Dr Ashwani K Sood    Professor & Head Unit-2,    Deptt of Paediatrics ,IGMC Shimla.1
2
3
Combating Antimicrobial    Resistance:   Aminoglycosides -    Back To The Future         4
Antimicrobial Resistance     AMR is the resistance of an microorganism to an    antimicrobial agent to which it was previ...
AMR is a natural biological                   phenomenon Once developed, resistance is usually irreversible or very    sl...
Factors for Antimicrobial Resistance Most important cause is the inappropriate use of antimicrobials1     Too Short a Ti...
Economic Impact of the Problem                                         2             Antibiotic resistance             inc...
Status of Antibiotics Resistance:                        Global and Indian Scenario MRSA alone infects more than 94,000 p...
Status of Antibiotics Resistance:                        Global and Indian Scenario Recent surveys have identified ESBLs ...
Status of Antibiotics Resistance: Global               and Indian Scenario 10 years ago, concern centred on Gram +ve bact...
The BuildingCrescendo ofMultidrug resistantGram NegativeOrganisms aroundthe world                12
Changing Resistance Patterns Antimicrobial resistance patterns in Indian hospitals differ    from that reported in Wester...
Much of this dissemination is undetected,with resistant clones carried in the normalhuman flora and only becoming evidentw...
Percentage of Carbapenem Resistance amongst        ICU blood cultures from 2006-200966. Deshpande Payal et al. New Delhi M...
Resistance Profile of E. coli & Klebsiella              to 1st line Agents7 Well over 50% of E. coli and Klebsiella strain...
Antimicrobial Resistance Rates ofE.coli in community acquired UTI8                                                        ...
Acinetobacter Baumannii                                                                                                   ...
Response of Acinetobacter species to           β lactam antibiotics13                                                     ...
Antimicrobial Resistance Pattern of        Klebsiellae pneumoniae14 Over 60% strains were resistant to chloramphenicol and...
Antimicrobial resistance rates of   Pseudomonas aeruginosa against           Penicillin group15                           ...
Antimicrobial resistance rates of       Pseudomonas aeruginosa against            Cephalosporin group15                   ...
Is This The End Of The Road For          Antibiotics?               23
The Dying Antibiotic Development12 In the past, medicine and science were able to stay ahead of the natural phenomenon of ...
The 10 X „20 Initiative16 Launched by IDSA (Infectious Diseases Society of America) Global Commitment to Develop 10 New ...
Aminoglycosides       26
Resurgence of Aminoglycosides Aminoglycoside antibiotics are bactericidal drugs that have been at the   forefront of anti...
Resurgence of Aminoglycosides In the era of increasingly MDR Gram -ve bacilli, it is important   and often necessary to c...
Aminoglycosides:                               Historical Perspective Discovery of Streptomycin by Waksman in 1944 initia...
Chemical structure &                 Characteristics Aminoglycosides are low-MW molecules (approx 300–600 daltons)20 Sha...
Chemical structure &                 Characteristics19 Aminoglycosides are minimally absorbed from the gut and penetrate ...
Advantages and Disadvantages of     the Aminoglycosides                                       •Relatively narrow therapeut...
Nephrotoxicity Aminoglycosides fell out of favor in the 1980s with the advent   of broad spectrum β-lactams, such as carb...
Nephrotoxicity20 Administering the drug once daily instead of in divided doses leads to   slower uptake in the PRTE cell...
Comparative NephrotoxicityDespite their structural similaritiesAminoglycosides have different affinitiestowards brush bord...
Comparative Nephrotoxicity               36
Optimization of Aminoglycoside                   Therapy21 Aminoglycoside optimization of dose can be defined as the    d...
Optimization of Aminoglycoside                  Therapy21Optimization of empirical aminoglycoside therapy with administrat...
Comparative OtotoxicityStudy* comparing the Ototoxicity of Amikacin, Tobramycin & Netilmicin, whereNetilmicin was the leas...
