1. Dr Ashwani K Sood
Professor & Head Unit-2,
Deptt of Paediatrics ,IGMC Shimla.
1

2. 2

3. 3

4. Combating Antimicrobial
Resistance:
Aminoglycosides -
Back To The Future
4

5. Antimicrobial Resistance
 AMR is the resistance of an microorganism to an
antimicrobial agent to which it was previously
sensitive.
AMR is the consequence of the use, particularly
the misuse, of antimicrobial medicines and
develops when a microorganism mutates or
acquires a resistance gene.
WHO fact sheet N* 194, March 2012
5

6. AMR is a natural biological
phenomenon
 Once developed, resistance is usually irreversible or very
slow to reverse1
 Resistance is a naturally occurring, continuous but slow
phenomenon1
 Irrational use of antimicrobial agents accelerates AMR and
selects resistant sub-populations which soon become the
dominating member of the species1
1. Indian J Med Res. 2010 November; 132(5): 482–486
6

7. Factors for Antimicrobial Resistance
 Most important cause is the inappropriate use of antimicrobials1
 Too Short a Time
 At Too Low a Dose
 At Inadequate Potency or
 For The Wrong Disease
 Absence or non adherence of standard treatment guidelines1
 High cost or Poor Access to medicines1
 Failure to adhere to recommended regimen1
 Self administration of drugs1
1. Indian J Med Res. 2010 November; 132(5): 482–486
7

8. Economic Impact of the Problem
2
Antibiotic resistance
increases the
economic burden
on the entire
healthcare system
Resistant infections
cost more to treat and
can prolong
healthcare use
2 http://www.cdc.gov/getsmart/
8

9. Status of Antibiotics Resistance:
Global and Indian Scenario
 MRSA alone infects more than 94,000 people and kills
nearly 19,000 in the US every year (more deaths than are caused by
HIV/AIDS, Parkinson’s disease, Emphysema, and Homicide combined)3
 Penicillin-resistant Streptococcal pneumoniae and
Vancomycin Resistant Enterococci (VRE) are more
frequently incriminated from many industrialized countries3
 Some non-fermenter Acinetobacter and Pseudomonas are
resistant to all good antibiotics and many
Enterobacteriaceae are resistant to all except
carbapenems3
3. Vipin M Vashishtha. Growing Antibiotics Resistance and the Need for New Antibiotics. Indian Pediatr 2010;47: 505-506
9

10. Status of Antibiotics Resistance:
Global and Indian Scenario
 Recent surveys have identified ESBLs in 70–90% of
Enterobacteriaceae in India4
 The growing prevalence of ESBL producers is a worldwide
public health concern since there are few antibiotics in reserve
beyond carbapenems4
 Already Klebsiella pneumoniae clones with KPC carbapenemase are a
major problem in the USA, Greece, and Israel, and plasmids encoding the
VIM metallo-carbapenemase have disseminated among K pneumoniae in
Greece4
4. Lancet Infect Dis 2010; 10: 597–602
10

11. Status of Antibiotics Resistance: Global
and Indian Scenario
 10 years ago, concern centred on Gram +ve bacteria,
particularly MRSA (Methicillin Resistant Staph. Aureus) and
VRE (Vancomycin Resistant Enterococcus)4
 Now, however, clinical microbiologists increasingly agree that
multidrug resistant Gram -ve bacteria pose the greatest
risk to public health4
 Not only is the increase in resistance of Gram -ve bacteria faster
than in Gram +ve bacteria, but also there are fewer new and
developmental antibiotics active against Gram -ve bacteria4
4. Lancet Infect Dis 2010; 10: 597–602
11

12. The Building
Crescendo of
Multidrug resistant
Gram Negative
Organisms around
the world
12

13. Changing Resistance Patterns
 Antimicrobial resistance patterns in Indian hospitals differ
from that reported in Western hospitals in having a high
prevalence of resistance among Gram -ve bacteria and a
much lower incidence of resistant Gram +ve bacteria5
 Increase in resistance of Gram -ve bacteria is mainly due
to mobile genes on plasmids that can readily spread
through bacterial populations4
 Moreover, unprecedented human air travel and migration
allow bacterial plasmids and clones to be transported
rapidly between countries and continents4
5. SUPPLEMENT TO JAPI. 2010 Dec; VOL. 58: 25-31 2. Lancet Infect Dis 2010; 10: 597–602
13

14. Much of this dissemination is undetected,
with resistant clones carried in the normal
human flora and only becoming evident
when they are the source of endogenous
infection
14

