Department of Pharmacology - Simplified way

1. BETA- LACTAM:
HISTORY, CURRENT
TREND & RECENT
ADVANCES
DR ANKITA NEGI
2ND YEAR POST
GRADUATION
DEPARTMENT OF
PHARMACOLOGY
MAULANA AZAD MEDICAL
COLLEGE
NEW DELHI
DATE – 1 MARCH 2022

2. OUTLINE
• Introduction
• History
• Current Trend
• Recent Advances

3. INTRODUCTION
The β-lactam antibiotics-
1. Penicillin
2. Cephalosporins
3. Carbapenems and
4. Monobactams
• Common structure (β-lactam ring) and mechanism of action.
• Bacterial resistance against the β-lactam antibiotics continues to increase.

4. BETA- LACTAM STRUCTURE
• Thiazolidine ring (A) is attached to
β-lactam ring (B)
• The penicillin are susceptible to
inactivation by amidases and lactamases.

5. Penicillin-binding proteins (PBPs) are membrane proteins
that cross-link peptidoglycan

6. MECHANISM OF ACTION
• Interfere with the synthesis of the bacterial cell wall peptidoglycan.
• Inhibit bacterial growth by interfering with transpeptidation reaction of
bacterial cell wall synthesis.
• Bactericidal event is inactivation of an inhibitor of autolytic enzymes in
the cell wall, leading to lysis of the bacterium

8. HISTORY

10. • World first antibiotic a british scientist Alexander Fleming in 1928 by accident studying
Staphylococcus variants at St. Mary’s Hospital in London.
• Discovered the compound in the fungus (Penicillium Notatum)
• The isolated compound he called Penicillin.
• Ernst Boris Chain and Lord Howard Florey resumed Fleming’s research and achieved
isolation of penicillin and its industrial scale production in 1940.
• Fleming, Flocey and Chain , Nobel prize in 1945 .
• 1943 Robert Robinson the chemical structure of penicillin

11. • Cephalosporium acremonium, the first source of the cephalosporins, was
isolated in 1948 by Brotzu from sea near a sewer outlet off the Sardinian coast
• Crude filtrates from cultures of this fungus were found to inhibit the in vitro
growth of S. aureus and cure staphylococcal infections and typhoid fever in
humans.

13. CURRENT TREND
1. Penicillin- Classification, Pharmacokinetics, uses, Adverse Drug reactions
2. Cephalosporins
3. Carbapenems
4. Monobactams
5. β-lactamase inhibitors
6. Resistance

14. PENICILLIN

15. CLASSIFICATION
• Narrow Spectrum
1) The Penicillin
• Penicillin V
• Penicillin G
• Benzathine Penicillin G
• Procaine Penicillin G
2) Antistaphylococcal penicillin
• Flucloxacillin, Cloxacillin, Nafcillin
Methicillin
• Extended Spectrum
1) Aminopenicillins- Ampicillin, Amoxicillin,
Talampicillin
2) Antipseudomonal Penicillin- Piperacillin,
Carbencillin, Ticarcillin

16. PHARMACOKINETICS
ABSOPTION-
Oral Administration- varies, depend stability in acid is impaired by food (exception is amoxicillin), give 1–2
hours before or after a meal.
• Penicillin V is two to five times better absorbed then penicillin G.
Parenteral Administration-
• IV - Penicillin G, Nafcillin, oxacillin
• IM---slow-release preparations such as benzathine benzylpenicillin ----syphilis.
• Benzathine and procaine penicillin are formulated to delay absorption, resulting in prolonged blood and
tissue concentrations.

17. DISTRIBUTION
• Widely distributed.
• Lipid-insoluble, do not enter mammalian cells and cross the blood–brain barrier.
• Concentrations of penicillins in CSF are variable but less than 1%
• Inflammation, increase to 5%

18. EXCRETION
• renal, 90% tubular secretion rest by glomerular filtration.
• Half-life is 30 minutes, renal failure go upto 10 hours.
• Clearance values are lower in neonates and infants, penicillin persists in the blood
several times longer.
• Nafcillin is cleared by biliary excretion.
• Oxacillin, dicloxacillin, and cloxacillin are eliminated by both.

19. 1.)PENICILLINS
Penicillin G and Penicillin V
• First naturally occurring Penicillins.
MICROORGANISMS-
1. Gram-positive cocci, drug of choice streptococci, meningococci, Treponema
pallidum.
2. Most anaerobic microorganisms- Clostridium
3. Ineffective against most strains of S. aureus.

20. THERAPEUTIC USES-
1. Pneumococcal Infections( Pneumonia, Meningitis)
2. β-Hemolytic Streptococcal Infections-Streptococcal pharyngitis (including scarlet
fever)
3. β-Hemolytic Streptococcal Toxic Shock and Necrotizing Fasciitis.
4. β-Hemolytic Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis.
5. Infections Caused by Other Streptococci and Enterococci- infectious endocarditis
6. Gonococcal Infections
7. Infections with Anaerobes- Pulmonary and periodontal infections etc

21. 2.) ANTI- STAPHYLOCOCCAL PENICILLINS
• Drugs- Flucloxacillin, Cloxacillin, Nafcillin, Methicillin, dicloxacillin
• Semisynthetic
MICROORGANISMS-
• Methicillin-susceptible and penicillin-resistant strains of staphylococci.
• Methicillin no longer used clinically ,high rates of adverse effects.