Comparative Vestibular Toxicity23     23 Ann Pharmacother. 2008 Sep;42(9):1282-9. Epub 2008 Jul 22.                       ...
Antimicrobial Susceptibility of  Isolates from Neonatal Septicemia24Study Design: Retrospective Analysis study of major ae...
Prophylactic role of Netilmicin in        Genitourinary surgery25Study Design:            Prospective, randomized, compara...
Sensitivity pattern of microorganisms (%) isolated from different specimens obtained from patients admitted in ICUs 26 Ac...
Low and stable resistance pattern of Netilmicin to P.aeruginosa in LRTI over a period of 3 years as comparedto other antib...
Resistance pattern of E. coli to various             antibiotics2828. Journal of Clinical and Diagnostic Research. 2011 Ju...
Netilmicin: Effective and Safest                                   Aminoglycoside29 Netilmicin has a lower potential for ...
Spectrum of Netilmicin30               • E. coli, Klebsiella-Enterobacter-Serratia group,                 Citrobacter     ...
Bacteremia, Septicemia                                    (including Neonatal sepsis)    Intra-abdominal                  ...
Conclusion31 By all accounts, Aminoglycosides, antibiotics with a rich history, are   experiencing a renaissance Never h...
Looking ahead at the problem  of Antimicrobial Resistance No single strategy can solve the antibiotic resistance problem;...
Any Questions?       51
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Combating Antimicrobial Resistance:Aminoglocisides Back To The Future

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  • Ref: 1. AMR WHO FAQ2. Indian J Med Res. 2010 November; 132(5): 482–486The use of an antimicrobial for any infection, in any dose and over any time period, causes a “selective pressure” on microbial populations. Under optimal conditions, the majority of the infecting microbes will be killed and the body’s immune system can deal with the rest. However, if a few resistant mutants exist in the population under selective pressure and the treatment is insufficient or the patient is immunocompromised, the mutants can flourish. Thus treatment may fail.
  • U.S. Antibiotic resistant infections are responsible for: • $20 billion in excess healthcare costs • $35 billion in societal costs • 8 million additional hospital days
  • Growing antibiotic resistance is a global phenomenon in both developed and developing countries. Penicillin-resistant Streptococcal pneumoniae and Vancomycin Resistant Enterococci (VRE)are more frequently incriminated from many industrialized countries forcing frequent changes of recommendations of management of diseases caused by these bugs1NDM-1 can render powerful antibiotics, which are often the last defence against multi-resistant strains of bacteria, ineffectiveRef: 1. Vipin M Vashishtha. Growing Antibiotics Resistance and the Need for New Antibiotics. Indian Pediatr 2010;47: 505-506
  • The growing prevalence of ESBL producers is sufficient to drive a greater reliance on carbapenems. Consequently, there is selection pressure for carbapenem resistance in Enterobacteriaceae, and its emergence is a worldwide public health concern since there are few antibiotics in reserve beyond carbapenems1Ref: 1.Lancet Infect Dis 2010; 10: 597–602ESBL: extended-spectrum β-lactamase
  • Bacteria from clinical and non-clinical settings are becoming increasingly resistant to conventional antibioticsRef: Lancet Infect Dis 2010; 10: 597–602MRSA: Meticillin-resistant Staphylococcus aureus
  • Ref: 1. SUPPLEMENT TO JAPI. 2010 Dec; VOL. 58: 25-312. Lancet Infect Dis 2010; 10: 597–602
  • DeshpandePayal et al. New Delhi Metallo-b lactamase (NDM-1) in Enterobacteriaceae: Treatment options with Carbapenems Compromised. JAPI. 2010 March; VOL. 58:147-149
  • Ref: Ref: Varghese K George et al. Bacterial Organisms and Antimicrobial Resistance Patterns. Supplement to JAPI 2010 Dec; Vol 58: 23-24Data from almost 11,000 samples with a positive yield in almost a third clearly confirm as is well known that Gram negative bacilli are the commonest cause of UTI’s (90%). E.coliaccounted for two-thirds of the gram negative isolates followed by Klebsiella in 18% and Pseudomonas in 8.4%.
