymyxins,
Tigecycline
David Livermore: Health Protection Agency:Colindale, London

14. Penicillin-binding proteins (PBP) (red); porins (green);
b-lactamases (yellow) efflux pump systems (turquoise).
Mechanisms of resistance
1 Increased b-lactamase quantity or potency
2. Porin loss
3 Alteration of PBP’s
4 Up-regulated efflux
Mechanisms of Resistance

15. Cytoplasmic
Membrane
PBP PBPPBP
Peptidoglycan
la
PBP
Outer
Membrane
Cytoplasmic
Membrane
PBP PBPPBP
Peptidoglycan
la
PBP
Outer
Membrane
Cytoplasmic
Membrane
PBP PBPPBP
Peptidoglycan
la
PBP
Outer
Membrane
Cytoplasmic
Membrane
PBP PBPPBP
la
PBP
Outer
Membrane
la
la
la
la
la
la
la
lala
la la
la
OprD
Porin
la
la
Transporter
Linker
Exit Portal

16. Risk factors for ESBL producing / MDR organisms
• Hospitalization > 48 hours
• Immunosuppression
• Receipt of total parenteral nutrition
• Indwelling urinary catheter & other
Instrumentation
• Residence in skilled nursing care or
long-term care facility
▪ Intensive Care unit admission
▪ Hospital stay in last 3 months
▪ Recent receipt of second / third-
generation ceph
▪ Postoperative infection
▪ Renal failure / Burns
▪ Pt above 65
▪ Diabetics
Ref: Pieracci FM et al. Scand J Sur. 2007; 96: 184-96

18. 1. New Delhi
2. Lucknow
3. Indore
4. Mumbai
5. Hyderabad
6. Bangalore
7. Chennai
8. Tamil Nadu
9. Kolkata
SMART:
2009
Study centers
across India
Hawser et al., AAC Aug 2009: 3280 - 3284

19. Hawser et al., AAC Aug 2009: 3280 - 3284
SMART: 2007

20. Serine enzymes Metallo (Zn) enzymes
Group C Group A Group D Group B
AmpC TEM / SHV /CTX-M OXA IMP/VIM
Bush. Rev Inf Dis 1987;10:681; Bush et al. Antimicrob
Agents Chemother 1995;39:12; Bush. Curr Opin Investig
Drugs 2002;3:1284
Beta-lactamases: Classification
ESBLs

21. AmpC -lactamase:
Found in SPICE bugs ( Serratia, Pseudomonas, Indole positive
proteae, Citrobacter and Enterobacter)
Resistant to penicillins & 3rd gen cephalosporins
cephamycins & BLIs (Cefepime is sensitive)
Klebsiella
spp.
E. Coli
Delhi, 2003 - -
Chennai, 2003 24.1% 37.%
Aligarh, 2003 - -
Chennai, 2005 20.8% 16.6%
Delhi, 2008 56.7% 70%
Rajni et al. Indian J Pract Doctor 2008 : 4
In India
Co-production of
ESBL+AmpC by
Enterobacteriaceae =
40%

22. Pen 3rd
Gen
Cep
cefo
xitin
Inhib by
clav
aztre
onam
cefe
pime
carba
pen
Likely operational resistance
mechanism
R
Amp
S S Yes S S S Classical
TEM 1,SHV 1
R R S Yes R R S ESBL Class A,
CTX M, SHV,TEM ,VEB…
R r S No R r S ESBL Class D OXA
R R R No R S S Class C AmpC
Extended Spectrum beta lactamases ( ESBLs)

23. Pen 3rd
Gen
Cep
cefo
xitin
Inhib by
clav
aztre
onam
cefe
pime
carba
pen
Likely resistance mechanism
R R R No R R R Carbapenemase MBL
NDM in
Enterobacteriaceae
R R R No S R R Carbapenemase MBL
VIM in P aeruginosa
R R R ? Yes R R R Carbapenemase Class
A KPC
Carbapenemases

27. The Tragedy of the Commons
It is our considered professional
judgement that this dilemma has no
technical solution….
Garrett Hardin

28. Recognize & Define the Problem

29. 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”
Masterton RG. Int J Antimicrob Agents. 2009 Feb;33(2):105-10
Impact of Resistance
Infections with resistant organisms results in
Higher
morbidity
Higher
mortality
Prolonged
hospitalization

30. Mechanism Isolates Affected Not affected
Common Plasmid
TEM 1, 2 SHV 1
Most GNB Amp. Carb Carbapenem
BL-BLI 2/3 ceph
monobactam
ESBL
TEM 3 – 28
SHV 2 - 8
Kleb, E.Coli
Serratia
Enterobacter
Above +
2/3 ceph
monobactam
Carbapenem
BL / BLI
Cefoxitin
Amp C
inducible
Hyperproducers
Enterobacter,
pseudo, serratia
citro proteae
Above +
BL / BLI
cefoxitin
? Cefepime
carbapenem
Zinc -lactamase S.malto
P.aeruginosa
Above +
carbapenem
? Aztreonam
Know your enemy ( lactamases)

31. New Treatment Paradigm
Hit hard and early with appropriate antibiotic
Short treatment duration
De-escalate where possible

