This is my 52nd powerpoint...deals with various drugs that inhibit cell-wall synthesis, their spectrum of activity, ADRs & important applications in infections. Newer molecules have also been elucidated here.
HAPPY READING!!
3. - Here, primarily, important catchpoints on the following will be made:
A. BETA-LACTAM ANTIBIOTICS
B. BETA-LACTAMASES
C. OTHER CELL-WALL SYNTHESIS INHIBITORS.
- Very precise insight into individual drugs, their doâs and dontâs & special
information has been elucidated
- For extensive insight, substantial referring of textbooks is advised!!!
HAPPY READING!!!
5. ï§Consist of drugs, that contain BETA-LACTAM RING in their
structure
ï§Act, by inhibiting cell-wall synthesis
ï§Include:
A. PENICILLINS
B. CEPHALOSPORINS
C. MONOBACTAMS
D. CARBAPENEMS
6. ï§ All BETA-LACTAM antibiotics are BACTERICIDAL in nature
ï§ Drugs ï bind to specific receptors on bacterial cell membrane(Penicillin Binding
Proteins, PBPs) ï inhibit TRANSPEPTIDASE enzyme ï prevents CROSS-
LINKING of PEPTIDOGLYCAN chains
ï§ Bacteria formed in the presence of beta-lactams ï lack CELL-WALL
ï§ Since cell-wall is vital for providing rigidity to the cell ï lack of cell-wall in
susceptible bacteriae causes IMBIBITION of water ï causes death of susceptible
organisms!
ï§ Bacteria like MYCOPLASMA ï lack CELL-WALL ï thus, INTRINSICALLY
RESISTANT TO BETA-LACTAMS & VANCOMYCIN!!
8. ï§ PENICILLIN G ï commercially obtained from Penicillium chrysogenum
ï§ PENICILLIN G ï only NATURAL OCCURRING PENICILLIN!!!
ï§ Important limitations of clinical use of Penicillin G include:
1. Drug ï undergoes rapid breakdown by acid inside stomach ï hence, NOT
EFFECTIVE ORALLY!
2. Drug ï rapidly excreted from kidney, via TUBULAR SECRETION ï thus, has
SHORT DURATION OF ACTION!
3. Drug ï covers mainly GRAM-POSITIVE BACTERIA ï has NARROW
SPECTRUM OF ACTIVITY!
4. Most of the Gram-positive bacteria have become resistant to Penicillin G, due
to the following reasons:
a. Development of BETA-LACTAMASE(penicillinase)
b. Development of altered PBPs!!
5. Penicillin G ï can cause severe hypersensitivity reactions!!
9. ï§ To overcome above shortcomings of Penicillin G ï newer penicillins have been
designed!
ï§ STRATEGIES to overcome Penicillin G shortcomings:
a. Development of ACID-RESISTANT PENICILLINS:
- Pn G(Penicillin G) is not effective orally due to high acid lability
- Newer penicillins have been developed that are ACID-RESISTANT ï thus can be
given orally!
- Include OXACILLIN, PENICILLIN V, DICLOXACILLIN, CLOXACILLIN,
AMOXICILLIN, AMPICILLIN, etc
b. Pn G is SHORT-ACTING. Strategies to overcome this problem include:
- Addition of BENZATHINE/ PROCAINE group to Pn G ï can make it long-acting
- BENZATHINE PN G ï longest-acting penicillin!
- PROBENECID ï if given with Penicillin G ï tubular secretion of latter will be
inhibited!
10. - Since Pn G has WIDE THERAPEUTIC INDEX ï HIGH INITIAL doses of drug
can be used!!
c. Strategy, to overcome narrow-spectrum activity of Pn G:
- Several new penicillins, with extended-spectrum have been developed
- Include AMINOPENICILLINS, CARBOXYPENICILLINS,
UREIDOPENICILLINS
d. Strategy to overcome resistance issues with Penicillin G:
- Beta-lactamase inhibitors ï if added to Penicillin G ï causes inhibition of
bacterial enzyme ï penicillins escape degradation!
- Administration of PENICILLINASE-RESISTANT PENICILLINS, like
CLOXACILLIN OXACILLIN, NAFCILLIN, DICLOXACILLIN &
METHICILLIN.
11. e. Strategies, to prevent risk of hypersensitivity with Pn G:
- Hypersensitivity reactions can occur with ANY PENICILLIN
- PENICILLINS ï most common drugs responsible for ANAPHYLACTIC SHOCK
- If a person is severely allergic to any penicillin ï NO BETA-LACTAM
ANTIBIOTIC SHOULD BE ADMINISTERED TO THAT PERSON!!(Except
AZTREONAM)
- To prevent severe allergic reactions ï INTRA-DERMMAL SKIN TESTING can
be opted!