  • A high resistance was seen for beta lactam antibiotics. A very high resistance was seen not only for ampicillin (aminopenicillin) but also for amoxycillin+clavulanic acid which is the combination of aminopenicillin with beta lactamase inhibitor and also a costlier drug. Resistance rate for third generation cephalosporins was significantly high which is indicative of production of extended spectrum beta lactamase (ESBLs) enzyme by the isolates from community.
  • Ref: 1. Lung India. 2010 Oct–Dec; 27(4): 217–2202. Scandinavian Journal of Infectious Diseases, 2010; 42: 741–7463. Annals of Thoracic Medicine-vol 5, issue 2, April-June 20104. CDC Fact Sheet. Get Smart About Antibiotics Week Monday, November 15, 2010. http://www.cdc.gov/getsmart/
  • K.pneumoniae strains from clinical cases were found highly susceptible to quinolones and aminoglycoside, amikacin and gentamycin. At the same time over 60% strains were found resistant to chloramphenicol and tetracycline. Twenty-eight to 76% of them were resistant to cephalosporins (ceftizoxime and cefotaxime).
  • Ref: CDC Fact Sheet, Get Smart About Antibiotics Week Friday, November 19, 2010. http://www.cdc.gov/getsmart/
  • Ref: Clinical Infectious Diseases 2010; 50:1081–1083
  • Ref: 1. International Journal of Antimicrobial Agents 10 (1998) 95–1052. Audiol Neurootol 2000;5:3–22
  • Ref: 1. AudiolNeurootol 2000;5:3–222. International Journal of Antimicrobial Agents 10 (1998) 95–105A knowledge of aminoglycoside structure is important in understanding their chemical properties
  • Ref: International Journal of Antimicrobial Agents 10 (1998) 95–105
  • Ref: 1. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2010, p. 2750–27512. Clinical Infectious Diseases 2007; 45:753–60Less frequent aminoglycoside administration would result in less aminoglycoside uptake and, ultimately, a lower rate of nephrotoxicity occurring during reasonably short courses of therapy
  • Ref: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2011, p. 2528–2531Less frequent aminoglycoside administration would result in less aminoglycoside uptake and, ultimately, a lower rate of nephrotoxicity occurring during reasonably short courses of therapy
  • Once a day dosing results in less drug accumulation and Netilmicin has the lowest binding affinity to the renal proximal tubular cell
  • The ∆ has an optimal value of 74.8 at an MIC value of 0.25 mg/liter, and the values decline to 69.4 and 55.3 at 0.5 and 1.0 mg/liter, respectively, with 2.0 and 4.0 mg/liter attaining values of 39.5 and 29.0, respectively, because of decrementing values of response probability. Of interest, the ∆ gets considerably worse, on average, when the dose is increased to 7 mg/kg (19.9 at 2.0 mg/liter and 6.5 at 4.0 mg/liter) or 10 mg/kg (∆=0 at both MIC values), even though there is a marginal increase in the response probability. This is because of the increase in mean nephrotoxicity probability at higher doses. In contrast, daily dosing, demonstrates that the 10-mg/kg dose provides an 80% probability of response, even for an MIC of 4.0 mg/ liter, with a negligible likelihood of toxicity.Nephrotoxicity was defined as an increase in the baseline serum creatinine concentration of 0.5 mg/dl or a 50% increase, whichever was greater, on two consecutive occasions any time during therapy or up to 1 week after the cessation of therapy
  • Incidence of vestibular toxicity is 10.9% for Gentamicin, 7.4% for Amikacin, 3.5% for Tobramycin, and 1.1% for Netilmicin
  • Ref: Agnihotri N, Kaistha N & Gupta V. Antimicrobial susceptibility of isolates from neonatal septicemia.Jpn J Infect Dis 2004;57:273-5.
