Piperacillin & Tazobactam

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Piperacillin & Tazobactam

  1. 1. Piperacillin & Tazobactam
  2. 2. COMPLICATION OF NOSOCOMIAL INFECTIONS Nosocomial infections are estimated to double the mortality and morbidity risks of any admitted patient
  3. 3. NOSOCOMIAL TROIKA  Staphylococcus aureus  Escherichia coli  Pseudomonas aeruginosa
  4. 4. What is Resistance?  ◦ Drug Resistance refers to unresponsiveness of a microorganism to an antimicrobial agent. ◦ Drug resistance is of two types:  Natural resistance  Acquired resistance
  5. 5. Natural resistance  ◦ Some microbes have always been resistant to certain antimicrobial agents. ◦ They lack the metabolic process or the target site that is affected by the particular drug.  Gram negative bacilli are normally unaffected by penicillin G  M. tuberculosis is insensitive to tetracyclines. ◦ This type of resistance does not pose significant clinical problem. Acquired resistance:  ◦ It is the development of resistance by an organism (which was sensitive before) due to the use of an antimicrobial agent over a period of time. ◦ This can happen with any microbe and is a major clinical problem. However, development of resistance is dependent on the microorganism as well as the drug.
  6. 6. Porins  Altered penicillin binding proteins  -lactamases 
  7. 7. CHALLENGES OF -LACTAMASES 1940 : Introduction of penicillins 1940 : First description of -lactamases published 1944 : Strains of staphylococcus aureus producing -lactamase 1960s : Clinical use of expanded spectrum penicillins - such as ampicillin and carbenicillin 1970s : plasmid mediated -lactamases assumed prominence in enterobacteriaceae and gram-negative bacteria 1980-90 : Development of broad-spectrum cephalosporins, cephamycins, monobactams and carbapenems 1990 : Increased resistance among gram-negative bacteria with inducible chromosomally-mediated lactamases JAC (1993); suppl A: 1-8
  8. 8. EGASTfeatures (212 isolates from India, 2000-2001) STUDY Listing of organisms tested and their resistance No. of isolates=61% Organism EGAST results Proteus vulgaris 74% S.epidermidis 73% Klebsiella spp. 68% Staphylococcus aureus 64% Escherischia coli 64% Citrobacter spp. 63% Pseudomonas aeruginosa 59% Enterobacter spp. 58% - 70% Proteus mirabilis 46% Acinetobacter species 36% Enterococcus faecalis 17% Haemophilus influenzae 17% International Journal of Antimicrobial Agents Volume 20, Issue 6, December 2002, Pages 426-431 Expert Group on Antibiotic Susceptibility Tests
  9. 9. FAILURE OF ANTIBIOTICS DUE TO BETA-LACTAMASE Current Rate of % increase in Resistance Resistance (99 v/s 94-98) Vancomycin/enterococci 25.9% 47% Methicillin/S. aureus 54.5% 43% Methicillin/Coagulase-negative 86.7% 2% staphylococci 3rd generation Cephalosporin 36.4% 3% Enterobacter spp Imipenem/P. aeruginosa 18.5% 35% Quinolone/P. aeruginosa 23.0% 49% Am J Infect Control 1999;27:520-32
  10. 10. SOLUTION -lactamase Inhibitors  Tazobactam – irreversible ‘suicide inhibitor’  Clavulanic acid  Sulbactam
  11. 11. INHIBITORY ACTIVITY OF -LACTAMASE INHIBITORS AGAINST -LACTAMASES Inhibitory Activityc Enzyme classa Organismb Tazobactam Clavulanic acid Sulbactam 1a Enterobacter cloacae + 0 + 1b Escherichia coli + 0 0 1c Bacteroides fragilis Proteus vulgaris +++ ++ + +/+ + + 1d Pseudomonas + 0 + aeruginosa II Proteus mirabilis +++ +++ ++ III E.coli TEM-1 +++ ++ 0 E.coli SHV-1 +++ +++ 0 IV Klebsiella pneumoniae +++ +++ + V E.coli OXA-1 + + + E.coli PSE-1 +++ +++ ++ Staphylococcus aureus ++ ++ + a Based on Richmond and Sykes Classification b Enzymes stated were those produced by organism studied c + + + = IC50 < 0.05 mg/L + + = IC50 > 0.05 - < 0.5 mg/L + = IC50 > 0.5 - < 5 mg/L; where IC50 is [the drug concentration required to reduce the initial rate of hydrolysis by 50%].
  12. 12. INTRODUCING…  The extended spectrum antipseudomonal penicillin: Piperacillin  And Tazobactam – the potent -lactamase inhibitor
