Third-generation cephalosporins like cefotaxime and ceftriaxone are often used in the ICU to treat gram-negative infections resistant to first and second-generation antibiotics. Fourth-generation cefepime provides extended coverage against Pseudomonas aeruginosa and other gram-negative bacteria. Due to rising antibiotic resistance, beta-lactam/beta-lactamase inhibitor combinations like cefoperazone/sulbactam are frequently used, as sulbactam prevents hydrolysis by beta-lactamases. Cefoperazone/sulbactam in a 2:1 ratio is effective against multidrug-resistant bacteria and provides better penetration at higher

1. Role Of Third And Fourth
Generation Cephalosporin in
ICU

3. CEPHALOSPORINS

4. Mode of action

5. Classification
• Based on Anti-microbial properties and
spectrum cephalosporin's are classified as
1st, 2nd, 3rd, 4th and 5th generation.
• Cephalosporin's are more active against
Gram + ve microorganisms but as the
generations increases its affect on Gram –
ve organisms increase with decreased effect
on Gram +ves

7. Spectrum of activity: Cephalosporins
Generation Spectrum
First Generation Good cover for aerobic G+ve cocci(staph/strep), some G- ves.
Second Generation Increased activity against aerobic G-ve and facultative(E.coli,
P.mirabilis, H.infl,B
.fragilis
Third Generation In addition, activity against B burgdorferi, greater activity against
aerobic G-ve than 2nd gen, shortlived activity against
enterobacteriaceae, no activity against p.aeroginosa except
ceftazidime
Fourth and Fifth Generation Good antipseudomonal and antistaph cover, also
enterobacteriaceae

8. Organisms not covered by cephalosporin's
• Listeria monocytogenes
• Atypical (Mycoplasma , Chlamydia, Legionella )
• MRSA
• Enterococci
• Amp C producers

9. Cephalosporin indication
• They are indicated for prophylaxis and treatment caused by the
susceptible organism
• They are broad spectrum antibiotics which can be used for
oRespiratory tract infections (CAP), pharyngitis, tonsillitis.
oSkin and soft tissue infection
oBone and joint infection
oMeningitis

10. Adverse effect
• Common adverse drug reaction (ADR) >1% of patient
associated with cephalosporin therapy include diarrhea, nausea,
rash, pain & inflammation at site of injection.
• Pseudo-membranous colitis: diarrhea associated with use of
broad spectrum antibiotic.
• Vomiting and fever

11. • They are the enzymes produced by microorganisms to resist against β-
lactam antibiotics.
• They can destroy 1st, 2nd generations of cephalosporin's and penicillin
• E.coli, Klebsiella, Enterobacteriaceae
β-lactamase Enzyme

12. Extended spectrum β-lactamase (ESBL’s)
• They are the enzymes produced by microorganisms to resist higher
generation ß-lactam antibiotics.
• They can destroy 1st, 2nd,3rd generation cephalosporin's, monobactams
and penicillin.
• E.coli, Acinetobacter , Klebsiella, Pseudomonas and Enterobacter spp
produce them.
• ESBLS are found mostly in hospitals and leads to increased mortality

13. Role Of Third And Fourth
Generation
Cephalosporin in ICU

14. Third-
generation
cephalosporins
• Include cefotaxime, ceftazidime,
cefdinir, ceftriaxone, cefpodoxime,
and cefixime.
• This generation has extended gram-
negative bacteria coverage often
used to treat gram-negative
infection resistant to the first and
second generation or other beta-
lactams antimicrobials
https://www.ncbi.nlm.nih.gov/books/NBK551517

15. https://www.ncbi.nlm.nih.gov/books/NBK549881/

16. Fourth-
generation
cephalosporin
• Includes cefepime. Cefepime is a broad-spectrum
antimicrobial that can penetrate the cerebral spinal
fluid.
• Similar to ceftazidime, cefepime, very importantly, can
cover for Pseudomonas aeruginosa.
• In addition to the gram-negative bacteria that third-
generation covers (Neisseria spp., H. influenza, and
Enterobacteriaceae), cefepime can coverage against
betalactamase- producing gram-negative bacilli.
• Although effective against both gram-positive and gram-
negative bacteria, cefepime is reserved for serious systemic
infection in patients who are likely to have multi-resistance
organisms
https://www.ncbi.nlm.nih.gov/books/NBK551517

17. • Resistance to cephalosporins is rising.
Due to rising resistance, there is need for antibiotic
which will not be hydrolyzed.
Hence, BL/BLs is a drug of choice has resistance for
ESBLs.

