1. Beta-Lactam antibiotics & Other Cell Wall Synthesis Inhibitors

2. Beta-Lactam antibiotics
Clinically useful families of beta-lactam compounds include the
Penicillins
Cephalosporins
Monobactams
Carbapenems

3. Introduction widely used have unique advantages
The penicillins constitute one of the most important groups of antibiotics
widely used
have unique advantages
choice for a large number of infectious diseases

4. History
The penicillins were the first antibiotics discovered as natural products from the mold Penicillium
Alexander Fleming
Bread mold (Penicillin notatum) growing on petri dish
Florey, Chain, and Associates
Began work on isolating and synthesis large amounts of Penicillin
Late available for general use in US

5. Structure
Penicillins as well as cephalosporins are called beta-lactam antibiotics and are characterized by three fundamental structural requirements:
Thiazolidine ring (A)
Β-Lactam ring
Side chain (R)

7. Classification
Narrow-spectrum penicillinase-suseptible agents (penicillin G and Penicillin V) –
gram positive and gram negative cocci, non-beta-lactamase-producing anaerobes
Very narrow spectrum penicillinase-resistant
nafcillin, methicillin, cloxacilline, oxacillin
resistant to staphylococcal beta-lactamases, active to staphylococci and streptococci

8. Classification Extended-spectrum penicillins (ampicillin, amoxicillin)
Gram negative organisms, but are destroyed by beta-lactamases
Mezlocillin, azlocillin, piperacillin, carbenicillin, ticarcillin
Pseudomonas, kelebsiella and gram-negative microorganism

9. Mechanisms of Drug Actions
All penicillin derivatives produce their bacteriocidal effects by:
Binding to specific enzymes (penicillin Binding Protein [PBP])
Inhibition of the transpeptidation reaction and cell wall synthesis
Activation of autolytic enzyme in microorganism

10. Mechanisms of Drug Actions
The cell walls of bacteria are essential for their normal growth and development.
Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked latticework structure
two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains. (NAG-NAM).

11. Mechanisms of Drug Actions
Binding to PBPs results in:
Inhibition of transpeptidase: transpeptidase catalyzes the cross-linking of the pentaglycine bridge with the fourth residue (D-Ala) of the pentapeptide. The fifth reside (also D-Ala) is released during this reaction. Spheroblasts are formed
Structural irregularities: binding to PBPs may result in abnormal elongation, abnormal shape, cell wall defects

13. Transpeptididase

14. Comparison of the structure and composition of gram-positive and gram-negative cell walls

15. Pharmacokinetics Oral Administration of Penicillin G.
About one-third of an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions
Food may interfere with enteric absorption of all penicillins, Gastric juice at pH 2 rapidly destroys the antibiotic Ingestion
should be administered at least 30 minutes before a meal or 2 hours after

16. Pharmacokinetics Oral Administration of Penicillin V.
It is more stable in an acidic medium, and therefore is better absorbed from the gastrointestinal tract
On an equivalent oral-dose basis, penicillin V (K+ salt PEN-VEE K, V-CILLIN K, others) yields plasma concentrations two to five times greater than those provided by penicillin G.

17. Parenteral Administration of Penicillin G
After intramuscular injection, peak concentrations in plasma are reached within 15 to 30 minutes. This value declines rapidly, since the half-life of penicillin G is 30 minutes.
Repository preparations of penicillin G are employed.
penicillin G procaine (maintained for as long as 4 to 5 days)
penicillin G benzathine. (duration of antimicrobial activity in the plasma is about 26 day)
Intrathecal administration is inadvisable particularly with benzylpenicillin as it can cause convulsions.

18. Distribution Penicillin G is distributed widely throughout the body
Volume of distribution is about 0.35 liters/kg
60% of the penicillin G in plasma is reversibly bound to albumin
Penicillin does not readily enter the CSF when the meninges are normal

19. Excretion Penicillin G is rapidly eliminated from the body, mainly by:
the kidney
in small part in the bile and by other routes
Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion.
Probenecid markedly decreases the tubular secretion of the penicillins
Clearance values are considerably lower in neonates and infants, because of incomplete development of renal function

20. Unitage of Penicillin
1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g
1.0 milligram of pure penicillin G sodium thus equals 1667 units
1.0 mg of pure penicillin G potassium represents 1595 units
The dosage and the antibacterial potency of the semisynthetic penicillins are expressed in terms of weight.

