TAZOBACTAM superiority over other antibiotics.ppt

Tazobactam superiorly

2. TAZOBACTAM
TAZOBACTAM -a penicillinic acid
sulfone β-lactamase inhibitor.
Tazobactam is highly
specific inhibitor of a wide
variety of β-lactamase
produced by common gram
negative and gram positive
aerobes and anaerobes.

3. -LACTAMASE INHIBITORS
(SULBACTAM, CLAVULANATE &
TAZOBACTAM)
“Suicide inhibitors”; prevent the action of -
lactamase on penicillin and is destroyed in the
process.
inhibit -lactamase produced by gram -ve bacteria
(increases activity of penicillin against resistant
bacteria that produce -lactamase).
offers strong affinity for plasmid -mediated -
lactamase, common cause of resistance to
cephalosporins.

4. PHARMACOKINETICS
In plasmaand different tissues after a 30-
min intravenous infusion 0.5 g of
tazobactam were investigatedin 18
patients
Some types of tissue collected are as
following -
plasma-maximum concentration of drug
in serum (values are means+/-standard
deviations) 27.9 +/-7.67 micrograms/ml
Fatty tissueand muscle tissue -were 10
to 13 %of the levelsin plasma.
Skin-concentrationsof tazobactam in
plasma were 49 to 93%of the levels in
Skin tissue.
Investigatedgastrointestinal tissues
(appendix, proximaland distal mucosa) -
exceeded levels in plasma after 1 h.

5. MACHANISM OF ACTION OF
TAZOBACTAM
By forming a protein complex with β-lactamase it
irreversibly blocks their destructive hydrolytic
activity
Tazobactam inactivates susceptible β-lactamase
by irreversible binding to the catalytic region of
the enzyme.
Inhibits biosynthesis of cell wall mucopeptide and
is effective during stage of active multiplication.

6. TAZOBACTAM IS SUPERIOR TO
SULBACTAM
Tazobactam was superiorto sulbactamin
enhancing the spectrum and potency of
piperacillin
Antimicrob Agents Chemother. 1989 November; 33(11): 1964 1969.
Tazobactamand clavulanic acid were superiorto
sulbactamin enhancing the therapeutic efficacy of
piperacillin in mice infected with beta-lactamase-
positive E. coli, K. pneumoniae, Proteus mirabilis,
and Staphylococcus aureus.
Antimicrob Agents Chemother. 1989 November; 33(11):1964 1969.

7. 
The observed stabilization of the transient intermediate of
tazobactam is thought to contribute to tazobactam's superior in
vitroand in vivoclinical efficacy.
Biochemistry,43(4), 843 -848, 2004.
Although the inhibitor-resistant TEM variants are resistant to
inhibition by clavulanic acidand sulbactam, thereby showing
clinical resistance to the beta-lactam--lactamase inhibitor
combinations of amoxicillin-clavulanate (Co-amoxiclav),
ticarcillin-clavulanate, and ampicillin/sulbactam, they remain
susceptible to inhibition by tazobactamand subsequently the
combination of piperacillin/tazobactam.
Wikipedia, the free encyclopedia, October 2006.
TAZOBACTAM IS SUPERIOR TO
SULBACTAM

8. SUPERIORITY OF TAZOBACTUM
OVER SULBACTUM AND
CLAVULANATE
Tazobactam forms twice as much stable inhibiting trans-enamineintermediate as sulbactam or
clavulanic acid Helfand, Totir et al Biochemistry (2003)

9. Disadvantages of standard empiric therapeutic regimens use of
two or more antibiotics
such as aminoglycosides(e.g. Gentamicin, Amikacin)and anti-anaerobic
agents(Metronidazole),
to achieve adequate aerobic and anaerobic coverage.
Drug-induced toxicity and high costs of treatment.
Justification of single-agent therapy with β-lactam/β-lactamase
inhibitor combinations
is a suitable and cost-effective alternative to multidrug regimens, as
well as to monotherapy with cephalosporins or carbapenems in the
treatment of
intra-abdominal, gynecologic, and diabetic foot infections, and brain
abscesses.
also suitable for use in perioperative prophylaxis
reduced incidence of surgical wound infections and lower costs.
THE ROLE OF -LACTAM/-LACTAMASE
INHIBITOR COMBINATIONS IN SURGICAL
INFECTIONS