  • i.m. : intramuscularly
  • In isolates from pus and exudates, the maximum resistance was observed for ampicillin 97(96.0%), followed by cotrimaxazole 84(83.2%), ciprofloxacin 69(68.3%), gentamicin 68(67.3%), amikacin 45(44.6%), cefotaxime 44(43.6%), and netilmicin 23(22.8%)
  • Ref: 1: Phil J Microbiol Infect Dis 1989; 18(2):47-52
  • No single strategy can solve the antibiotic resistance problem; a multi‐pronged approach is required Because it will be many years before new antibiotics are available to treat some resistant infections, we must do a better job of emphasizing appropriate use of the antibiotics that are currently available We must educate everyone about the growing threat of antibiotic resistance and the appropriate use of antibioticsPatients, healthcare providers, hospital administrators, and policy makers must work together to employ effective strategies for improving appropriate antibiotic use – ultimately saving lives
  • Combating Antimicrobial Resistance:Aminoglocisides Back To The Future

    1. 1. Dr Ashwani K Sood Professor & Head Unit-2, Deptt of Paediatrics ,IGMC Shimla.1
    2. 2. 2
    3. 3. 3
    4. 4. Combating Antimicrobial Resistance: Aminoglycosides - Back To The Future 4
    5. 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. 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 species11. Indian J Med Res. 2010 November; 132(5): 482–486 6
    7. 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. 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 use2 http://www.cdc.gov/getsmart/ 8
    9. 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. 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. 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 bacteria44. Lancet Infect Dis 2010; 10: 597–602 11
    12. 12. The BuildingCrescendo ofMultidrug resistantGram NegativeOrganisms aroundthe world 12
    13. 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 continents45. SUPPLEMENT TO JAPI. 2010 Dec; VOL. 58: 25-31 2. Lancet Infect Dis 2010; 10: 597–602 13
    14. 14. Much of this dissemination is undetected,with resistant clones carried in the normalhuman flora and only becoming evidentwhen they are the source of endogenousinfection 14
    15. 15. Percentage of Carbapenem Resistance amongst ICU blood cultures from 2006-200966. Deshpande Payal et al. New Delhi Metallo-b lactamase (NDM-1) in Enterobacteriaceae: Treatment options withCarbapenems Compromised. JAPI. 2010 March; VOL. 58:147-149 15
    16. 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 drugs7. Varghese K George et al. Bacterial Organisms and Antimicrobial Resistance Patterns. Supplement to JAPI 2010Dec; Vol 58: 23-24 16
    17. 17. Antimicrobial Resistance Rates ofE.coli in community acquired UTI8 N=208 =127 =818. 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 17
    18. 18. Acinetobacter Baumannii 12Acinetobacter species are aerobic gram -vecoccobacilli that have emerged as importantopportunistic pathogens, especially amongcritically ill patients9In the last 2 decades, Acinetobacter baumanniihas become an important nosocomial pathogenthroughout the world, and is a major problem dueto multidrug resistance10Acinetobacter sp are frequently encounteredagents responsible for Hospital AcquiredPneumonia (HAP) especially the late onsetVentilator associated Pneumonia (VAP)119. Lung India. 2010 Oct–Dec; 27(4): 217–22010. Scandinavian Journal of Infectious Diseases, 2010; 42: 741–74611. Annals of Thoracic Medicine-vol 5, issue 2, April-June 201012. CDC Fact Sheet. Get Smart About Antibiotics Week Monday, November 15, 2010. http://www.cdc.gov/getsmart/ 18
    19. 19. Response of Acinetobacter species to β lactam antibiotics13 PG: Penicillin AM: Ampicillin Am: Amoxicillin PC: Piperacillin CF: Cefotaxime Ca: Ceftazidime Ci: Ceftriaxone CB: CefuroximeAll 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 19
    20. 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 InternationalConference on Food Engineering and Biotechnology IPCBEE vol.9 (2011) Pg. 130-134 20
    21. 21. Antimicrobial resistance rates of Pseudomonas aeruginosa against Penicillin group15 N=5615. Javiya, et al.: Antibiotic susceptibility patterns of P. aeruginosa in Gujarat. Indian J Pharmacol . Oct 2008; Vol 40:230-234 21