21. Mechanisms of Bacterial Resistance to Penicillins
Resistance to penicillins and other beta lactams is due to one of general mechanisms:
Inactivation of the antibiotic by beta lactamase
Modification of target PBPs
Imparied penetration of drug to target PBPs
The presence of an efflux pump
Production of biofilms
There are more than 300 different types of beta lactamase enzymes. The process is genetically controlled commonly with plasmids.
beta-lactamase production is particularly important in Staphylococci, Neisseria gonorrhoeae, Hemophilus

23. Adverse effects
Hypersensitivity Reactions
rash, urticaria, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis and anaphylaxis
Penicillins and their breakdown products act as haptens after covalent reaction with proteins
The most abundant breakdown product is the penicilloyl (major) moiety
Very high doses of penicillin G can cause seizures in kidney failure
These are cross-reactions between various types of penicillins.

24. Management of the Patient Potentially Allergic to Penicillin
Adverse effects
Evaluation of the patient‘s history
Desensitization occasionally is recommended for patients who are allergic to penicillin and who must receive the drug
Management of the Patient Potentially Allergic to Penicillin

25. Other Adverse Reactions
mild-to-severe diarrhea. These manifestations often are related to the dose of the drug
sterile inflammatory reactions at the sites of intramuscular injections, reactions that are related to concentration.
bone marrow depression, granulocytopenia
Hepatitis ( oxacillin and nafcillin)

26. Adverse effects cont
Convulsions and encephalopathy can occur, especially at higher doses and especially if administered intrathecally (NOT advised).
Interstitial nephritis (Methicillin)
Coomb's positive hemolytic anemia
Neutropenia (especially the b-lactamase -resistant penicillins)
Decreased platelet aggregation (carbenicillin and ticarcillin)
Hypernatremia and hypokalemia (carbenicillin)

27. Drug-drug Interactions
Penicillins bind to and inactivate aminoglycosides. This is a form of chemical antagonism.
When an aminoglycoside and a penicillin are administered, the infusions should be staggered by about 1 to 2 hours.

28. Cephalosporins
Mechanism of Action: Cephalosporins are composed of a dihydrothiazine ring and a b-lactam ring. The mechanism of action is identical to penicillins
Mechanism of Resistance: Same as penicillins
Cephalosporins are less susceptible to Staphylococcus beta-lactamase; Methicillin-resistant Staphylococcus is resistant to most cephalosporins.
Classification: The cephalosporins are classified as first, second, third generation or forth generation cephalosporins. This classification is dependent on the antimicrobial activity.

29. Cephalosporins  
First Generation        Second Generation       Third Generation       Fourth Generation
Cefadroxil *
  Cefaclor *
Cefdinir
Cefepime
  Cefazolin 
  Cefamandole 
Cefoperazone 
 Cefpirome
  Cephalexin *
  Cefonicid 
Cefotaxime
 Cefclidine
  Cephalothin 
  Ceforanide
Ceftazidime
Cefozopran
  Cephaprin 
  Cefotetan
Ceftibuten
  Cephradine *
  Cefoxitin 
Ceftizoxime
Cefuroxime
Ceftriaxone
Cefixime
                    * Oral Agent

30. First generation cephalosporins
Cephalothin, cefazolin, cephalexin
Gram positive cocci (Streptococcus, pneumococcus but not or methicillin-resistant Staphylococcus)
Gram negative organisms (Escherichia coli, Klebsiella pneumoniae, and the indole negative Proteus mirabilis)
Anaerobic cocci (Peptococcus and Peptostreptococcus, but NOT Bacteroides fragilis).
They are ineffective against Pseudomonas aeruginosa, Enterobacter, and indole-positive Proteus species.
These drugs do not cross the blood-brain barrier.

31. Second generation cephalosporins
cefuroxime, cefamandole, cefoxitin, cefaclor, cefotetan
The spectrum is extended to more Gram negative bacteria Enterobacter species, Klebsiella species, and indole-positive Proteus species.
Cefamandole, cefuroxime, cefonicid, ceforanide, and cefaclor
Haemophilus influenza (meningitis)
cefoxitin, cefmetazole, and cefotetan
Bacteroid Fragilis
These drugs do not achieve adequate levels in the CSF.

32. Third generation cephalosporins
less active than first-generation agents against gram-positive cocci
more active against the Enterobacteriaceae, including b-lactamase-producing strains
cross the blood-brain barrier
The spectrum is extended to include: Enterobacter, Pseudomonas (ceftazidime and cefoperazone only), Serratia, b-lactamase producing Haemophillus influenza and Neisseria species.
Only ceftizoxime and moxalactam retain good activity against Bacteroides fragilis.