12. HOW TO REMEMBER NAMES OF ACID-RESISTANT
PENICILLINS???
USE THE CODE âVODKAâ!!
âVâ: Penicillin V
âOâ: Oxacillin
âDâ: Dicloxacillin
âKâ: Cloxacillin
âAâ: Amoxicillin, ampicillin!!
13. HOW TO REMEMBER THE NAMES OF PENICILLINASE-
RESISTANT PENICILLINS??
USE THE CODE: âCONDOMâ!!
âCâ: Cloxacillin
âOâ: Oxacillin
âN: Nafcillin
âDOâ: Dicloxacillin
âMâ: Methicillin!!
14. HOW TO REMEMBER NAMES OF EXTENDED-
SPECTRUM PENICILLINS??
USE THE CODE: âACT MAPâ!!
1. AMINOPENICILLINS:
âAâ: Ampicillin, amoxicillin
2. CARBOXYPENICILLINS:
âCâ: Carbenicillin
âTâ : Ticarcillin
3. UREIDOPENICILLINS:
âMâ: Mezlocillin
âAâ: Azlocillin
âPâ: Piperacillin!!
15. ï§All extended-spectrum penicillins ï effective against Gram-
negative bacteria like E.coli, salmonella, shigella(except
AMOXICILLIN!!)
ï§CT-MAP Penicillins ï effective against PSEUDOMONAS!!
ï§MAP-penicillins ï effective against KLEBSIELLA!!
16. PHARMACOKINETICS:
- 1 gram of PENICILLIN ï equivalent to 1.6 million units
- Gastric acid ï breaks down penicillins ï results in reduced oral bioavailability
- Pn G ï used ORALLY only for those infections, in which clinical experience has
proven efficacy!
- AMPICILLIN & NAFCILLIN ï excreted partly in bile
- Benzyl penicillin is given by i.m injection
- Drug ï has short t1/2ï thus given 6-12 hourly
- Procaine & benzathine penicillin are LONG-ACTING(due to slow release)
17. CLINICAL USES OF DIFFERENT PENICILLINS:
A. PENICILLIN G:
- DOC for SYPHILIS
- Role of BENZATHINE PENICILLIN in SYPHILIS:
i. For PRIMARY, SECONDARY & EARLY LATENT SYPHILIS : 2.4 million units
i.m, as single dose
ii. For LATE LATENT & TERTIARY SYPHILIS: Duration of treatment is 3
weeks(once weekly!)
- DOC for NEUROSYPHILIS: Aq. Pn G(Since benzathine Pn has little CNS
permeability)
- Given also, for GRAM(+) cocci, MENINGOCOCCI, etc
- Most staphylococci & gonococci are now resistant
- Effective against ANAEROBES (except Bacteroides)!
18. B. METHICILLIN, NAFCILLIN, OXACILLIN & CLOXACILLIN:
- Although mainly given for S.aureus infections ï resistant organisms have been
isolated
- MRSA ï developed, due to formation of ALTERNATIVE PBPs ï possess less
affinity for drugs
- In cases of MRSA ï treatment of choice is VANCOMYCIN/ TEICOPLANIN
- In case of VANCOMYCIN resistance(VRSA) ï treatment of choice is
LINEZOLID/ STREPTOGRAMINS.
19. C. AMPICILLIN, AMOXICILLIN:
- Wide-spectrum, penicillinase-sensitive antibiotics
- In addition to Gram (+) organisms ï they are also effective against:
i. Enterococci
ii. Listeria
iii. Hemophilus organisms!
- Activity of above drugs ï enhanced, when used in combination with BETA-
LACTAMASE INHIBITORS(sulbactam, clavulanic acid).
- Special uses of AMPICILLIN:
i. DOC for Listeria meningitis(cephalosporins are ineffective here!)
ii. DOC for UTI caused by E.faecalis.
20. D. PIPERACILLIN, TICARCILLIN, CARBENICILLIN, AZLOCILLIN,
MEZLOCILLIN:
- Possess activity against GRAM-NEGATIVE RODS (including Pseudomonas
species!)
- Used along with BETA-LACTAMASE INHIBITORS & along with
AMINOGLYCOSIDES
- UREIDOPENICILLINS ï highly effective against KLESIELLA species!!