10. Interactions of tazobactam and clavulanate with
inducibly-and constitutively-expressed Class I ß-
lactamases
(piperacillin + tazobactam &ticarcillin + clavulanate)
Tazobactam, but not clavulanate,also had some ability to inhibit the
AmpC Class I enzymes ofM. morganii, C. freundii, Ps. aeruginosa, E.
cloacae and S.marcescens.
The piperacillin + tazobactam combination, unliketicarcillin + clavulanate,
showed some degree of synergy againstmost derepressed strains of these
species.
This behaviour depended upon the greater inhibitory activity of tazobactam
for the enzymes.
Due to Antagonism characteristics tazobactam is a weaker
inducer than clavulante:
The synergy between piperacillin and tazobactamwas greatest for M. morganii
and C. freundii,
But least for Ps.aeruginosa and E. cloacae.
For the lasttwo species that these enzymes pose the greatest resistance
threat Tazobactam caused little or no antagonism of piperacillinagainst ß-
lactamase inducible species, whereas clavulanateantagonized ticarcillin
against ß-lactamase induciblestrains of E. cloacae and M. morganii(not other
species).
Theantagonism of ticarcillin was attributable to ß-lactamaseinduction.

11. EFFECT OF BETA-LACTAMASE-INHIBITOR
CONCENTRATIONS ON IN VITRO TEST RESULTS
WITH PIPERACILLIN/TAZOBACTAM AND
PIPERACILLIN/SULBACTAM
It shows that the in-vitro activity of P/T exceedthose of P/Snot
only in Piperacillin-resistant but also in Piperacillinintermediate
E. coli.
These results are credible because of the stronger inhibition of
TEM-1 lactamases by Tazobactam in comparison to Sulbactam.

12. RATIONALE FOR THE
COMBINATION OF CEFTRIAXONE
AND TAZOBACTAM COMBINATION

13. By the MIC studies, 88.6% of the strains appeared to be
resistant to ceftriaxone with the MIC90 value being > 256
microg/ml. When the MIC were done to ceftriaxone in
combination with tazobactam, the resistance rate dropped
to 4.8%with the MIC90value being 4.0 microg/ml.
Ceftriaxone and tazobactam isanexcellent therapeutic
alternative with 94.6% of ceftriaxone resistant strains being
susceptible in vitro to this combination.
J Assoc Physicians India. 2005 Jul;53:595-8
RATIONALE FOR THE
COMBINATION OF CEFTRIAXONE
AND TAZOBACTAM COMBINATION

14. RATIONALE FOR THE COMBINATION OF
CEFTRIAXONE AND TAZOBACTAM
COMBINATION

15. Whentazobactamwas added to ceftriaxone, ceftriaxone-
resistant strains regained their sensitivity.
The results show that ceftriaxonesensitive strainsof K.
pneumoniaeand E. coliwere eradicated by ceftriaxone
alone in 8-24 h.When added in one dose, tazobactam
shortenedthe time needed for bacterial clearance to 4-6 h.
Journal of Antimicrobial Chemotherapy (1999) 43, 497-501© 1999
RATIONALE FOR THE COMBINATION OF
CEFTRIAXONE AND TAZOBACTAM
COMBINATION

16. The bacterial killing curves of both ceftriaxone-sensitive
andceftriaxone-resistant E. cloacaeisolates demonstrate
no effectfrom ceftriaxonein monotherapy.
Failure of monotherapy withcephalosporins has been
reported in other animal models, especiallywhen testing E.
cloacae.
A satisfactoryexplanation of in-vivo bacterial persistence
despite singleantibiotic treatment remains elusive.
Journal of Antimicrobial Chemotherapy (1999) 43, 497-501© 1999
RATIONALE FOR THE COMBINATION OF
CEFTRIAXONE AND TAZOBACTAM
COMBINATION

17. Against beta-lactamase-producing strains of the Bacteroides
fragilis group, B. capillosus, and Prevotella species all
combinations of ceftriaxone and tazobactam showed enhanced
in vitro activity.
By comparison ceftriaxone and tazobactam showed superior
or equal activityto
Ampicillin and sulbactam.
Piperacillin,and tazobactam.
Amoxicillin and clavulanate.
Ticarcillin and clavulanate.
Metronidazole against these same strains.
Diagn Microbiol Infect Dis. 1994 Aug;19(4):227-34
RATIONALE FOR THE COMBINATION OF
CEFTRIAXONE AND TAZOBACTAM
COMBINATION

