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Dr Ashwani K SoodProfessor & Head Unit-2, Deptt of Paediatrics ,IGMC Shimla.

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Combating Antimicrobial Resistance:

Aminoglycosides - Back To The Future

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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

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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

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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

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Economic Impact of the Problem

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/

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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

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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

Status of Antibiotics Resistance: Global and Indian Scenario

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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

4. Lancet Infect Dis 2010; 10: 597–602

Status of Antibiotics Resistance: Global and Indian Scenario

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

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

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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

Changing Resistance Patterns

5. SUPPLEMENT TO JAPI. 2010 Dec; VOL. 58: 25-31 2. Lancet Infect Dis 2010; 10: 597–602

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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

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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

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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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Antimicrobial Resistance Rates of E.coli in community acquired UTI8

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

N=208

♀=127 ♂=81

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Acinetobacter Baumannii

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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Response of Acinetobacter species to β lactam antibiotics13

13. Indian J Med Res 128, August 2008, pp 178-187

PG: PenicillinAM: AmpicillinAm: AmoxicillinPC: PiperacillinCF: CefotaximeCa: CeftazidimeCi: CeftriaxoneCB: 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

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Antimicrobial Resistance Pattern of Klebsiellae pneumoniae14

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

Over 60% strains were resistant to chloramphenicol and tetracycline. 28 to 76% of them were resistant to cephalosporins (ceftizoxime and cefotaxime)

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Antimicrobial resistance rates of Pseudomonas aeruginosa against

Penicillin group15

15. Javiya, et al.: Antibiotic susceptibility patterns of P. aeruginosa in Gujarat. Indian J Pharmacol . Oct 2008; Vol 40 :230-234

N=56

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Antimicrobial resistance rates of Pseudomonas aeruginosa against

Cephalosporin group15

15. Javiya, et al.: Antibiotic susceptibility patterns of P. aeruginosa in Gujarat. Indian J Pharmacol . Oct 2008; Vol 40 :230-234

The organism showed remarkable resistance against cephalosporin group of antibiotics, ranging from 67.86% for ceftazidime to 94.64% for cephalexin

N=56

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Is This The End Of The Road For Antibiotics?

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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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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

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Aminoglycosides

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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

Resurgence of Aminoglycosides

17. Clinical Infectious Diseases 2007; 45:753–60

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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

Resurgence of Aminoglycosides

17. Clinical Infectious Diseases 2007; 45:753–60

18. Antimicrobial Agents And Chemotherapy, June 2010, p. 2750–2751

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Aminoglycosides: Historical Perspective

Discovery of Streptomycin by Waksman in 1944 initiated

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

Aminoglycosides in current clinical use19

19. International Journal of Antimicrobial Agents 10 (1998) 95–105 20. Audiol Neurootol 2000;5:3–22

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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

Chemical structure & Characteristics

19. International Journal of Antimicrobial Agents 10 (1998) 95–10520. Audiol Neurootol 2000;5:3–22

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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

Chemical structure & Characteristics19

19. International Journal of Antimicrobial Agents 10 (1998) 95–105

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Advantages and Disadvantages of the Aminoglycosides

• Familiarity among physicians • Broad spectrum of activity • Rapid bactericidal action • Relatively low cost• Chemical stability • Rare association with allergic reactions• Synergism with β-lactamantibiotics and vancomycin

• Relatively narrow therapeutic Ratio• Nephrotoxicity, Ototoxicity, NM

blockade (rare)• Poor penetration into certain body fluids such as CSF and bile• Lack of enteral absorption• Biologic distribution affected by certain host factors• Inactivity against anaerobes

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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; 45:753–6018. Antimicrobial Agents And Chemotherapy, June 2010, p. 2750–2751

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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

20 Antimicrobial Agents And Chemotherapy, June 2011, p. 2528–2531

Daily administration, by decrementing the likelihood of toxicity, allows higher doses to be employed with more acceptable probabilities of toxicity

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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

Comparative Nephrotoxicity

Ref: Data on file

Despite their structural similarities

Aminoglycosides have different affinities

towards brush border membrane of the tubular

cells

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Comparative Nephrotoxicity

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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 better21. Drusano G.L. and Arnold Louie. Optimization of Aminoglycoside Therapy. Antimicrobial Agents And Chemotherapy, June 2011, p. 2528–2531

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Optimization of empirical aminoglycoside therapy with daily administration

Optimization of empirical aminoglycoside therapy with administration every 12 h

Optimization of Aminoglycoside Therapy21

Drusano G.L. and Arnold Louie. Optimization of Aminoglycoside Therapy. Antimicrobial Agents And Chemotherapy, June 2011, p. 2528–2531

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Comparative OtotoxicityStudy* 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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Comparative Vestibular Toxicity23

23 Ann Pharmacother. 2008 Sep;42(9):1282-9. Epub 2008 Jul 22.

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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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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

reactions25. Bajaj J, Singh SJ & Bedi PS. Indian J Pharmacol 2007;39(2):121-2.

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Sensitivity pattern of microorganisms (%) isolated from different specimens obtained from patients admitted in ICUs 26

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

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

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Low and stable resistance pattern of Netilmicin to P. aeruginosa in LRTI over a period of 3 years as compared to other antibiotics27

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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60

70

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90

100

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

Trends in antimicrobial resistance pattern of P. aeruginosa during 2006–2009 (in %age) (Phase II)

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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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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

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Spectrum of Netilmicin30

Gram –ve organisms :

• 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

• Hemophilus influenzae, Salmonella sp., Shigella sp.

• Acinetobacter sp

Gram +ve organisms

• Penicillinase and non-penicillinase-producing Staphylococcus including methicillin-resistant strains (MRSA)

• Some strains of Providencia sp., and Aeromonas sp. are also sensitive

30. Netromycin Prescribing Information.

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Bacteremia, Septicemia (including

Neonatal sepsis)

Serious infections of the Respiratory

tact

Kidney and Genitourinary

Tract infections

Skin, soft tissue infections

Bone, joint infections

Burns, wounds, peri-operative

infections

Intra-abdominal infections (including peritonitis)

Indications30

30. Netromycin Prescribing Information.

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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

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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

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Any Questions?