33. Fourth generation cefepime, cefpirome, cefclidine, cefozopran
more resistant to some beta­lactamases
active against P aeruginosa, Enterobacteriaceae , S aureus , and S pneumoniae ,Haemophilus and Neisseria sp
Penetrate well into CSF
Good activity against gr+ and gr- bacteria

34. Cephalosporins Active Against Methicillin-Resistant Staphylococci
Ceftobiprole, ceftaroline
methicillin-resistance in staphylococci
activity against enterococci and broad gram-negative spectrum
powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance

35. Pharmacokinetics
Some cephalosporins may be given orally but most are given parenterally (IM or IV).
They are widely distributed in the body like penicillins.
Some such as cefuroxime (2nd genereation), cefoperazone, cefotaxime,, ceftriaxone, and ceftazidime (third generation) also cross the blood-brain barrier and are drugs of choice for meningitis due to Gram-negative intestinal bacteria.

36. Pharmacokinetics
Almost all are primly eliminated via the kidneys and are actively secreted by the renal tubules. Cefoperazone and ceftriaxone are eliminated through the biliary tract.

37. Adverse effects Hypersensitivity
Nephrotoxicity (cephaloridine) and intolerance to alcohol (disulfiram like reaction)
cefamandole, cefotetan, moxalactam, cefoperazone
Diarrhea may occur with oral forms (cefoperazone)
During treatment with such drugs, these resistant organisms as well as fungi, often proliferate and may induce superinfection.
Hypoprothrombinemia, Thrombocytopenia, Platelet dysfunction.
Administration of vitamin K (10mg) twice a week can prevent this.

38. THERAPEUTIC USES
A cephalosporin with or without an aminoglycoside is first-line treatment of Klebsiella.
First generation cephalosporins are used for surgical prophylaxis of wound infection.
Third generation cephalosporins are used to treat meningitis due to pneumococci, meningococci, and Haemophillus influenza.
Ceftriaxone is the drug of choice for treating beta-lactamase producing Neisseria gonorrhea.

39. Carbapenems Doripenem, ertapenem, imipenem, meropenem
structurally similar to the penicillins. These drugs were developed to deal with beta‑lactamase producing Gram-negative organisms, which were resistant to broad spectrum and extended spectrum penicillins.
Carbapenems are derived from Streptomyces

40. Imipenem Mechanism of action Antimicrobial spectrum
binds to PBP, disrupts cell wall synethesis and is bactericidal
Antimicrobial spectrum
It is a broad-spectrum antibiotic
gram-negative rods, including P aeruginosa,  gram-positive organisms, and anaerobes
Enterococcus faecium,  methicillin-resistant strains of staphylococci, Clostridium difficile are resistant.

41. Imipenem
Metabolism:
hydrolyzed by dehydropeptidase,
it is always administered with cilastatin, an inhibitor of dipeptidase.
Side efects: Individuals who are allergic to the penicillins may demonstrate cross-reactivity with imipenem.
Imipemem may produce nausea and vomiting.
Seizures have been reported with high doses, particularly in patients with renal failure.

42. Meropenem, Doripenem It is 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.
They have slightly greater activity against gram-negative aerobes and slightly less activity against gram-positives

43. Ertapenem longer serum t1/2 that allows once-daily dosing
inferior activity against P. aeruginosa
activity against gram-positive organisms, Enterobacteriaceae and anaerobes
May use in intra-abdominal and pelvic infections.

44. Monobactam
Aztreonam: This drug is a monocyclic beta-lactam (a monobactam)
Mechanism of action: Aztreonam interacts with penicillin binding proteins and induces the formation of long filamentous bacteria.
Antimicrobial spectrum
resembles the spectrum of the aminoglycosides.
Gram positive and anaerobic bacteria are resistant.
Susceptible organisms include: Enterobacteriaceae, Pseudomonas, Hemophillus and Neisseria. Aztreonam is resistant to the beta-lactamase produced by gram negative organisms.
Side effects: Generally, the drug is well tolerated. Patients who are allergic to penicillins do not exhibit cross-reactions with aztreonam.

45. Beta-Lactamase Inhibitors
Clavulanic Acid, Sulbactam and tazobactam
Mechanism of action:
They are potent inhibitors of many bacterial beta-lactamases and can protect hydrolyzable penicillins from inactivation by these enzymes.
They are included in combination with amoxacillin (Augmentum) or with ticaricillin. In particular, clavulanic acid is an irreversible, "suicide" inhibitor of beta-lactamase.