32. Mortality Associated With Initial Inappropriate* Therapy
0 20 40 60 80 100
Luna (1997) – VAP*1
Ibrahim (2000) – Septicemia,
severe sepsis, or bloodstream infection†4
Kollef (1998) – VAP*3
Harbarth (2003) –
Severe sepsis*5
Rello (1997) – VAP†2
Initial
appropriate
therapy
Initial
inappropriate
therapy
Mortality (%)
Vallés (2003) –
Bloodstream infection*6
91%
37%
38%
15.6%
33.3%
60.8%
28.4%
61.9%
24%
39%
63%
30.6%
1. Luna CM et al. Chest. 1997;111:676–685. 2. Rello J et al. Am J Respir Crit Care Med. 1997;156:196–200.
3. Kollef MH et al. Chest. 1998;113:412–420. 4. Ibrahim EH at al. Chest. 2000;118:146–155.
5. Harbarth S et al. Am J Med. 2003;115:529–535. 6. Vallés J et al. Chest. 2003;123:1615–1624.
* Crude (overall)
mortality
† Infection-related
mortality
* Based on the 2005 ATS/IDSA guidelines for HAP/VAP/HCAP (Am J Respir Crit Care Med
2005;171:388-416),
Critically-Ill Patients With VAP or Septicemia, Severe Sepsis,
or Community-Acquired Bloodstream Infection

33. Delay versus Outcome
0
10
20
30
40
50
60
70
80
90
0.5 1 2 3 4 5 6
Delay in treatment (hours) from hypotension onset
Survivial(%)
Each hour off delay
of appropriate
antibiotic carries
7.6% reduction in
survival
Kumar et al. Crit Care Med 2006; 34:1589-
1596.

34. Regional Variations of
resistances
KNOW YOUR
LOCAL
ORGANISMS
AND
SENSITIVITIES
BECAUSE THAT
DETERMINES
ALL OF YOUR
ANTIBIOTIC CHOICES

35. “Dead bugs don’t
mutate”
Prescribing the most active agents at
optimal doses is the best start…
Sandiumenge et al. Intensive Care Med 2003;29:876–883;
Vidaur et al. Intensive Care Med Yearbook 2004

36. Mortality in ESBL-producing K. pneumonia
Paterson et al CID 2004;39: 31-7.
3.7
36.3
40
50
0
10
20
30
40
50
60
Type of therapy
All
cause 14-
day
mortality
(%)
Carbapenem
monotherapy
Quinolone
monotherapy
Cephalosporin
monotherapy
b-lactam /
b-lactamase
inhibitor
(n=27) (n=11) (n=5) (n=4)

37. Remember 4 D’s of Antimicrobial therapy
Glynn etal. Current Anaesthesia & Critical Care (2005) 16, 221–230

38. No
Change
(n=245)
Mortality%
Escalated
(n=61)
De-escalated
(n=88)
0
5
10
20
30
15
25
35
23.7
17.0
42.6
40
45
50
Kollef MH et al. Chest 2006;129:1210-1218
P = 0.001

39. Possible options
ESBLs are susceptible to:
• Carbapenems
• Tigecycline
• BL+BLI ?
• Cephamycins (Cefoxitin)
• Polymyxin and Colistin
• Nitrofurantoin
• Fosfomycin
• Temocillin
Amp C & OXA are susceptible to:
• Carbapenems
• Tigecycline
• Polymyxins and Colistin
• Cefepime

40. When BL+ BLIs don’t work?
• Multiple ESBL production
• Hyperproduction of ESBLs in serious infections like Sepsis,
Peritonitis ( Inoculum effect)
• ESBL + Porin loss / Efflux pumps
• ESBL + Amp C
• OXA type ESBL
• BLI resistant TEM mutants (CMT-1 to -4)

41. Window of opportunity
• Early recognition
• Selecting appropriate therapy
• Optimal dose
• PK/PD optimization

42. Better diagnostics
• Redefine resistance breakpoints
• Heterogeneous isolates
• ESBL detection
• In-vivo vs. in-vitro (inoculum effect)
MMWR 2004:53;322-3

43. Choice
• Carbapenem – extended infusion
• Aztreonam
• Temocillin
• Sulbactam
• Colistin/Polymyxin
• Tygecycline
• Fosfomycin
• Trisidine
• Combination

44. PK/PD terminology

45. PK / PD optimization
• Serum drug levels & TDM
• Dosage guidelines
• Extended & continuous infusion
• Combination therapy

46. Target Attainment
► Target attainment for maximum bactericidal effect
► Commonly accepted maximum targets are:
Forrest ,1993; Drusano, 1997
Carbapenems
-Lactams
Quinolones
40% of time >MIC
50% of time >MIC
AUC:MIC ratio >125
Antibiotic Target

47. Carbapenem by Infusion
• Meropenem by continuous infusion
(1 g over 360 min every 6 h), vs
• intermittent infusion (1 g over 30
min every 6 h).
Lorente et al. Ann Pharmacother. 2006;40:219-23.
90.5%
59.6%
0
10
20
30
40
50
60
70
80
90
100
Continuous
infusion
Std infusion
(p < 0.001)
clinical cure rate

48. Roberts et al. J Antimicrob Chemother 2009; 64, 142–150.
Meropenem Infusion in the Critically Ill

49. Roberts et al. J Antimicrob Chemother 2009; 64, 142–150.
Meropenem Infusion in the Critically Ill

50. 6am 2pm 10pm10am 2am6pm
8hr
8hr8hr
4hr
4hr
4hr
6am
E.g. of Meropenem 4hr Infusion (1-2gm 8hrly)
1st dose
(50% bolus)
1st dose
(next day)
2nd dose 3rd dose
24hr

51. Challenges
• Newer drugs
• Virulence inhibitors
• Vaccination
• Rapid diagnostic tests
• Implement guidelines
• Infection control

53. Save Antibiotics
Just a handful left
We can make a difference

54. “Antibiotics are a non-
renewable resource”….
…..use them wisely!