18. Treatment of nosocomial infections & surgical prophylaxis
Bacterial Septicemia
Lower Respiratory Tract Infections
Meningitis
Skin and Soft Tissue Infections like Cellulitis
Chronic Suppurative Bacterial Otitis Media
Intra-abdominal Infections like Peritonitis, Cholecystitis
Bone & Joint Infections like Osteomyelitis
Urinary Tract Infections (Complicated by underlying urological
abnormalities)
Infections in dialysis unit.
WHERE THIS COMBINATION
CAN BE MOST USEFUL

19. USE IN PREGNANCY AND LACTATION
There are no adequate and well –controlled
studies in pregnant women.This drug should be
used during pregnancy only if clearly needed.
Low concentration of Ceftriaxone and Tazobactam
are excreted in human milk. Caution should be
exercised when this combination administered to a
nursingwoman.

20. USE IN PEDIATRIC PATIENTS
Although Ceftriaxone and Tazobactam in
combination has not been evaluated their safety
has been evaluated as single agents.
Tazobactam have been documented to be safe in
neonates and children.

21. Piperacillin/tazobactam monoterapy is as effective as
cefepime monotherapy in febril neutropenia of pediatric cancer
patients.
Pediatric Hematology and Oncology, Volume 23, Issue 3 April 2006
A single intramuscular dose of ceftriaxone had a similar
effect on the prevalence of antibiotic-resistant Gram-negative
facultative bacilli in the stool of healthy children when
compared with commonly used oral agents.
Pediatr Infect Dis J. 2007 Jan;26(1):25-30
TAZ/PIPC were useful against lower respiratory tract
infection caused by H. influenzae including BLNAR in
children.
USE IN PEDIATRIC PATIENTS

22. LEGIONNAIRES'DISEASE
Legionellosisis an infection caused by the genus of Gram
negative bacteria Legionella, notably Legionella pneumophila
The broth microdilution MICs that inhibited 90%of strains
testedwere 2 and 1 microgram/mlfor ceftriaxone and
tazobactam, respectively.
No significant intracellularanti-L. pneumophilaactivity was
observed for ceftriaxone (32 micrograms/ml) ), tazobactam
alone (16 micrograms/ml)or tazobactam in combination with
ceftriaxone(ceftriaxone/tazobactam at 32/4 and 16/16
micrograms/ml
It is very unlikely that tazobactamor clavulanate, alone or in
combination with beta-lactam antimicrobialagents, will be
effectivefor the treatment of Legionnaires'diseasein humans.
Antimicrob Agents Chemother. 1994 February; 38(2): 200-204

23. USE IN GERIATRIC POPULATION
The pharmacokinetics in elderly is minimally
altered therefore dosage adjustment is not
necessary for these patients with maximum
dosages up to grams per day.

24. ADVERSE REACTIONS
Local reaction-Pain,induration and tenderness
was cverall less than 1 %.
Hypersensitivity-rash(1.7%),fever or chills.
Hematologic–Eosinophilia(6%), thrombocytosis
(5.1) and leukopenia(2.15%)
Gastrointestinal-less frequently reported (<1%)
were nausea or vomiting and dyspepsia.

25. Hepatic-less frequently reported (<1%) were
elevations of bilirubin.
Renal-less frequently reported (<1%) were
elevations of creatinine. Central nervous
system:headache or dizziness were reported
occasionally(<1%)
Genitourinary-Moniliasis or vaginitis were
repoted occasionally (<1%)
ADVERSE REACTIONS

26. DOSAGE IN COMBINATION
ADULTS-the usual adult daily DOSE of ( )is 1.125 to
2.250 gm given once a day (or in equally divided doses
twice a day) depending upon type and sensitivity of
infection.
PEDIATRICS-for the treatment of serious infections
other than meningitis,the recommended totally daily dose
of ( ) is 56.25 to 84.38 mg/kg given in divided doses
every 12 hrs.the total daily dose should not exceed
2.250gm.

27. vial dosage size Amt. Of diluents to be
added
Ceftriaxone(250mg)+Tazobactam(31.25)2ml
Ceftriaxone(500mg)+Tazobactam(62.5)5ml
Ceftriaxone(1000mg)+Tazobactam(125)5ml
ADMINISTRATION
Intramuscular Administration
Intravenous Administration
vial dosage size Amt. Of diluents to be
added
Ceftriaxone(250mg)+Tazobactam(31.255ml
Ceftriaxone(500mg)+Tazobactam(62.5)10ml
Ceftriaxone(1000mg)+Tazobactam(125)10ml