15. Percentage of Carbapenem Resistance amongst
ICU blood cultures from 2006-20096
6. Deshpande Payal et al. New Delhi Metallo-b lactamase (NDM-1) in Enterobacteriaceae: Treatment options with
Carbapenems Compromised. JAPI. 2010 March; VOL. 58:147-149
15

16. Resistance Profile of E. coli & Klebsiella
to 1st line Agents7
Well over 50% of E. coli and Klebsiella strains are resistant to commonly
used Gram -ve drugs
7. Varghese K George et al. Bacterial Organisms and Antimicrobial Resistance Patterns. Supplement to JAPI 2010
Dec; Vol 58: 23-24
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17. Antimicrobial Resistance Rates of
E.coli in community acquired UTI8
N=208
=127
=81
8. Rani Hena et al. Choice of Antibiotics in Community Acquired UTI due to Escherichia Coli in Adult Age groupJournal of .
Clinical and Diagnostic Research. 2011 June, Vol-5(3): 483-485
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18. Acinetobacter Baumannii
12
Acinetobacter species are aerobic gram -ve
coccobacilli that have emerged as important
opportunistic pathogens, especially among
critically ill patients9
In the last 2 decades, Acinetobacter baumannii
has become an important nosocomial pathogen
throughout the world, and is a major problem due
to multidrug resistance10
Acinetobacter sp are frequently encountered
agents responsible for Hospital Acquired
Pneumonia (HAP) especially the late onset
Ventilator associated Pneumonia (VAP)11
9. Lung India. 2010 Oct–Dec; 27(4): 217–220
10. Scandinavian Journal of Infectious Diseases, 2010; 42: 741–746
11. Annals of Thoracic Medicine-vol 5, issue 2, April-June 2010
12. CDC Fact Sheet. Get Smart About Antibiotics Week Monday, November 15, 2010. http://www.cdc.gov/getsmart/
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19. Response of Acinetobacter species to
β lactam antibiotics13
PG: Penicillin
AM: Ampicillin
Am: Amoxicillin
PC: Piperacillin
CF: Cefotaxime
Ca: Ceftazidime
Ci: Ceftriaxone
CB: Cefuroxime
All A. baumannii isolates were resistant to penicillin and cefuroxime at 512-1024 μg/ml.
More than 90% isolates were resistant to ampicillin, amoxicillin, and piperacillin at 512-
1024 μg/ml
13. Indian J Med Res 128, August 2008, pp 178-187
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20. Antimicrobial Resistance Pattern of
Klebsiellae pneumoniae14
Over 60% strains were resistant to chloramphenicol and tetracycline. 28 to 76% of
them were resistant to cephalosporins (ceftizoxime and cefotaxime)
14. Sikarwar S Archana. Challenge to healthcare: Multidrug resistance in Klebsiella pneumoniae. 2011 International
Conference on Food Engineering and Biotechnology IPCBEE vol.9 (2011) Pg. 130-134
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21. Antimicrobial resistance rates of
Pseudomonas aeruginosa against
Penicillin group15
N=56
15. Javiya, et al.: Antibiotic susceptibility patterns of P. aeruginosa in Gujarat. Indian J Pharmacol . Oct 2008; Vol 40
:230-234
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22. Antimicrobial resistance rates of
Pseudomonas aeruginosa against
Cephalosporin group15
N=56
The organism showed remarkable resistance against cephalosporin group of antibiotics, ranging from 67.86%
for ceftazidime to 94.64% for cephalexin
15. Javiya, et al.: Antibiotic susceptibility patterns of P. aeruginosa in Gujarat. Indian J Pharmacol . Oct 2008; Vol 40 :230-234
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23. Is This The End Of The Road For
Antibiotics?
23

24. The Dying Antibiotic Development12
In the past, medicine and
science were able to
stay ahead of the natural
phenomenon of
resistance through the
discovery of potent new
antimicrobials
12. CDC Fact Sheet. Get Smart About Antibiotics Week Monday, November 15, 2010. http://www.cdc.gov/getsmart/
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25. The 10 X „20 Initiative16
 Launched by IDSA (Infectious Diseases Society of America)
 Global Commitment to Develop 10 New Antibacterial Drugs by
2020
 Recent reports demonstrate that there are few candidate drugs
in the pipeline that offer benefits over existing drugs and few
drugs moving forward that will treat infections due to the so-
called “ESKAPE” pathogens(Enterococcus faecium, Staphylococcus
aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa,
and Enterobacter sp.)
16. Clinical Infectious Diseases 2010; 50:1081–1083 25

