Here is the presentation of Beta lactam antibiotics- Cephalosporins antibiotics

1. Dr Akhil Nagar
RCP IPER
Shirpur
Cephalosporins

2. Cephalosporin
5-thia-1-azabicyclo-oct-2-ene
7-aminocephalosporanic acid (7-ACA)
Cepham
Cephem

4. In the preparation of semisynthetic cephalosporins, the
following improvements are sought:
(a) increased acid stability
(b) improved pharmacokinetic properties, particularly
better oral absorption
(c) broadened antimicrobial spectrum
(d) increased activity against resistant microorganisms
(as a result of resistance to enzymatic destruction, improved
penetration, increased receptor affinity, etc.),
(e) decreased allergenicity, and
(f) increased tolerance after parenteral administration.

5. Mechanism
Cephalosporins, among -Beta lactam antibiotics, exhibit uniquely
potent activity against most species of Klebsiella.
The derivatives shows important characteristics like:
(a) resistance to inactivation by -lactamases,
(b) permeability of bacterial cells, and
(c) intrinsic activity against bacterial enzymes involved in cell
wall synthesis and cross-linking.
Oral activity can also be conferred in certain cephalosporins by
esterification of the 3-carboxylic acid group to form acid-stable,
lipophilic esters that undergo hydrolysis in the plasma.
Parentral: Hydrolysis of the ester function, catalyzed by hepatic
and renal esterases, is responsible for some in vivo inactivation of
parenteral cephalosporins containing a 3-acetoxymethyl
substituent (e.g., cephalothin, cephapirin, and cefotaxime).

6. These has been conventionally classified into four generations
based on GenerationSystem
• This is based on chronological sequence of development, but more
importantly, takes into consideration the overall antibacterial spectrum
as wellaspotency.
• First-generation cephalosporins are predominantly active against
Gram-positive bacteria, and successive generations have increased
activityagainst Gram-negativebacteria.

7. They are mostly active against Staphylococci, streptococci, and
Pneumoniae.Eg:Cephalexin,cephaloridine,cephalothin.
Second generation : They are mostly active against gram negative
bacteria than 1 gen. They have greater efficacy against H.
influenza Eg: Cephaclor, cefamamdole.
Third generation : They are mostly active against microbes and have
broadspectrumofactivity.
Eg:Cefoperazone.

8. ORAL Cephalo
1. Cephalexin 2. Cephradine 3. Cefadroxil 4. Cefachlor
5. Cefprozil 6. Loracarbef 7. Cefuroxime
axetil
8. Cefpodoxime
9. Cefixime
Parentral Cephalo
1. Cephalothin 2. Cephapirin 3. Cefazolin 4. Cefamandole
5. Cefonicid 6. ceforanide 7. Cefuroxime 8. Cefotaxime
9. Ceftizoxime 10. Ceftriaxone 11. Ceftazidime 12. Cefoperazone
Parentral Cephamycins
1. Cefoxitin 2. Cefotetan 3. Cefmetazole

9. Oral Cephalosporins Parenteral Cephalosporins
Parenteral Cephamycins
GenerationwiseCephalosporins

11. First Generation Cephalosporins
Cefalothin Cefalexin
Cefadroxil Cefazolin

12. SecondGeneration Cephalosporins
Cefuroxime (Oral) Cefotetan

13. Third Generation Cephalosporins
Cefotaxime Ceftriaxone
Ceftazidime

14. Fourth Generation Cephalosporins
Cefepime

17. Lactamase Resistance
• The “penicillinase” resistance of cephalosporins appears to be a
property of the bicyclic cephem ring system rather than of the
acyl group.
• In cephaloisporins, there occurred variation in rates of
hydrolysis by the enzyme.
• When tested in vitro, cephalothin and cefoxitin are the most
resistant, and cephaloridine and cefazolin are the least
resistant.
• The introduction of polar substituents in the aminoacyl
moiety of cephalosporins appears to confer stability to some beta-
lactamases.
• Thus, cefamandole and cefonicid, contain an ά-
hydroxyphenylacetyl and ceforanide, has an o-aminophenyl
acetyl group are resistant to a few β-lactamases

18. Structural features confer broadly based resistance
to β-lactamases among the cephalosporins –
(a) an alkoximino function in the aminoacyl group
(b) a methoxyl substituent at the 7-position of the cephem
nucleus having stereochemistry.
(c) oximino substituent, eg ceftazidime, with 2-
methylpropionic acid substituent.
(d) 7-methoxylcephalosporins or cephamycins eg: cefoxitin,
cefotetan, cefmetazole

19. Monobactam

20. • The development of useful monobactam antibiotics began
with the independent isolation of sulfazecin and other
monocyclic -lactam antibiotics.
• Sulfazecin as found to be weakly active as an
antibacterial agent but highly resistant to lactamases.
• 3-methoxy group, which was in part responsible for -
lactamase stability in the series, contributed to the low
antibacterial potency and poor chemical stability of these
antibiotics.
• A 4-methyl group, however, increases stability to
lactamases and activity against Gram-negative bacteria at
the same time.