22. 1) AMINOPENICILLINS
• Drugs- Ampicillin, Amoxicillin
• Greater activity than penicillin against Gram negative bacteria(ability to
penetrate)
• Inactivated by many β-lactamases hence coformulation with β-lactamase
inhibitors.

23. Amoxicillin Ampicillin
• Better absorbed orally.
• 250–500 mg three times daily, is equivalent to
the same amount of ampicillin given four times
daily
• Intake of food prior to ingestion of ampicillin
diminishes absorption
• Stable in acid , absorbed more rapidly and
completely from the GI tract than ampicillin.
• stable in acid
• less active and less effective than ampicillin for
shigellosis
Adjustment of the dose of ampicillin is required in
the presence of renal dysfunction.
• Peak plasma concentrations of amoxicillin are
2–2.5 times greater
Ampicillin appears in the bile, undergoes
enterohepatic circulation, and is excreted in the
feces
• Food does not interfere with absorption
USE- Bacterial sinusitis, otitis, and lower
respiratory tract infections,UTI
Shigellosis, Meningitis

24. 2) ANTIPSEUDOMONAL PENICILLIN
• Carboxypenicillins and Ureidopenicillins
• Drugs- Piperacillin, Carbencillin, Ticarcillin
MICROORGANISMS-
• Broaden the spectrum of penicillins against Gram negative pathogens

25. CARBENCILLIN TICARCILLIN PIPERACILLIN
• Oral • semisynthetic penicillin • Piperacillin extends the spectrum
of ampicillin
• Use- UTI caused by Proteus,
P
.aeruginosa
• more active than carbenicillin
versus P
. aeruginosa, but less active
than piperacillin
• P
. aeruginosa,
Enterobacteriaceae many
Bacteroides
• USE- intra-abdominal and urinary
tract infections.
• Combined with a β-lactamase
inhibitor (piperacillin-
tazobactam)
• USA- the manufacture of ticarcillin
alone and in combination
discontinued.
• broadest antibacterial spectrum
of the penicillin
• mixed intra-abdominal infections

26. • Well tolerated
• Serious adverse effects hypersensitivity.
• Penicillin skin testing may also be used to evaluate Type I hypersensitivity.
• Anaphylactic shock (very rare—0.05%)
• Serum sickness–type reactions -fever, joint swelling, angioedema, pruritus
• Oral lesions, interstitial nephritis, eosinophilia, hemolytic anemia and other hematologic disturbances, and vasculitis

27. • In patients with renal failure, penicillin in high doses cause seizures.
• Nafcillin is associated with neutropenia
• Oxacillin can cause hepatitis
• Ampicillin has been associated with pseudomembranous colitis.
• Ampicillin and amoxicillin - skin rashes
• Piperacillin-tazobactam, combined with vancomycin, has been associated with acute
kidney injury

29. CLASSIFICATION

32. ANTIPSEUDOMONAL CEPHALOSPORINS OR 4TH
GENERATION

33. CEPHALOSPORINS ACTIVE AGAINST METHICILLIN
RESISTANT STAPHYLOCOCCI OR 5TH GENERATION
• Beta-lactam antibiotics with activity against methicillin-resistant
staphylococci.
• Ceftaroline fosamil, the prodrug of active metabolite ceftaroline,
first such drug to be approved for clinical use in the USA.
• Ceftolozane

34. ADVERSE REACTIONS
ALLERGY
• Hypersensitivity reactions
(anaphylaxis, fever, skin rashes,
nephritis)
• H/O anaphylaxis to penicillins not
receive first- or second-generation
• Third and fourth-generation should
be administered.
TOXICITY
• Thrombophlebitis after IV
injection
• Bleeding disorders.
• Rare- renal toxicity,
encephalopathy and
nonconvulsive status
epilepticus.

35. CARBAPENEMS

37. MONOBACTAMS

39. β-lactamase inhibitors

40. MECHANISM OF ACTION
These agents resemble B- lactam antibiotics only structurally ( no antimicrobial action)
Bind irreversibly to B- lactamases ( produce bacteria) (drug resistance)
Prevent hydrolysis of penicillin
• New drugs – Relebactam – Phase 3 trial
• Zidebactam- Preclinical phase