21. HOW TO REMEMBER IMPORTANT USES OF
PENICILLIN G(DOC)???
USE THE CODE : âLAST MANâ!!!
âLâ : Leptospira
âAâ: Actinomyces
âSâ: Streptococcus, staphylococcus(non-penicillinase
producing)
âTâ: Treponema, Tetanus(also gas gangrene!)
âMâ: Meningococcus
âANâ: Anthrax(Ciprofloxacin is also 1st line agent!)
22. TOXICITY ISSUES WITH PENICILLINS:
1. HYPERSENSITIVITY REACTIONS:
- Serum sickness
- Anaphylaxis
- It is MANDATORY to conduct INTRA-DERMAL SENSITIVITY TESTING before
giving PENICILLINS!
- If a patient develops hypersensitivity reaction to Penicillins ï ALL OTHER
BETA-LACTAM ANTIBIOTICS are CONTRAINDICATED(except
AZTREONAM!!!)
2. AMPICILLIN ï if used in patients with viral diseases like âinfectious
mononucleosisâ ï can cause development of MACULOPAPULAR SKIN RASHES!
3. METHICILLIN ï can cause ACUTE INTERSTITIAL NEPHRITIS
4. NAUSEA & DIARRHEA with oral drugs like AMOXICILLIN & AMPICILLIN
23. 5. AMPICILLIN ï incompletely absorbed ï causes increased suppression of
normal microbial flora ï can cause higher incidence of DIARRHEA!
6. AMPICILLIN ï can also cause PSEUDOMEMBRANOUS COLITIS
7. PROCAINE PENICILLIN ï given in high doses ï can cause SEIZURES &
CNS ABNORMALITIES
8. OXACILLIN ï can cause HEPATITIS
9. NAFCILLIN ï can cause NEUTROPENIA
10. CARBENICILLIN ï given in high dose ï can cause BLEEDING!
27. PHARMACOKINETICS:
- Most cephalosporins ï excreted via kidney through TUBULAR SECRETION
- CEFOPERAZONE & CEFTRIAXONE ï secreted in the BILE
- Nephrotoxicity of cephalosporins ï enhanced with concurrent use of LOOP
DIURETICS!
28. SPECIAL USES & IMPORTANT FEATURES OF
CEPHALOSPORIN GENERATIONS:
A. FIRST-GENERATION CEPHALOSPORINS:
- Active against Gram(+) cocci, including STAPHYLOCOCCI
- MRSA is resistant to cephalosporins as well!
- DOC for SURGICAL PROPHYLAXIS : CEFAZOLIN!
29. B. SECOND-GENERATION CEPHALOSPORINS:
- Has less activity against Gram(+) organisms(compared to 1st generation)
- Extended Gram(-) coverage
- Drugs active against BACTEROIDES FRAGILIS(anaerobe):
i. Cefotetan
ii. Cefmetazole
iii. Cefoxitin.
- CEFUROXIME ï attains higher CSF levels (compared to other 2nd generation
drugs) ï thus, can be used for BACTERIAL MENINGITIS!(Ceftriaxone is
preferred as empirical, though).
- LORACARBEF ï chemically similar to CEFACLOR
30. C. THIRD GENERATION CEPHALOSPORINS:
- Active against GRAM-NEGATIVE ORGANISMS(resistant to other BETA-
LACTAM ANTIBIOTICS)
- Penetrate BBB easily (except CEFOPERAZONE & CEFIXIME)
- Third-generation drugs, active against PSEUDOMONAS:
i. Cefoperazone
ii. Ceftazidime(most active, when used along with aminolglycosides!)
- CEFTAZIDIME ï DOC for MELIOIDOSIS (caused by Burkholderia
pseudomallei)
- CEFTIZOXIME ï has maximum activity against BACTEROIDES!
- CEFOTAXIME ï metabolized to an active metabolite (desacetyl-cefotaxime)
31. - CEFTRIAXONE:
âą FIRST-CHOICE DRUG for:
a. Gonorrhea
b. Salmonellosis(including typhoid)
c. E.coli sepsis
d. Proteus species
e. Serratia
f. Hemophilus
g. Bacterial meningitis(empirical therapy).
âą Long-term use of > 2g/day of CEFTRIAXONE can result in :
a. Biliary sludging syndrome
b. Cholelithiasis(due to drug precipitation in bile).
32. D. FOURTH-GENERATION CEPHALOSPORINS:
- Possess activity against Gram(-ve) organisms(including PSEUDOMONAS),
resistant to 3rd generation ones!
