A Medico-Marketing Presentation on Piperacillin & Tazobactam

1. Piperacillin &
Tazobactam

2. COMPLICATION OF NOSOCOMIAL
INFECTIONS
Nosocomial infections are
estimated to double the
mortality and morbidity risks
of any admitted patient

3. NOSOCOMIAL TROIKA
 Staphylococcus aureus
 Escherichia coli
 Pseudomonas aeruginosa

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. 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. Porins

Altered penicillin binding proteins

-lactamases


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. 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. 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. SOLUTION
-lactamase Inhibitors
 Tazobactam – irreversible
‘suicide inhibitor’
 Clavulanic acid
 Sulbactam

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. INTRODUCING…
 The extended spectrum
antipseudomonal penicillin:
Piperacillin
 And Tazobactam – the potent
-lactamase inhibitor

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. 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. 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. 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. 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. 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. 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. 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. 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. 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