26. Aminoglycosides
26

27. Resurgence of Aminoglycosides
 Aminoglycoside antibiotics are bactericidal drugs that have been at the
forefront of antimicrobial therapy for almost five decades17
 Aminoglycosides were widely used in empirical therapy throughout the
1970s and much of the 1980s17
 With the advent of broad-spectrum β-lactams (e.g., 3rd and 4th
generation cephalosporins; β-lactam and β -lactamase inhibitor
combinations, such as piperacillin and tazobactam; and
carbapenems, such as imipenem plus cilastatin and
meropenem) and fluoroquinolones, use of aminoglycosides
decreased17
17. Clinical Infectious Diseases 2007; 45:753–60
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28. Resurgence of Aminoglycosides
 In the era of increasingly MDR Gram -ve bacilli, it is important
and often necessary to consider aminoglycosides for
treatment18
 MDR Pseudomonas and Acinetobacter infections, as well as infections
caused by ESBL Enterobacteriaeceae sp., are often resistant to most or
even all of the newer agents. Frequently, only the aminoglycosides and
the polymyxins are available for therapy17
 Multiple studies have demonstrated the ability to improve the
appropriateness of empirical β-lactam therapy by ∼15% with
the addition of an aminoglycoside18
17. Clinical Infectious Diseases 2007; 45:753–60
18. Antimicrobial Agents And Chemotherapy, June 2010, p. 2750–2751
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29. Aminoglycosides:
Historical Perspective
 Discovery of Streptomycin by Waksman in 1944 initiated Aminoglycosides in
current clinical use19
the era of aminoglycoside antibiotic therapy19
 In the 50 years since their discovery, aminoglycosides
have seen unprecedented use20
 They were the long-sought remedy for tuberculosis and
other serious bacterial infections20
 Side effects of renal and auditory toxicity, however, led to
a decline of their use in the 70s & 80s20
19. International Journal of Antimicrobial Agents 10 (1998) 95–105
20. Audiol Neurootol 2000;5:3–22
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30. Chemical structure &
Characteristics
 Aminoglycosides are low-MW molecules (approx 300–600 daltons)20
 Share a similar structure consisting of several, (usually 3) rings20
 Hallmark is the presence of amino groups and a hydroxyl group attached to the
various rings which convey the major chemical properties, namely high water
solubility and a basic character20
 They are basic, strongly polar compounds that are positively charged (cationic)19
 They are highly soluble in water, relatively insoluble in lipids, and have enhanced
antimicrobial activity in alkaline rather than acidic environments19
19. International Journal of Antimicrobial Agents 10 (1998) 95–105
20. Audiol Neurootol 2000;5:3–22
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31. Chemical structure &
Characteristics19
 Aminoglycosides are minimally absorbed from the gut and penetrate the blood–
brain barrier poorly, even when inflammation is present
 However, higher concentrations are achieved in synovial fluid, bone, and
peritoneal fluid. They achieve excellent urinary concentrations, typically 25–100
times that of serum
 They are excreted unchanged in the urine. Therefore, their half-life is
determined primarily by renal clearance.
 They have a relatively narrow therapeutic-to toxic ratio, emphasizing the
need to monitor antibiotic concentrations
19. International Journal of Antimicrobial Agents 10 (1998) 95–105
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32. Advantages and Disadvantages of
the Aminoglycosides
•Relatively narrow therapeutic
Ratio
•Nephrotoxicity, Ototoxicity, NM
•Familiarity among physicians blockade (rare)
•Broad spectrum of activity •Poor penetration into certain
•Rapid bactericidal action body fluids such as CSF and bile
•Relatively low cost •Lack of enteral absorption
•Chemical stability •Biologic distribution affected by
•Rare association with allergic certain host factors
reactions •Inactivity against anaerobes
•Synergism with β-lactam
antibiotics and vancomycin
32

