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.
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
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