21. Aztreonam
EFFECTIVEAGAINST:
• Grampositive +Gram
negative+Anaerobic bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
• Resistant to beta-lactamase
enzymes
• Not active againstMRSA
SIDE-EFFECT:
• Diarrhoea
• Nausea
• Vomiting

22. Tigemonam

23. Tigemonam is a newer monobactam that is orally active. It
is highly resistant to -lactamases. The antibacterial spectrum
of activity resembles that of aztreonam.
It is very active against E. coli, Klebsiella, Proteus,
Citrobacter, Serratia, and Enterobacter.
It also exhibits good potency against H. influenzae and N.
gonorrhoeae.

24. BETA-LACTAMASEINHIBITORS
• Resemble β-lactam antibiotic structure
• Bind to β-lactamase and protect the antibiotic from destruction
• Most successful when they bind the β-lactamase irreversibly
• Three important in medicine:
» ClavulanicAcid
» Sulbactam
» Tazobactam

25. Beta–lactam Resistance

26. Resistance-TheGlobal Battle.!!!
What isResistance?
•Drug resistance refers to unresponsiveness of amicroorganism
to an antimicrobialagent.
•Drug resistance are of twotypes:
---Natural Resistance
---Acquired Resistance

27. Natural Resistance:
•Somemicrobes have always been resistant to certain anti-microbial agent.
•Theylack the metabolic process or the target side thai is affectedby
particular drug.
E.g:Gramnegative bacilli are normally unaffected by PenicillinG.
M. tuberculosis is insensitive toTetracyclines.
•This type of resistance does not pose significant clinicalproblem.
Acquired Resistance:
•It is the development of resistance by an organism whichwassensiive before
due to the use of antimicrobial agent over aperiod of time.
•This can happen with any microbe and is amajor clinical problem.
However, the development of resistance is dependent on themicroorganism
aswell asthe drug.

28. Porins
Altered penicillin bindingproteins
-lactamases
MECHANISMS OF RESISTANCE

29. MECHANISMS FOR ACQUIRING RESISTANCE
69

30. CHALLENGES OF -LACTAMASES
1940
1940
1944
: Introduction of penicillins
: First description of -lactamasespublished
: Strains of staphylococcus aureusproducing
-lactamase
: Clinical useof expanded spectrum penicillins
- such asampicillin and carbenicillin
: plasmid mediated -lactamases assumed prominence in
enterobacteriaceae and gram-negative bacteria
: Development of broad-spectrum cephalosporins, cephamycins,
monobactams and carbapenems
: Increased resistance among gram-negative bacteria with inducible
chromosomally-mediated  lactamases
JAC(1993); suppl A: 1-8
1960s
1970s
1980-90
1990

31. Beta–lactamases

32. Beta-Lactamase Enzyme
Functional
Classification
Group 1
(Cephalosporinases*)
Group 2
(Penicillinases,
Cephalosporinases)
Group 3
(Metalloenzymes*)
Group4
(Penicillinases*)
* Not inhibited by ClavulanicAcid

33. Beta-Lactamase Enzyme
Molecular
Classification
SerineBased
ClassA ClassC ClassD
Metallo
B-lactamases
ClassB

34. Beta-Lactamase Enzyme
Molecular
Classification
SerineBased
ClassA ClassC ClassD
Metallo
B-lactamases
ClassB

35. ESBLs are enzymes that mediate resistance to extended-
spectrum (third generation) cephalosporins (e.g.,
ceftazidime, cefotaxime, and ceftriaxone) and
monobactams (e.g., aztreonam) but do not affect
cephamycins (e.g., cefoxitin and Cefotetan) or
carbapenems (e.g., meropenem or imipenem).
Extended spectra Beta-Lactamase
(ESBL)

36. WHYSHOULDWEDETECTTHESEENZYMES?
• Thepresence of an ESBL-producingorganism in aclinical infectioncan
result in treatment failure if one of the above classes of drugs is used.
• ESBLs can be difficult to detect because they have different levels of
activity against various cephalosporins. Thus, the choice of which
antimicrobial agents to test is critical. For example, one enzyme may
actively hydrolyze ceftazidime, resulting in ceftazidime minimum
inhibitory concentrations (MICs) of 256 µg/ml, but have poor activity on
cefotaxime, producing MICsof only 4µg/ml.
• If an ESBL is detected, all penicillin's, cephalosporins, and aztreonam
should be reported as resistant, even if in vitro test results indicate
susceptibility

37. RISK FACTORS FOR ESBL INFECTION
• Length of hospital stay
• Severity of illness
• Time in the ICU
• Intubation and mechanical ventilation
• Urinary or arterialcatheterization
• Previous exposure to antibiotics

38. Metallo Beta-lactamase
• Resistant against broad spectrum of beta-lactam antibiotics
• These include the antibiotics of the carbapenem family.
• This class of β-lactamases is characterized by the ability to
hydrolyze carbapenems and by its resistance to the
commercially available β-lactamase inhibitors but susceptibility
to inhibition by metal ion chelators.
• The most common bacteria that make this enzyme are Gram
negative such as Escherichia coli and Klebsiella pneumoniae ,
Pseudomonas aeroginosa.

39. BETA-LACTAMASEINHIBITORS
• Resemble β-lactam antibiotic structure
• Bind to β-lactamase and protect the antibiotic from destruction
• Most successful when they bind the β-lactamase irreversibly
• Three important in medicine:
» ClavulanicAcid
» Sulbactam
» Tazobactam