33. Nephrotoxicity
 Aminoglycosides fell out of favor in the 1980s with the advent
of broad spectrum β-lactams, such as carbapenems & broad
spectrum cephalosporins, as well as β-lactams combined with
β-lactamase inhibitors. Part of the move away from the
aminoglycosides came from their nephrotoxicity18
 Aminoglycoside toxicity is driven by the uptake by proximal
renal tubular epithelial (PRTE) cells of aminoglycosides from
their luminal surface17
 Key issue here is that the uptake is saturable17
17. Clinical Infectious Diseases 2007; 45:753–60
18. Antimicrobial Agents And Chemotherapy, June 2010, p. 2750–2751
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34. Nephrotoxicity20
 Administering the drug once daily instead of in divided doses leads to
slower uptake in the PRTE cell
 This means that for any specific duration of therapy, there will be less
aminoglycoside toxicity, when daily administration is employed
Daily administration, by decrementing the likelihood of
toxicity, allows higher doses to be employed with more
acceptable probabilities of toxicity
20 Antimicrobial Agents And Chemotherapy, June 2011, p. 2528–2531
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35. Comparative Nephrotoxicity
Despite their structural similarities
Aminoglycosides have different affinities
towards brush border membrane of the tubular
cells
 This is due to the number of free amino
groups in the chemical structure
 Netilmicin has the least number of free
amino groups (3) has the lowest binding
affinity
Ref: Data on file
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36. Comparative Nephrotoxicity
36

37. Optimization of Aminoglycoside
Therapy21
 Aminoglycoside optimization of dose can be defined as the
dose having the highest likelihood of a good outcome and the
lowest likelihood of toxicity
 A method for explicitly evaluating ∆ (optimization function) for
different daily doses of drug and different schedules of
administration was developed in the study by Drusano et al.
 The metric ∆ is simply the difference between the likelihood of
a good clinical effect and the likelihood of toxicity, with higher
values being better
21. Drusano G.L. and Arnold Louie. Optimization of Aminoglycoside Therapy. Antimicrobial Agents And Chemotherapy, June
2011, p. 2528–2531
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38. Optimization of Aminoglycoside
Therapy21
Optimization of empirical aminoglycoside therapy with administration every 12 h
Optimization of empirical aminoglycoside therapy with daily administration
Drusano G.L. and Arnold Louie. Optimization of Aminoglycoside Therapy. Antimicrobial Agents And Chemotherapy, June
2011, p. 2528–2531
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39. Comparative Ototoxicity
Study* comparing the Ototoxicity of Amikacin, Tobramycin & Netilmicin, where
Netilmicin was the least ototoxic in comparison to Amikacin & Tobramycin
22. Gatell JM, Ferran F, Araujo V, et al. Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients
receiving aminoglycosides. Antimicrob Agents Chemother. 1987;31:1383-7.
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40. Comparative Vestibular Toxicity23
23 Ann Pharmacother. 2008 Sep;42(9):1282-9. Epub 2008 Jul 22.
40

