Cephalosporins & beta lactams

1. CEPHALOSPORINS,
CARBAPENEMS & MONOBACTAMS

2.  What are cephalosporins?
 How do they act and against which organisms?
 What are the methods by which bacteria became
resistant to cephalosporins?
 What are the different classes of cephalosporins?

3.  How are they used and what are the safety
precautions during their use?
 What are carbapenems and monobactams?
 What is their antimicrobial spectrum and
what infections are they used for?
 What are their advantages and
disadvantages?

4.  Among the most frequently prescribed class.
 Beta-lactam ring structure that interferes
with the synthesis of bacterial cell wall
 7-aminocephalosporanic acid

5. HISTORY
 Semi-synthetic group of antibiotics.
 First isolated from cultures of Cephalosporium acremonium
from a sewer in 1948 by Italian scientist, Giuseppe Brotzu.
 Derived from cephalosporin C, an acid-stable molecule
with antibacterial activity, produced from Cephalosporium
acremonium.
 The first agent Cephalothin was launched by Eli Lilly in
1964.

6. Cephalosporium
acremonium

7.  The site of action of beta-lactam antibiotics is
the penicillin binding protein (PBP) on the
inner surface of the bacterial cell membrane
that are involved in the synthesis of the cell
wall.
Penicillin Binding
Proteins

8. MOA
 Bactericidal
 All bacterial cells have a protective cell wall
 Cephalosporins disrupt the synthesis of the
peptidoglycan layer of bacterial cell walls
 Causes the walls to break down and eventually the
bacteria die.

9. MOA
• Each organism has several PBPs and PBPs obtained from
different species differ in their affinity towards different
β-lactam antibiotics.
• Hence, differing sensitivity to the various β-lactam
antibiotics.

10. MOA

11. Acquired resistance due to:
 Alteration in target proteins (PBPs) reducing
affinity for the antibiotic.
 Impermeability to the antibiotic
 Efflux mechanisms
 β-lactamases which destroy specific
cephalosporins (cephalosporinases).

12.  “Generations" based on their spectrum of
antimicrobial activity as well as potency.
 Also based on chronological sequence of
development.
 The first cephalosporins were designated first
generation
 Upto 5th generation till date

13.  Each newer generation of cephalosporins has
significantly greater gram-negative antimicrobial
properties.
 Fourth generation cephalosporins have true broad
spectrum activity.
Classification

14.  Cefazolin (prototype)
- least toxic
 Cefadroxil
 Cephalexin
 Cephaloridine
 Cephalothin
 Cephapirin
 Cephradine

15.  Moderate spectrum agents.
 Effective against gram +ve aerobes.
 For treating staphylococcal and streptococcal infections
 Alternatives for skin and soft-tissue infections, as well as for
streptococcal pharyngitis.
 Cephazolin is an alternative to anti-staphylococcal penicillin
for patients who are allergic to penicillin. It is also preferred
in surgical prophylaxis.

16. Cefaclor
Cefoxitin
Cefprozil
Cefamandole
Cefonicid
Cefprozil
Loracarbef
Ceforanide
Cefuroxime.

17.  Antibacterial spectrum > 1st generation cephalosporins with
extended gram -ve coverage.
 Active against β-lactamase-producing H. influenzae or Moraxella
catarrhalis, e.g, Cefuroxime against ampicillin-resistant H.
Influenzae.
 Useful for treating upper and lower respiratory tract infections and
sinusitis.
 Also active against E. coli, Klebsiella and Proteus, hence useful in UTI
 NO ACTION against Pseudomonas

18. Cefotaxime (prototype)
Cefdinir
Cefixime
Cefpodoxime
Ceftibuten
Ceftriaxone
Ceftizoxime
Ceftazidime
Cefoperazone
Moxalactam

19.  >> action against gram -ve organisms
 Some are able to cross BBB
 Resistant to beta-lactamases from gram –ve bacteria
 Parenteral 3rd generation cephalosporins (ceftriaxone,
cefotaxime) have excellent activity against most strains of
penicillin resistant Streptococcus pneumoniae
 Less active against gram +ve cocci and anerobes
 Useful in mixed aerobic-anaerobic infections in cancer patients,
those undergoing colorectal surgery, obstetric complications

20.  Cefepime
 Cefluprenam
 Cefozopran
 Cefpirome
 Cefquinome

21.  Extended spectrum agents with similar activity
against gram+ve organisms as 1st generation
cephalosporins.
 >> activity against Enterobacteriaceae
 Greater resistance to beta-lactamases than 3rd
cephalosporins.
 Many can cross blood brain barrier and are effective in
meningitis.

22. 4th generation cephalosporins
Cefepime is effective in many serious infections like
hospital-acquired pneumonia, febrile neutropenia,
bacteraemia, septicaemia etc.
Cefpirome has zwitter ion character which permits better
penetration through porin channels of gram-negative
bacteria.

23.  Ceftaroline
 Ceftabiprole
 Increased binding to PBP 2a, which mediates
methicillin-resistance in Staphylococci, resulting
in bactericidal activity against these strains.
 Some activity against enterococci and gram –
ve organisms
 Not active against extended-spectrum β-
lactamase (ESBL)producing strains.