  13. 13. MODE OF ACTION Piperacillin inhibits cell wall synthesis by binding to penicillin-binding proteins in the cytoplasmic membrane of bacteria. B e ta -la cta m Pr oin P o rin P n illinB d g e ic in in P e n ic illin B ind in g Poe s( B ) r t in P P P ro te in s (P B P ) c ll w ll s nh s e a y t e is c e ll w a ll sy n th e s is Ly s is
  14. 14. PHARMACOKINETICS  Administered parenterally (IM, IV)  Piperacillin: Tazobactam available in 8: 1 ratio  Rapid Distribution within 30 minutes  Good concentration in the lungs, G.I. tissue and muscle/fat tissues  Minimally protein bound  Excretion via kidneys Drugs 1999;57:805-843
  15. 15. SERIOUS NOSOCOMIAL LRTIs a. Serious Nosocomial LRTIs Piperacillin-tazobactam plus tobramycin v/s ceftazidime plus tobramycin (n = 155) (n = 145) In serious nosocomial LRTIs- Superior to Cef tazidime + Tobramycin 30% P.aeruginosa 67% 33% S.aureus 69% 50% H.inf luenzae 100% Bacterial 38% eradication 78% 50% Clinical ef f icacy 74% Cef azidime + tobramycin 0% 20% 40% 60% 80% 100% 120% Piperacillin + tazobcatam % Efficacy Conclusion: Piperacillin-Tazobactam proved to be superior to ceftazidime plus tobramycin in the treatment of serious nosocomial LRTIs J. Antimicrob Chemotherapy 1999; 43, 389-397
  16. 16. INTRA-ABDOMINAL INFECTIONS Piperacillin-tazobactam (4.5 g 8 hourly) v/s. Imipenem-cilastatin (500 mg /500 mg 8 hourly) n = 134 Piperacillin-Tazobactam Imipenem/Cilastatin 100 92 91 75.5 80 69 60 % Efficacy 40 16 20 2 2 2 0 te te tin s re ra Ra ca ilu i e e ur ad a s tF r lc ap le el en ica ca R m i lin at og C re ol ri T e ct Ba Conclusion: Data showed statistically significant difference in favour of piperacillin/tazobactam Drugs 1999; 57(5): 836
  17. 17. FEVER IN NEUTROPENIC CANCER PATIENTS Piperacillin-tazobactam (4.5 g 8 hourly) v/s. ceftazidime (2 g 8 hourly) plus amikacin (15 mg/kg IV/day) n=83 patients PIP/TAZ CEFTAZIDIME 100% 83% 90% 81% 80% 70% Success rate 60% 50% 40% 30% 20% 10% 0% Conclusion: Piperacillin-tazobactam is a safe and effective monotherapy Fever in Neutropenic Cancer Patients Support Care. Cancer 1998; 6: 402-409
  18. 18. BACTEREMIA  Data were retrospectively pooled from nine studies  The underlying infections most often associated with bacteraemia in these studies were:  Urinary tract infection (28%)  Neutropenia (27%) and  Intra-abdominal sepsis (15%)  n = 142 had microbiologically documented bacteraemia  No. of pathogens = 162  No. of pathogens eradicated = 151  Bacteriological cure = 93% J Antimicrob Chemo 1993; 31(suppl A): 97-104
  19. 19. OTHER INFECTIONS Piperacillin-tazobactam achieved a high clinical efficacy and bacteriological eradication rate in various other infections as given below: Bacterial Efficacy Clinical Efficacy Skin and Soft Tissue 92.9% 95% Infection Urinary Tract 86% 82% Infections Gynaecological 78% 71% Infections Bone & Joint 96% 91% Infections 0 20 40 60 80 100 120 % Efficacy Drugs 1999; 57(5): 827
  20. 20. SAFETY AND TOLERABILITY 30 P ip-Ta z + a m ino glyc o side P ip-Ta z IP M /C In cide nc e (% o f p atien ts ) 25 20 15 10 5 0 D ia rrh oe a N a us ea O th er G I R a sh O th er sk in e ve nts e ve nts
  21. 21. HIGHLIGHTS Piperacillin–Tazobactam is an injectable antibacterial  Piperacillin sodium is a extended spectrum penicillin belonging to ureidopenicillin class  Tazobactam sodium is a penicillanic acid sulfone and a potent -lactamase inhibitor (suicide inhibitor)  Distribution of both piperacillin-tazobactam is rapid and occurs within 30 minutes of infusion.  Good penetration in many tissues, with concentrations which exceed the MIC90s of most bacterial species
  22. 22. HIGHLIGHTS Remarkable success in the treatment of various polymicrobial infections like  Lower respiratory tract infection  Intra-abdominal infections  Complicated urinary tract  Serious skin and soft tissue infections  Febrile Neutropenia  Good safety profile  Low sodium content therefore can be safely used in patients on salt restricted diets

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