41. Antimicrobial Susceptibility of
Isolates from Neonatal Septicemia24
Study Design: Retrospective Analysis study of major aerobic bacterial
isolates from cases of neonatal septicemia at the
Government Medical College Hospital, Chandigarh
Patients: 3,064 blood samples for blood culture were obtained from
neonates over a period of 5 years
Primary Endpoint: To determine the bacterial profile, the antimicrobial
susceptibility of the isolates, and the change in trends over
the 5 year study period
Conclusion: Predominant organism was S. aureus. (35.3%)
Most isolates of S. aureus were resistant to
ampicillin/amoxycillin
Netilmicin was found to be the drug of choice
against S.aureus
24. Agnihotri N, Kaistha N & Gupta V. Jpn J Infect Dis 2004;57:273-5
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42. Prophylactic role of Netilmicin in
Genitourinary surgery25
Study Design: Prospective, randomized, comparative study of 50 patients undergoing
elective urinary or genital surgery.
Design: Group A (Study Group)-received single dose of netilmicin sulphate 300
mg i.m., 1 hour prior to surgery
Group B (Control Group)-received the first dose of ampicillin sodium 500
mg and of gentamicin sulphate 80 mg i.m. 1 hour prior to surgery and
then, ampicillin sodium 500 mg at 6 -hour intervals and gentamicin
sulphate 80 mg i.m. twice a day for 5 days postoperatively.
Primary Endpoint: To evaluate netilmicin sulphate as a prophylactic antibiotic in
genitourinary surgery and to compare its clinical efficacy and safety with
ampicillin sodium and gentamicin sulphate
Result: None of the patients in the group receiving netilmicin suffered
from UTI post-operatively in comparison to three patients in the
ampicillin and gentamicin group (p <0.05)
None of the patients who received Netilmicin preoperatively
developed any Tinnitus, Hearing impairment, Vertigo or Allergic
reactions
25. Bajaj J, Singh SJ & Bedi PS. Indian J Pharmacol 2007;39(2):121-2.
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43. Sensitivity pattern of microorganisms (%) isolated from
different specimens obtained from patients admitted in
ICUs 26
 Acinetobacter was found
to be multidrug-resistant
and sensitive only to
Netilmicin in 45.5%
isolates
 E. Coli was 100%
sensitive to Imepenem,
Meropenem, & Netilmicin
26. Sharma PR & Barman P. Antimicrobial consumption and impact of "Reserve antibiotic indent form" in an intensive care unit. Indian J
Pharmacol 2010;42(5):297-300
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44. Low and stable resistance pattern of Netilmicin to P.
aeruginosa in LRTI over a period of 3 years as compared
to other antibiotics27
Trends in antimicrobial resistance pattern of P. aeruginosa during 2006–2009 (in %age) (Phase II)
100
90
80
70
60
50
40
30
20
10
0
CTX CTa CTi AC G AK CF Mr PC PT Az NT Of
2006–2007 2007–2008 2008–2009
CTX = Ceftriaxone, CTa = Ceftazidime, CTi = Ceftizoxime, AC = Amoxy-Clav, G = Gentamicin, AK = Amikacin, CF = Ciprofloxacin, Mr
= Meropenem, PC = Piperacillin, PT = Piperacillin tazobactom, Az = Aztreonam, NT = Netilmycin, Of = Ofloxacin
27. Gagneja D, Goel N, Aggarwal R, Chaudhary U. Changing trend of antimicrobial resistance among gram-negative bacilli isolated from
lower respiratory tract of ICU patients: A 5-year study. Indian J Crit Care Med 2011;15:164-7
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45. Resistance pattern of E. coli to various
antibiotics28
28. Journal of Clinical and Diagnostic Research. 2011 June, Vol-5(3): 486-490
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46. Netilmicin: Effective and Safest
Aminoglycoside29
 Netilmicin has a lower potential for ototoxicity and
nephrotoxicity than the other aminoglycosides
 Single dose regimen (SD) of Netilmicin is as effective as the
multiple dose regimen (MD) in the eradication of gram-negative
bacteria and the treatment of systemic infections
 An effective and safe single dose regimen of Netilmicin may
permit the outpatient management of some systemic infections,
thus avoiding the cost and inconveniences of hospitalization
29 Limson BM, Genato VX and Yusi G. A Randomized Multicenter Study of the Single Daily Dose Regimen Vs. the Multiple Daily
Dose Regimen of Netilmicin in the Treatment of Systemic Infections. Phil J Microbiol Infect Dis 1989; 18(2):47-52
46

47. Spectrum of Netilmicin30
• E. coli, Klebsiella-Enterobacter-Serratia group,
Citrobacter
• Proteus sp. (indole +ve and indole -ve), including Proteus
mirabilis, P. morganii, P. rettgeri, P. vulgaris,
• Pseudomonas aeruginosa and Neisseria gonorrhoea
Gram –ve • Hemophilus influenzae, Salmonella sp., Shigella sp.
organisms : • Acinetobacter sp
• Penicillinase and non-penicillinase-producing
Staphylococcus including methicillin-resistant strains
(MRSA)
Gram +ve • Some strains of Providencia sp., and Aeromonas sp. are
organisms also sensitive
30. Netromycin Prescribing Information.
47

48. Bacteremia, Septicemia
(including Neonatal sepsis)
Intra-abdominal
Serious
infections
infections of the
(including
Respiratory tact
peritonitis)
Burns, wounds, Indications30 Kidney and
peri-operative Genitourinary
infections Tract infections
Bone, joint Skin, soft tissue
infections infections
30. Netromycin Prescribing Information.
48

49. Conclusion31
 By all accounts, Aminoglycosides, antibiotics with a rich history, are
experiencing a renaissance
 Never having been completely abandoned in the clinic thanks to their
highly desirable antibacterial spectrum, they increasingly fill emerging
needs
 Mounting bacterial resistance to other mainstay drugs require
aminoglycosides for successful chemotherapy
 The utility of aminoglycosides against resistant bacteria stems in part
from their relatively restrained use during the last decades lowering the
development of global resistance to them
31. Xie, J., Talaska A. and Schacht J., New developments in aminoglycoside therapy and ototoxicity, Hearing
Research 2011; 281. 28-37
49

50. Looking ahead at the problem
of Antimicrobial Resistance
 No single strategy can solve the antibiotic resistance problem; a
multi‐pronged approach is required
 Emphasize appropriate use of the antibiotics that are currently
available
 Educate everyone about the growing threat of antibiotic resistance
and the appropriate use of antibiotics
 Patients, healthcare providers, hospital administrators, and policy
makers must work together to employ effective strategies for
improving appropriate antibiotic use – ultimately saving lives
50

51. Any Questions?
51