18. β-lactam/β-lactamase inhibitor combinations
currently in clinical use include
a. Amoxicillin/clavulanic acid
b. Ampicillin/sulbactam
c. Piperacillin/tazobactam
d. Cefoperazone Sulbactam
e. Ceftriaxone Sulbactam
There is a rise in resistance rate with
piperacillin/tazobactam

19. Rationale for
Combination of beta-lactam/beta-lactamase inhibitor
 Cefoperazone Sodium 1000 mg
 Sulbactam Sodium 500 mg

20. Why Cefoperazone
Broad spectrum 3rd Generation cephalosporin
 Activity comparable to piperacillin
Pseudomonas
 Unlike cefotaxime and ceftriaxone, cefoperazone is more active against MDR
Pseudomonas
 Does not induce production of class C beta-lactamases
Good activity against Enterobacteriaceae, gram positive and anaerobes

21. Why Sulbactam
Unlike other beta-lactamase inhibitors
Binds to PBPs, causing change in permeability of the outer membrane , thus
resulting in better penetration of beta-lactam
Does not induce the production of chromosomal beta-lactamases and possess
bactericidal action.
Only inhibitor having intrinsic activity against Acinetobacter
Effective inhibitor of several important gram-negative beta-lactamases and
penicillinases.
Wider volume of distribution than cefoperazone, hence reaches the site of infection
earlier than cefoperazone, inhibiting beta-lactamase and allowing cefoperazone to be
fully effective
Achieves high concentration in intraperitoneal fluid, intestinal mucosa, blister fluid and
lungs.

22. Pharmacokinetics
Cefoperazone
C max:1 gm is 153mcg/mL
2 gm is 253 mcg/mL
T1/2 : 1.6 to 2.4 hrs
Mainly excreted by bile
Well distributed in various
tissues like lungs, bile, bone
Max dose : 8 to 12 grams/day
Sulbactam
C max: 20 mg/L
T1/2 : 1 to 1.3 hrs
Mainly excreted by kidneys
Well distributed in various
tissues like lungs, peritoneal
fluid etc.
Max dose : 4 grams/day

23. Do increase in inoculum size affect the MIC of cefoperazone
sulbactam?
No increase in MIC of cefoperazone/sulbactam against
Pseudomonas and Enterobacteriaceae
Sulbactam reduced the MIC of cefoperazone against
Pseudomonas by 4 -8 fold
Synergistic action observed against beta-lactamases
negative bacteria

24. In today’s scenario infections are more tough to handle hence
we need to optimize the therapy by giving the right amount of
the drug
Cefoperazone maximum dose is up to 8gms,hence by giving
Viatran(2:1),we are providing which is safe and highly effective
for tough infections
Why 3 gm of Viatran
(2:1)

25. As we increase the amount of cefoperazone the
serum concentration increases and it results in faster
killing
Why 3 gm of Viatran
(2:1)

26. Higher dose offers better penetration means better
killing
Higher dosage offers early out comes so cost effecting
Less chances of resistance
Why 3 gm of Viatran
(2:1)

27. Rationale for 2:1 cefoperazone/sulbactam
• Delay in appropriate drug increases the mortality
• In severe infections high dose of cefoperazone is
recommended to maximize clinical outcome
• Cmax increases with increase in cefoperazone dose

28. Indications
• Respiratory Tract Infections (Upper and Lower)
• Urinary Tract Infections (Upper and Lower)
• Peritonitis, Cholecystitis, Cholangitis, and Other Intra-Abdominal Infections
• Septicemia
• Meningitis
• Skin and Soft Tissue Infections
• Bone and Joint Infections
• Pelvic Inflammatory Disease, Endometritis, Gonorrhea, and Other Infections
of the Genital Tract

29. Clinical Evidence

30. Jpn J Antibiot. 1996 Mar;49(3):250-5

32. The THAI Journal of SURGERY 2013;34:51-55.
Official Publication of the Royal College of Surgeons of Thaila

33. Efficacy Highlights:
• Effective and safe in patients not responding to
carbapenems and 4th Gen cephalosporins
• Effective in patients not responding to cefoperazone
• Efficacy similar to Imipenem/cilastatin
• Safe and effective in intra-abdominal infections

34. Dosage and Administration
Cefoperazone/Sulbactam (2:1)
Usual adult dose: 3 g to 6 g /day
Severe infections : 12 g/day
Maximum dose of cefoperazone: 12 g/day
Maximum dose sulbactam : 4g/day

35. Dosage and Administration
• Renal Impairment
Cr CL : 15 and 30 mL/min: 1 g of sulbactam q12 hours
(maximum daily dosage of 2 g sulbactam)
Cr CL < 15 mL/min : 500 mg of sulbactam q12 hours (maximum
daily dosage of 1 g sulbactam).
In severe infections it may be necessary to administer additional
cefoperazone. The pharmacokinetic profile of sulbactam is significantly
altered by haemodialysis. The serum half-life of cefoperazone is reduced
slightly during haemodialysis. Thus, dosing should be scheduled to follow a
dialysis period.

36. Warnings and Precautions
Hepatic impairment
Dose modification may be necessary in cases of severe biliary
obstruction, severe hepatic disease or in cases of renal
dysfunction coexistent with either of those conditions.
Dose should not exceed more than 2g/day of cefoperazone
Can result in Vitamin K deficiency; hence monitor prothrombin
time in malabsorbed and patients receiving anti-coagulation
therapy, exogenous vitamin K administered is indicated.

37. Reconstitution
Reconstitute the content of vial with appropriate amount of
5% dextrose
0.9 % NaCl
Sterile Water for Injection
This is further diluted to 20 mL of the same solution
Infusion time: 15-60 minutes

38. Conclusion

39. Thank you