24. Individual cephalosporins differ in their:
 Antibacterial spectrum & relative potency against specific
organisms.
 Susceptibility to β-lactamases elaborated by different organisms.
 PK: A – many injected, some oral; M & E - majority not metabolized
excreted rapidly by kidney; have short t1/2 probenecid inhibits their
tubular secretion.
 Local irritancy on IM injection; few cannot be injected IM.
CEPHALOSPORINS: GENERATION GAP

25. 1st GENERATION CEPHALOSPORINS:
CEFADROXIL (PO) - 0.5-1 g qd-bid
CEPHALEXIN (PO) - 0.25-0.5 g qid
CEFAZOLIN (IV) - 0.5-2 g q8h
2nd GENERATION CEPHALOSPORINS:
CEFOXITIN (IV) - 1-2 g q6-8h
CEFOTETAN (IV) - 1-2 g q12h
CEFUROXIME (IV) - 0.75-1.5 g q8h
3rd AND 4th GENERATION CEPHALOSPORINS:
CEFOTAXIME (IV) - 1-2 g q6-12h
CEFTAZIDIME (IV) - 1-2 g q8-12h
CEFTRIAXONE (IV) - 1-4 g q24h
CEFEPIME (IV) - 0.5-2 g q12h

26.  Organic acids, hydrophilic
 Poor oral bioavailability, unstable in acidic environment
 Readily excreted by kidneys, via tubular secretion in the proximal
convoluted tubule. This results in high concentrations of the drug in
urine
 Exceptions are Cefalexin which is stable in acid and henceforth
suitable for oral administration and Ceforperazone which is excreted
in bile rather than in urine.

27.  Cephalosporins are considered to be among the safest
antimicrobials in use
 Prolonged treatment/high doses may produce hemopoetic
effects with anaemia and bone marrow depression.
 Hypersensitivity and allergic reactions may occur including
anaphylaxis, fever, skin rashes and granulocytopenia.
 Drugs with the methylthiotetrazole ring can also cause severe
disulfuram-like reactions; consequently, alcohol and alcohol-
containing medications must be avoided.

28.  Often painful when given IM
 Thrombophlebitis, especially severe with cephalothin.
 >> doses cause nephrotoxicity, maximum with
cephaloridine.
 Bleeding tendency because of interference with the
formation of vitamin K in the gut.
 Cross allergy with penicillins.
 Neutropenia and thrombocytopenia rarely (Ceftazidime).
 Nausea, vomiting and diarrhoea
Adverse Effects & Contraindications

29. Q. Disulfiram like reaction is seen with which
cephalosporin?

30.  Treatment of bacterial infections caused by
susceptible organisms.
 Less or not active against enterococci and Listeria
monocytogenes.

31.  Respiratory tract infections (pneumonia, tonsillitis,
bronchitis) with cefuroxime, cefotaxime, ceftriaxone
 Septicaemias caused by gram -ve organisms in
combination with an aminoglycoside
 Skin infections
 Urinary tract infections
Indications

32. • Enteric fever (Ceftriaxone, reserve drug)
• Bacterial meningitis
• Gonorrhoea
• For surgical prophylaxis before, during, and after surgery
• Sometimes with other antibiotics to increase the
spectrum of activity.
Indications

33.  New class of beta lactams
 Imipenem, Meropenem, Faropenem, Doripenem
 Developed to deal with beta-lactamase producing
Gram-ve organisms
 Derived from Streptomyces species e.g,
semisynthetic imipenem which acts in the same
way as the other beta-lactams.

34.  Antimicrobial spectrum: Broad-spectrum antibiotic with
excellent activity against a variety of gram +ve and gram -
ve organism (both aerobic and anaerobic)
 Resistant to most forms of beta-lactamase, including that
produced by Staphylococcus
 Susceptible organisms - Streptococci, Enterococci,
Staphylococci, Listeria, Enterobacteriaceae, Pseudomonas,
Bacteroides, and Clostridium
 However, methicillin-resistant staphylococcus usually
resistant

35. PK
Rapidly hydrolyzed by the enzyme,
dihydropeptidase, which is found in the brush
border of the proximal renal tubule.
It is always administered with cilastatin, an
inhibitor of dipeptidase.

36.  Individuals who are allergic to the penicillins
may demonstrate cross-reactivity with
imipenem
 Nausea and vomiting
 Seizures have been reported with high doses,
particularly in patients with renal failure.

37. Meropenem
Similar to imipenem.
It is not degraded by dehydropeptidase, thus no
cilastatin is needed.
Excessive levels in kidney failure can cause seizures
with imipenem but not with meropenem.

38. Aztreonam:
Monocyclic beta-lactam (a monobactam).
Mechanism of action:
Aztreonam interacts with penicillin binding
proteins and induces the formation of long
filamentous bacteria.

39.  Unusual spectrum with activity only against Gram-
ve aerobic rods. More closely resembles the
spectrum of the aminoglycosides.
 Gram +ve and anaerobic bacteria are resistant
 Susceptible organisms include Enterobacteriaceae,
Pseudomonas, Hemophillus and Neisseria
 Resistant to the beta-lactamase produced by
gram negative organisms.

40.  Generally, the drug is well tolerated
 No cross reactivity with penicillins