- Efficacy against G(+) cocci ï similar as that of 3rd generation ones!
- Inactive against ANAEROBES!
34. TOXICITY ISSUES WITH CEPHALOSPORINS:
1. Hypersensitivity reactions
2. Drugs, containing METHYLTHIOTETRAZOLE group can cause
HYPOPROTHROMBINEMIA & DISULFIRAM-LIKE REACTION with
ALCOHOL, that include:
- Cefamandole
- Cefoperazone
- Moxalactam
- Cefotetan
3. CEFTAZIDIME ï can cause NEUTROPENIA!!
4. LORACARBEF ï in high doses ï can cause SEIZURES!
36. ï§ Includes AZTREONAM
ï§ Active against GRAM-NEGATIVE RODS(including Pseudomonas)
ï§ Inactive against Gram-positive organisms/anaerobes
ï§ Given i.v
ï§ T1/2ï prolonged in renal failure
ï§ ONLY BETA-LACTAM ANTIBIOTIC, that can be used in patients having
SEVERE ALLERGY TO PENICILLINS/ CEPHALOSPORINS(since it is not
cross-allergenic!!)
38. ï§ Includes:
a. Imipenem
b. Meropenem
c. Doripenem
d. Ertapenem
âą Have wide activity against:
a. Gram (+) cocci
b. Gram (-) rods
c. Anaerobes.
39. ï§ MEROPENEM ï most active against PSEUDOMONAS
ï§ ERTAPENEM ï least active against PSEUDOMONAS
ï§ CARBAPENEMS ï BETA-LACTAMASE RESISTANT!!
ï§ For activity against Pseudomonas infections ï carbapenems should be given in
combination with AMINOGLYCOSIDES!!
ï§ DOC for :
i. Enterobacter
ii. Klebsiella
iii. Acinobacter species
âą Since CARBAPENEMS are the ONLY BETA-LACTAM ANTIBIOTICS that are
efficacious against ESBL(Extended Spectrum Beta-Lactamases) ï they are also
DOC for ESBL-producing bacteria!!
40. ï§ IMIPENEM ï rapidly inactivated by RENAL DEHYDROPEPTIDASE I ï thus
given in combination with CILASTATIN(cilastatin inhibits this enzyme)!
ï§ Additional benefits of CILASTATIN when given with IMIPENEM:
a. Cilastatin ï increases t1/2 of imipenem
b. Cilastatin ï prevents formation of nephrotoxic metabolite
âą Main ADRs of IMIPENEM-CILASTATIN combination:
a. Seizures
b. GI distress.
âą MEROPENEM, DORIPENEM & ERTAPENEM ï not metabolized by RENAL
DEHYDROPEPTIDASE ï less risk of SEIZURES!!
âą ERTAPENEM ï very long-acting!!
42. ï§Refer to âenzymes, that HYDROLYZE beta-lactam
antimicrobials, by acting on BETA-LACTAM ringâ
ï§There are 2 basic types of BETA-LACTAMASE
classifications:
A. MOLECULAR CLASSIFICATION(AMBER
CLASSIFICATION):
- Based on STRUCTURE(amino acid sequence)
- Classified into 4 categories: A,B,C & D
- Class âAâ, âDâ & âCâ enzymes ï require serine residue to
hydrolyze beta-lactams
- Class âBâ enzymes ï require ZINC IONS ï hence also
known as âMETALLO-BETA LACTAMASESâ!
43. B. FUNCTIONAL CLASSIFICATION(BUSH
CLASSIFICATION):
- Based on the type of SUBSTRATE of BETA-
LACTAMASE(i.e, which beta-lactam is hydrolyzed)
- Also takes into consideration whether THE ENZYME IS
INHIBITED BY CLAVULANIC ACID(CA)/ OTHER DRUGS
44. BETA-LACTAMASE MOLECULAR GROUP INHIBITED BY SUBSTRATES
CEPHALOSPORINASE C NONE Cephalosporins,
aztreonam
SERINE BETA-
LACTAMASES
A/D CA & TZB
PENICILLINASE A CA & TZB Penicillin G & early
cephalosporins
ESBL A CA & TZB Penicillins,
cephalosporins(NOT
CARBAPENEMS!)