46. Beta-Lactamase Inhibitors
They are available only in fixed combinations with specific penicillins:
Ampicillin + sulbactam
Amoxicillin + clavulanic acid
Ticarcillin + clavulanate potassium
Piperacillin + tazobactam sodium

47. Vancomycin Mechanism of Action:
inhibits cell wall synthesis by interfering with second stage of synthesis of peptidoglycan (inhibit transglycosilation by binding to the D-Ala-D-Ala terminus)
no cross resistance with penicillin
may also have effect of inhibiting synthesis of RNA

48. Vancomycin Antimicrobial Activity Pharmacokinetics
excellent activity against gram-positive aerobes (especially staphylococci, streptococci, and enterococci)
Vancomycin+gentamicin
Enterococcus faecium , enterococcus fecalis
Pharmacokinetics
poorly absorbed from GI tract
penetrates well into most areas in body except CNS
not removed by hemodialysis

49. Vancomycin Side Effects:
ototoxicity is most common serious side effect (is usually permanent)
nephrotoxicity rarely seen, higher incidence with concomitant use of aminoglycosides
"red man syndrome" (histamine release )

50. Vancomycin Clinical Applications Sepsis, endocarditis (+gentamicin)
Drug of choice for MRSA, coagulase-negative staphylococci, and Corynebacterium jeikeium;
Alternate drug in staphylococcal, streptococcal, and enterococcal infections (penicillin allergic patients)
Clostridium difficile colitis (orally) and this regimen is much more expensive than metronidazole

51. Teicoplanin Teicoplanin is a glycopeptide antibiotic
It is like vancomycin in mechanism of action, spectrum of activity, and renal elimination.
T1/2 >vancomycin
i.m administration
MECHANISMS OF ACTION
Teicoplanin inhibits cell-wall synthesis by binding to the D-Ala-D-Ala terminus of cell wall precursor ( bactericidal)

52. Dalbavancin mechanism of action same as vancomycin
It 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
Dalbavancin has an extremely long half-life of 6–11 days

53. Telavancin
Like vancomycin, telavancin inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus
disruption of membrane potential and increases membrane permeability
it is active versus gram-positive bacteria, including strains with reduced susceptibility to vancomycin

54. Fosfomycin trometamol
Mechanism of Action:
Blocks very early step in bacterial cell wall synthesis
It inactivates enzyme enolpyruvyl transferase
Blocking the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine
Reduces bacterial adherence to epithelial cells
bactericide

55. Fosfomycin Antimicrobial Activity
E. coli (less effective than TMP-SMX and fluoroquinolones)
Enterococcus faecalis
activity against other aerobic gram-negative rods not clearly known
Safe for use in pregnancy

56. Fosfomycin Pharmacokinetic: long half life
• Side Effects: diarrhea (10%), headache (10%), and vaginitis (8%)
Clinical Applications
acute uncomplicated urinary tract infection in adults caused by either E. coli or Enterococcus faecalis

57. Daptomycin Mechanism of Action Antimicrobial Activity
Daptomycin (Cubicin) is in a novel antibiotic class known as a cyclic lipopeptides (bactericide)
bind to the cell membrane via calcium-dependent insertion of its lipid tail
depolarize cell membrane with potassium efflux and rapid cell death
Antimicrobial Activity
extremely good activity against gram-positive pathogens (anaerbic,aerobic), including MRSA
active against vancomycin-resistant strains of enterococci and S aureus

58. Daptomycin
• Pharmacokinetic: long half life allows for once daily dosing; available in IV form only • Side Effects: few adverse effects; elevation in CPK in about 3%, nephrotoxicity with aminoglycoside • Clinical Applications: complicated skin and soft tissue infections (MRSA); under investigation for endocarditis; VSEF*, not indicated for pneumonia (did not perform well in pneumonia trials) *vancomycin susceptible E. faecalis

60. BACITRACIN
The bacitracins are a mixed group of polypeptide antibiotics. The major constituent is bacitracin A.
inhibits cell wall formation
Interfer dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall

61. BACITRACIN gram-positive & gram-negative cocci and bacilli Neisseria
H.influenzae, and Treponema pallidum
Dosage forms
ophthalmic and dermatologic ointments
the antibiotic also is available as a powder for the preparation of topical solutions

62. Cycloserine Cycloserine is a structural analog of D-alanine
inhibit alanine racemase
inhibits the incorporation of D-alanine into peptidoglycan pentapeptide
inhibits many gram-positive and gram-negative organisms
treat tuberculosis caused by strains of Mycobacterium tuberculosis  resistant to first-line agents

63. Cycloserine Adverse effects
headaches, tremors, acute psychosis, and convulsions