1. (Cephalosporins and β-Lactam) Laith Mohammed Abbas Al-Huseini
Antimicrobials
Cell Wall Inhibitors
(Cephalosporins and β-Lactam)
Laith Mohammed Abbas Al-Huseini
M.B.Ch.B., M.Sc, M.Res, Ph.D
Department of Pharmacology and Therapeutics

2. Cephalosporins
Cephalosporins are similar to Penicillins, but more stable to many bacterial β lactamases and therefore have a broader spectrum of activity.
The 1st source of Cephalosporins, Cephalosporium acremonium (Fungus), was isolated in 1948 by Giuseppe from the sea near a sewer outlet of the Sardinian Coast.
The nucleus of Cephalosporins, 7-aminocephalosporanic acid bears a close resemblance to 6-aminopencillanic acid.
The core of the basic cephalosporin molecule consists of a two ring system which includes a β-lactam ring condensed with dihydrothiazine ring.

3. Structure

4. Mechanism of Action
Cephalosporins exert bactericidal effect in manner similar to that of Penicillins.
Binding to specific PBPS
Inhibition of cell wall synthesis by inhibiting transpeptidation of Peptidoglycan
Activation of Autolytic enzymes: Autolysins or Murein Hydrolases

5. Classification
Cephalosporins can be classified into four major groups or generations, depending mainly on the spectrum of antimicrobial activity.
Recently, Fifth generation cephalosporins were developed in the lab to specifically target against resistant strains of bacteria particularly Methicillin Resistance Staphlococcus Aureus (MRSA).

6. 1st Generation Cephalosporins
Have good activity against gram-positive cocci, such as pneumococci, streptococci and staphylococci but not active against methicillin-resistant strains of staphylococci, and relatively modest activity against gram-negative microorganisms (E.Coli and Klebsiella pnumoniae).
Oral drugs may be used for the treatment of urinary tract infections and staphylococcal or streptococcal infections, including cellulitis or soft tissue abscess.
They do not penetrate the central nervous system and cannot be used to treat meningitis.
Excretion is mainly by glomerular filtration and tubular secretion into the urine.
Drugs that block tubular secretion, eg, probenecid, may increase serum levels substantially.
In patients with impaired renal function, dosage must be reduced.
Include: Cephalexin (PO), Cefazolin (IV/IM), Cefadroxil (PO), Cephalothin (IV/IM), Cefapirin (IV/IM), Cefradine (PO), Cefacetrile, Cefaloglycin, Cefalonium, Cefaloridine, Cefatrizine, Cefazedone.

7. 2nd Generation Cephalosporins
These compounds show modest activity against gram-positive bacteria (less active than 1st generation drugs) and display greater activity against gram-negative microorganisms including Haemophilus influenza, some Enterobacter aerogenes and Neisseria Species.
They have been primarily used to treat sinusitis, otitis, and lower respiratory tract infections
There are marked differences in half-life, protein binding, and interval between doses.
All are renally cleared and require dosage adjustment in renal failure.
Intramuscular administration is painful and should be avoided.
Include: Cefaclor (PO), Cefamandole (IV/IM), Cefonicid (IM/IV), Cefuroxime (IV/IM/PO), Cefprozil (PO), Loracarbef (PO), Ceforanide (IM/IV), Cefoxitin, Cefotiam, Cefotetan, Cefmetazole.

8. 3rd Generation Cephalosporins
They are greatly inferior to 1st generation cephalosporins in regard to their activity against gram-positive cocci.
The 3rd generation cephalosporins exhibit much more activity against gram-negative bacilli, most other enteric organisms and β- lactamase producing strains of Haemophilus and Neisseria.
Drugs of this group have superiority over the other two generation in having ability to reach CNS (cross BBB).
The excretion of cefoperazone and ceftriaxone is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency.
The others are excreted by the kidney and therefore require dosage adjustment in renal insufficiency.
They include: Cefoperazone (IV/IM), Cefotaxime (IV/IM), Ceftriaxone (IV/IM), Cefixime (PO), Ceftazidime (IV/IM), Moxalactam (IM/IV), Ceftizoxime, Cefpodoxime proxetil, Cefdinir, Cefditoren pivoxil, Ceftibuten.

9. 4th Generation Cephalosporins
They have an extended spectrum of activity as compared to the 3rd generation and have increased stability from hydrolysis by plasmid and chromosomally mediated β- lactamases.
Aerobic gram-negative bacilli resistant to 3rd generation cephalosporins can be successfully treated with 4th generation drugs.
More resistant to hydrolysis by chromosomal β lactamases.
Good activity against P aeruginosa, Enterobacteriaceae, S aureus,
S pneumoniae, Haemophilus and Neisseria sp.
Drugs included in this class are: Cefepime (IV), Cefpirome (IV), Cefozopran (IV), Cefoselis, Cefquinome, Cefclidine, Cefluprenam.