CARBENICILLINASE A CA & TZB Cloxacillin, oxacillin
OXACILLINASE A/D CA & TZB Cloxacillin, oxacillin,
most cephalosporins(not
aztreonam),
carbapenems, cefamycins,
etc
METALLO-BETA
LACTAMASES
B EDTA Carbapenems
45. EXTENDED-SPECTRUM BETA-LACTAMASES: A BRIEF
INSIGHT:
- Enzymes , that offer resistance to MOST BETA-LACTAM antibiotics (Penicillins,
cephalosporins, monobactams)
- Mainly found in G(-ve) organisms, like KLEBSIELLA & E.coli
- Important features include:
a. Can be inhibited by CLAVULANIC ACID/TAZOBACTAM
b. Can hydrolyze:
i. Penicillins
ii. Cephalosporins
iii. Monobactams
46. c. Cannot hydrolyze:
- CEFAMYCINS(Cefoxitin, cefotetan, cefmetazole)
- CARBAPENEMS
d. CARBAPENEMS ï DOC for infections caused by bacteria producing ESBL!!
48. ï§ Include:
1. Clavulanic acid
2. Sulbactam
3. Tazobactam
4. Vaborbactam
âą More active against PLASMID-ENCODED BETA-LACTAMASES(produced by
gonococci & E.Coli), than against INDUCIBLE CHROMOSOMAL BETA-
LACTAMASES(produced by PSEUDOMONAS & ENTEROBACTER)!
âą AMOXICILLIN ï combined with clavulanic acid
âą AMPICILLIN ï combined with SULBACTAM
âą PIPERACILLIN ï combined with TAZOBACTAM
49. ï§ CEFTAZIDIME-AVIBACTAM combination ï FDA-approved for :
a. Complicated UTI (including PYELONEPHRITIS)
b. Complicated intra-abdominal infections
âą MEROPENEM-VABORBACTAM ï new combination, approved for
COMPLICATED UTI!!!
54. A. VANCOMYCIN:
- Drug ï inhibits âbacterial transglycosylase enzymeâ ï prevents CHAIN
ELONGATION ï causes inhibition of bacterial cell-wall synthesis
- Narrrow-spectrum antibiotic
- Mainly effective against G(+ve) organisms, including MRSA, pneumococci &
C.difficile
- Generally administered via i.v route
- Excreted unchanged in urine
- Rapid i.v infusion of high doses of Vancomycin ï results in RED MAN
SYNDROME(diffuse flushing, due to HISTAMINE release)
- Vancomycin ï not absorbed from GIT ï thus higher concentration of drug can
reach the colon ï thus it can BE USED ORALLY FOR THE TREATMENT OF
PSEUDOMEMBRANOUS COLITIS
55. ï§ Toxic effects of vancomycin include:
1. Chills
2. Ototoxicity
3. Nephrotoxicity
âą Dose should be reduced in RENAL FAILURE
âą In VANCOMYCIN RESISTANCE(to S.aureus & Enterococci)ï terminal
ALANINE-ALANINE is replaced by ALANINE-LACTATE(of peptidoglycan) ï
this reduces affinity of drug for TRANSGLYCOSYLASE.
âą Vancomycin is DOC for:
1. MRSA
2. Corynebacterium jeikeium
3. Serious infection in PENICILLIN-ALLERGIC PATIENTS!!
56. B. TEICOPLANIN:
- Similar features as that of vancomycin
- Given once daily, due to long half-life(45-70 hours)
- Given by either i.v/i.m route
- Excreted unchanged in urine
- Does not cause RED MAN SYNDROME/NEPHROTOXICITY!!
C. ORITAVANCIN:
- Newer glycopeptide
- Used for MRSA infections!
57. D. TELAVANCIN:
- Approved for COMPLICATED SKIN & SKIN STRUCTURE INFECTIONS
- Effective against MRSA
- Other than that of vancomycin MOA ï it also DISRUPTS MEMBRANE
POTENTIAL of susceptible organisms!!
E. DALBAVANCIN:
- Given as ONCE-WEEKLY DRUG
- Same mechanism as vancomycin
- Additional benefits: Effective against MRSA & VRSA!!!!
61. ï§Potent cell-wall synthesis inhibitor
ï§Due to high risk of NEPHROTOXICITY ï indicated ONLY
FOR TOPICAL USE!
ï§Selectively active against G(+ve) bacteria!
64. CONCLUSION:
- Basically, drugs that inhibit BACTERIAL CELL-WALL SYNTHESIS has been
explained here
- Summarized names/classes of drugs include:
a. BETA-LACTAM ANTIBIOTICS(Penicillins, cephalosporins, monobactams,
carbapenems)
b. GLYCOPEPTIDE ANTIBIOTICS
c. FOSFOMYCIN
d. BACITRACIN
e. CYCLOSERINE!