NOSOCOMIAL TROIKA

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NOSOCOMIAL TROIKA

• Staphylococcus aureus
• Escherichia coli
• Pseudomonas aeruginosa

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COMPLICATION OF NOSOCOMIAL INFECTIONS

• Nosocomial infections are estimated to double the
  mortality and morbidity risks of any admitted
  patient

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RESISTANCEThe Global Battle

• What is resistance?
• Acquired resistance

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MECHANISMS OF RESISTANCE

• Porins
• Altered penicillin binding proteins
• b-lactamases

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TYPES OF CLINICALLY IMPORTANT ?-LACTAMASES
?-lactamases
Chromosomal
Plasmid mediated
Acquired, Transferable (e.g. TEM, OXA, PSE, SHV)
Inherited
Now increasingly becoming important
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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

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EGAST STUDY
No. of isolates61

• Organism EGAST results
• Proteus vulgaris 74S.epidermidis 73Klebsiella
  spp. 68Staphylococcus aureus 64Escherischia
  coli 64Citrobacter spp. 63Pseudomonas
  aeruginosa 59Enterobacter spp. 58 -
  70Proteus mirabilis 46Acinetobacter
  species 36Enterococcus faecalis 17Haemophilus
  influenzae 17

Indian J Intern Med 1995 (suppl 5)35-44
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RICHMOND AND SYKES CLASSIFICATION OF ?-LACTAMASES
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(No Transcript)
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FAILURE OF ANTIBIOTICS DUE TOBETA-LACTAMASE
Am J Infect Control 199927520-32
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SOLUTION

• b-lactamase inhibitors
• Tazobactam irreversible suicide inhibitor
• Clavulanic acid
• Sulbactam

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INHIBITORY ACTIVITY OF b-LACTAMASE INHIBITORS
AGAINST b-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 lt 0.05 mg/L IC50 gt
  0.05 - lt 0.5 mg/L IC50 gt 0.5 - lt 5 mg/L
• where IC50 is the drug concentration required to
  reduce the initial rate of hydrolysis by 50.

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Introducing

• The extended spectrum antipseudomonal penicillin
• and Tazobactam-potent ? -lactamase inhibitor

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TAZACT MODE OF ACTION

• Piperacillin inhibits cell wall synthesis by
  binding to penicillin-binding proteins in the
  cytoplasmic membrane of bacteria.

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TAZACT 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 199957805-843
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TAZACT SERIOUS NOSOCOMIAL LRTIs
a. Serious Nosocomial LRTIs Piperacillin-tazobac
tam plus tobramycin v/s ceftazidime plus
tobramycin (n 155)
(n 145)
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
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TAZACT INTRA-ABDOMINAL INFECTIONS

• Piperacillin-tazobactam (4.5 g 8 hourly) v/s.
  Imipenem-cilastatin(500 mg /500 mg 8 hourly)
• n 134

Efficacy
Conclusion Data showed statistically
significant difference in favour of
piperacillin/tazobactam Drugs 1999 57(5) 836
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TAZACT 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)

n83 patients
PIP/TAZ
CEFTAZIDIME
100
83
90
81
80
70
60
Success rate
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
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TAZACT 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

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TAZACT OTHER INFECTIONS
Piperacillin-tazobactam achieved a high clinical
efficacy and bacteriological eradication rate in
various other infections as given below
Efficacy
Drugs 1999 57(5) 827
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SAFETY AND TOLERABILITY (Contd.)
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PIPERACILLINTAZOBACTAM HIGHLIGHTS

• Tazact (piperacillintazobactam) 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 b-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

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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