    22. 22. Antimicrobial resistance rates of Pseudomonas aeruginosa against Cephalosporin group15 N=56The 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 22
    23. 23. Is This The End Of The Road For Antibiotics? 23
    24. 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 antimicrobials12. CDC Fact Sheet. Get Smart About Antibiotics Week Monday, November 15, 2010. http://www.cdc.gov/getsmart/ 24
    25. 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. 26. Aminoglycosides 26
    27. 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 27
    28. 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 28
    29. 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 29
    30. 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 30
    31. 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 concentrations19. International Journal of Antimicrobial Agents 10 (1998) 95–105 31
    32. 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-lactamantibiotics and vancomycin 32
    33. 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 33
    34. 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 34
    35. 35. Comparative NephrotoxicityDespite their structural similaritiesAminoglycosides have different affinitiestowards brush border membrane of the tubularcells 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 35
    36. 36. Comparative Nephrotoxicity 36
    37. 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 better21. Drusano G.L. and Arnold Louie. Optimization of Aminoglycoside Therapy. Antimicrobial Agents And Chemotherapy, June2011, p. 2528–2531 37
    38. 38. Optimization of Aminoglycoside Therapy21Optimization of empirical aminoglycoside therapy with administration every 12 h Optimization of empirical aminoglycoside therapy with daily administrationDrusano G.L. and Arnold Louie. Optimization of Aminoglycoside Therapy. Antimicrobial Agents And Chemotherapy, June2011, p. 2528–2531 38
    39. 39. Comparative OtotoxicityStudy* comparing the Ototoxicity of Amikacin, Tobramycin & Netilmicin, whereNetilmicin 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. 39
    40. 40. Comparative Vestibular Toxicity23 23 Ann Pharmacother. 2008 Sep;42(9):1282-9. Epub 2008 Jul 22. 40
    41. 41. Antimicrobial Susceptibility of Isolates from Neonatal Septicemia24Study Design: Retrospective Analysis study of major aerobic bacterial isolates from cases of neonatal septicemia at the Government Medical College Hospital, ChandigarhPatients: 3,064 blood samples for blood culture were obtained from neonates over a period of 5 yearsPrimary Endpoint: To determine the bacterial profile, the antimicrobial susceptibility of the isolates, and the change in trends over the 5 year study periodConclusion: 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.aureus24. Agnihotri N, Kaistha N & Gupta V. Jpn J Infect Dis 2004;57:273-5 41
    42. 42. Prophylactic role of Netilmicin in Genitourinary surgery25Study 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 sulphateResult: 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. 42
    43. 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 43
    44. 44. Low and stable resistance pattern of Netilmicin to P.aeruginosa in LRTI over a period of 3 years as comparedto 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 2008–2009CTX = 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 = Ofloxacin27. Gagneja D, Goel N, Aggarwal R, Chaudhary U. Changing trend of antimicrobial resistance among gram-negative bacilli isolated fromlower respiratory tract of ICU patients: A 5-year study. Indian J Crit Care Med 2011;15:164-7 44
    45. 45. Resistance pattern of E. coli to various antibiotics2828. Journal of Clinical and Diagnostic Research. 2011 June, Vol-5(3): 486-490 45
    46. 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. 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. areorganisms also sensitive 30. Netromycin Prescribing Information. 47
    48. 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 infections30. Netromycin Prescribing Information. 48
    49. 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. 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. 51. Any Questions? 51

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