10. 5th Generation Cephalosporins
These 5th generation cephalosporins are active against Methicillin-resistant staphylococci.
Agents under this class include: Ceftaroline Fosamil (IV), Ceftobiprole (IV), Ceftolozane
Ceftaroline is a novel cephalosporin with activity against MRSA for complicated skin and skin structure infections
Ceftobiprole exerts its antibacterial activity by binding to important penicillin-binding proteins and inhibiting their transpeptidase activity which is essential for the synthesis of bacterial cell walls. 
The recommended dose is 500 mg as 2-hour infusion every 8 hours. It is mainly excreted renally.
SE: Serious hypersensitivity reactions and Clostridium difficile-associated diarrhea

11. Resistance to Cephalosporins
Resistance to cephalosporins can be due to following mechanisms:
Poor penetration of drug into bacteria
Lack of specific PBPS for a particular agent
Degradation of the drug by β-lactamases
Failure of activation of Autolytic enzymes in the bacterial cell wall.

12. Therapeutic Uses
Cephalosporins are widely used antibiotics. Unfortunately, overuse of these agents in situations where drugs with less broad spectrum activity would be more appropriate has led to the emergence of wide array of cephalosporin resistant bacteria.
Cephalosporins are effective as both Prophylactically & Therapeutically.
Alternative to Penicillins
Respiratory tract infections caused by Klebsiella, Enterobacter, Proteus, Providencia, and Haemophilus species.
Gonorrhoea
Typhoid fever
Meningitis

13. Adverse Effects
Allergic Reactions (Patients who have had an anaphylactic response, Stevens-Johnson syndrome, or toxic epidermal necrolysis to penicillins should not receive cephalosporins)
Nephrotoxicity (interstitial nephritis and tubular necrosis)
Diarrhoea
Disulfiram like Reaction
Hypoprothrombinemia and Bleeding Disorder
Superinfections

14. Other β-Lactam Antibiotics
β-Lactamase Inhibitors
Clavulanic Acid
Salbactum
Tazobactum
Monobactams
Aztreonam
Carbapenems
Imipenem
Ertapenem
Meropenem
Doripenem

15. β-Lactamase Inhibitors
They contain a β-lactam ring but, by themselves, do not have significant antibacterial activity or cause any significant adverse effects.
Although β-lactamase inhibitors have little antibiotic activity of their own, they instead inhibit the activity of β-lactamases (a family of enzymes that break the beta-lactam ring) that allows penicillin-like antibiotics to work, thereby conferring bacterial resistance.
Instead, they bind to and inactivate β-lactamases, thereby protecting the antibiotics that are normally substrates for these enzymes.
β-lactamase inhibitors are used in conjunction with a β-Lactam antibiotic to extend its spectrum of activity.

16. An example is Co-Amoxiclav [Augmentin], which is a combination of amoxicillin and clavulanic acid. Sulbactam usually combined with Ampicillin (Unasyn) and Tazobactam with Piperacillin (Zosyn).
The indications for penicillin-β-lactamase inhibitor combinations are empirical therapy for infections caused by a wide range of potential pathogens in both immunocompromised and immunocompetent patients and treatment of mixed aerobic and anaerobic infections, such as intra-abdominal infections.

17. Monobactams Drugs with a monocyclic β- lactam ring.
They are resistant to β-lactamases and active against aerobic gram-negative rods.
They have no activity against gram-positive bacteria or anaerobes.
Aztreonam is the only commercially available monobactam.
It is administered either IV or IM and can accumulate in patients with renal failure.
Relatively nontoxic, but it may cause phlebitis, skin rash and, occasionally, abnormal liver function tests.
Penicillin-allergic patients tolerate aztreonam without reaction.

18. Carbapenems
Synthetic β-lactam antibiotics differ in structure from the penicillins in that the sulfur atom of the thiazolidine ring has been externalized and replaced by a carbon atom.
Penetrate body tissues and fluids well, including CSF.
All are cleared renally, and the dose must be reduced in patients with renal insufficiency
Broad spectrum of antimicrobial activity with bactericidal activity against most Gram-positive and Gram-negative aerobic and anaerobic pathogenic bacteria.
They resist hydrolysis by most β- lactamases.
Pseudomonas are naturally resistant

19. Imipenem has good activity against gram- negative, gram-positive and anaerobic organisms.
Imipenem is inactivated by dehydropeptidases in renal tubules.
It is administered with an inhibitor of renal dehydropeptidase, cilastatin, for clinical use.
Meropenem and ertapenem are not degraded by renal dehydropeptidase.
IM ertapenem is irritating, so it is formulated with 1% lidocaine.
Doripenem is similar to imipenem but has slightly greater activity against gram-negative aerobes and slightly less activity against gram-positives.