41. Clavulanic acid Sulbactam Tazobactam Avibactam Vaborbactam
• “Suicide” inhibitor that
binds β-lactamases
(gram-positive and
gram-negative)
• It is available
for IV or IM
ampicillin+
cefoperazone
• Parenteral
combination
products with
piperacillin and
ceftolozane.
• New β-
lactamase
inhibitor that is
structurally
dissimilar from
the older
generation,
• Broader
spectrum of
inhibition.
cyclic boronic acid
β-lactamase
inhibitor (BLI)
• Amoxicillin(Oral) +
ticarcillin( Parenteral)
• USE-
Multidrug-
resistant
Acinetobacter
infections.
• parenteral
combination
product with
ceftazidime.
broad spectrum of
activity against
various serine β-
lactamases,
including KPC
carbapenemases
• non–β-lactam β-
lactamase
inhibitor
combination of
vaborbactam and
meropenem is
approved in the
United States and

42. BACTERIAL RESISTANCE

43. Mechanism of Resistance-
1. Inactivation of antibiotic by β-lactamase - comman
2. Modification of target PBPs
3. Impaired penetration of drug to target PBPs
4. Antibiotic efflux

44. Inactivation of antibiotic by
β-lactamase
Modification of target PBPs Impaired penetration of
drug to target PBPs
Antibiotic efflux
• e.g β-lactamase
produced by Staph
aureus, Haemophilus
influenzae, and E-coli
etc
• Basis of methicillin
resistance in
staphylococci
• Penicillin resistance in
pneumococci
• Gram-negative species • Gram- negative
• Consists of cytoplasmic
and periplasmic protein
components
• P
.aeruginosa and
Enterobacter hydrolyse (
Penicillin &
Cephalosporins)
• Resistant organisms
produce PBPs that have
low affinity for binding
β-lactam antibiotics
• Have Porin channels
• Absence of proper
channel
• Impair drug entry into
the cell
• Hydrolyze drug faster
FUNCTION-transport some
β-lactam antibiotics from
the periplasm back across
the cell wall outer
membrane

45. RECENT ADVANCES

46. Ref- https://doi.org/10.1016/j.ejmech.2020.112510

48. • Benzothiaole-β-lactam hybrids- has ability to inhibit breast cancer cell growth and
invasiveness in vitro and in vivo.
• 1,2,3-Triazole-β-lactam hybrids-reduced the tumor growth bared by human gastric cancer
cells in vivo with no signs of adverse side effects

49. • MPTP - impair motor behavior and
marked increase in inflammatory
mediators and oxidative stress
• decrease in brain-derived neurotrophic
factor (BDNF)
• ceftriaxone (200 mg/kg) improvement in
motor behavioral deficits and oxidative
damage
• Restored the decreased activity
of BDNF in striatum
Ref-https://doi.org/10.1016/j.pathophys.2017.02.001

50. Ref- https://doi.org/10.3109/00207454.2014.991821
Ref-doi: 10.3390/ph13050080

51. • PTZ model (70 mg/kg), pretreatment with Cefipime (200 and 600 mg/kg) significantly
decreased the duration of convulsions and severity in rats
• Cefazolin was shown to exhibit a significant proconvulsant effect at a dose of 800 mg/kg,
but not 400 mg/kg, in rats and mice
• Dose dependent effect- Low dose- Increased GLT1 activity is related with decreased
glutamate activity so anticonvulsant effect.
• High dose- inhibition of GABA signaling system- proconvulsant effect

52. • Carbapenems is used for the treatment of Gram-negative bacterial infections.
• Parenteral route
• Currently used- Japan
Ref-10.1080/14787210.2018.1496821

54. Ref- https://doi.org/10.1186/s12879-019-4409-1

55. • Carbapenem-resistant Enterobacteriaceae (CRE) an important global threat.
• Combination therapy was associated with lower mortality.
• CAZ-AVI is a promising antibiotic.
• Safety and tolerability in clinical trials has been excellent, with few serious drug-related
adverse events.
• Limitation is its inability to inhibit metallo-b-lactamases

56. Published online 2018 Sep 12. doi: 10.2147/IDR.S150447

57. Ref-https://doi.org/10.1093/cid/ciy576

58. https://doi.org/10.1093/cid/ciy576

61. • Metallo-b-lactamases (MBLs) result in resistance to nearly all b-lactam antimicrobial
agents.
• Mechanisms of action ranging from zinc chelation to zinc-independent enzyme
inhibition and novel gene silencing are in the preclinical pipeline.
•
DOI: 10.1128/AAC.02271-20
Published June 2021

62. • LYS228 is a single-agent monobactam that is effective
against Enterobacteriaceae strains, including those expressing ESBLs, SBLs, and
MBLs

63. SUMMARY
• Beta-lactam antibiotics include penicillin, cephalosporins and
related compounds.
• Act by inhibiting cell wall synthesis
• Bacterial resistance against beta-lactam antibiotics is increasing at
a significant rate and has become a common problem in primary
care medicine.
• Antimicrobial susceptibility testing supports antibiotic choices.

64. REFERENCES
• Goodman & Gilman “The Pharmacological Basis Of Therapeutics”, 13th ed.
McGraw-Hill Education pg. 1024-1035
• Bertram G. Katzung “ Basic and clinical Pharmacology”, 14th ed.
• Rang and Dale pharmacology, 9th ed
• Research Articles