20. Cell Wall Destructors
Glycopeptides (Vancomycin, Teicoplanin, Telavancin, Dalbavancin)
Daptomycin
Fosfomycin
Polymyxin
Bacitracin
Cycloserine

21. Vancomycin
Active against gram-positive bacteria, particularly staphylococci.
Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan pentapeptide, which as a result inhibits transglycosylase, preventing peptidoglycan elongation and cross-linking.
The cell membrane is also damaged.
β-lactamase producing staphylococci and those resistant to nafcillin and methicillin are killed by vancomycin.
Poorly absorbed from the GI tract.
It is used orally only for antibiotic-associated enterocolitis caused by C. difficile.

22. Metronidazole is preferred as initial therapy and vancomycin is reserved for refractory cases.
Parenteral vancomycin is used in sepsis caused by methicillin-resistant staphylococci.
Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection.
90% of the drug is excreted by glomerular filtration.
A common reaction is "red man" or "red neck" syndrome.
This infusion-related flushing is caused by release of histamine.
It can be largely prevented by prolonging the infusion period to 1-2 hours or increasing the dosing interval.

23. Teicoplanin
A glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum.
Unlike vancomycin, it can be given intramuscularly as well as intravenously.
Has a long half-life (45–70 hours), permitting once-daily dosing.
It is less likely than vancomycin to cause ototoxicity or nephrotoxicity.
This drug is available in Europe but has not been approved for use in the United States.

24. Telavancin A semisynthetic lipoglycopeptide derived from vancomycin.
Active versus gram-positive bacteria.
Has two mechanisms of action. Like vancomycin, telavancin inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan in the growing cell wall.
In addition, it disrupts the bacterial cell membrane potential and increases membrane permeability.
The half-life is approximately 8 hours, which supports once-daily intravenous dosing.
Used for treatment of complicated skin and soft tissue infections and hospital-acquired pneumonia.
Unlike vancomycin therapy, monitoring of serum levels is not required.
Is potentially teratogenic.

25. Dalbavancin A semisynthetic lipoglycopeptide derived from teicoplanin.
Shares the same mechanism of action as vancomycin and teicoplanin
Has improved activity against many gram-positive bacteria including methicillin resistant and vancomycin-intermediate S aureus.
It is not active against most strains of vancomycin-resistant enterococci.
Has an extremely long half-life of 6–11 days, which allows for once-weekly intravenous administration.
Has been studied for the treatment of skin and soft tissue infections and catheter-associated bloodstream infections.

26. Daptomycin
A novel cyclic lipopeptide fermentation product of Streptomyces roseosporus
It is similar to vancomycin but is active against vancomycin-resistant enterococci and S. aureus.
It appears to bind to and depolarize the cell membrane, causing potassium efflux and rapid cell death.
Used for treatment of skin, soft tissue infections, bacteremia and endocarditis once daily.
Excreted by kidney.
It can cause myopathy, so creatine kinase levels should be monitored regularly while individual undergo daptomycin therapy.

27. Fosfomycin
It inactivates the cytoplasmic enzyme, enolpyruvate transferase which is a very early stage of bacterial cell wall synthesis)
Active against both gram-positive and gram-negative organisms.
Available in both oral and parenteral formulations.
Used for treatment of uncomplicated urinary tract infections.
The half-life is approximately 4 hours.
The active drug is excreted by the kidney.
Appears to be safe for use in pregnancy.

28. Polymyxins
Polymyxins antibiotic primarily used for resistant Gram-negative infections.
Alters bacterial outer membrane permeability by binding to a lipopolysaccharide layer resulting in disruption of membrane integrity.
Polymyxin B is applied topically to treat infections such as those of the eye, ear, and skin. Polymyxin E, also known as colistin, is used frequently for diarrhea in children. 
Because polymyxins also react with the membranes of human cells, they can cause kidney damage and neurotoxicity. The availability of better antibiotics limits the use of polymixins.

29. Bacitracin
A cyclic peptide mixture first obtained from the Tracy strain of Bacillus subtilis in 1943.
It is active against gram-positive microorganisms.
Inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall.
Highly nephrotoxic when administered systemically and is only used topically.
Bacitracin is poorly absorbed. Topical application results in local antibacterial activity without systemic toxicity.
Bacitracin, an ointment base (often combined with polymyxin or neomycin) indicated for the suppression of mixed bacterial flora in surface lesions of the skin, in wounds, or on mucous membranes.
Solutions of bacitracin in normal saline can be used for irrigation of joints, wounds, or the pleural cavity.

30. Cycloserine Antibiotic produced by Streptomyces orchidaceous
A structural analog of D-alanine and inhibits the incorporation of D-alanine into peptidoglycan pentapeptide
Inhibits many gram-positive and gram-negative organisms
Used mainly to treat tuberculosis resistant to first-line agents.
Causes serious CNS toxicity with headaches, tremors, acute psychosis, and convulsions.