Antibiotics inhibiting cell wall synthesis- All you need to know, by RxVichuZ!
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.
- Here, primarily, important catchpoints on the following will be made:
A. BETA-LACTAM ANTIBIOTICS
C. OTHER CELL-WALL SYNTHESIS INHIBITORS.
- Very precise insight into individual drugs, their do’s and dont’s & special
information has been elucidated
- For extensive insight, substantial referring of textbooks is advised!!!
Consist of drugs, that contain BETA-LACTAM RING in their
Act, by inhibiting cell-wall synthesis
All BETA-LACTAM antibiotics are BACTERICIDAL in nature
Drugs bind to specific receptors on bacterial cell membrane(Penicillin Binding
Proteins, PBPs) inhibit TRANSPEPTIDASE enzyme prevents CROSS-
LINKING of PEPTIDOGLYCAN chains
Bacteria formed in the presence of beta-lactams lack CELL-WALL
Since cell-wall is vital for providing rigidity to the cell lack of cell-wall in
susceptible bacteriae causes IMBIBITION of water causes death of susceptible
Bacteria like MYCOPLASMA lack CELL-WALL thus, INTRINSICALLY
RESISTANT TO BETA-LACTAMS & VANCOMYCIN!!
PENICILLIN G commercially obtained from Penicillium chrysogenum
PENICILLIN G only NATURAL OCCURRING PENICILLIN!!!
Important limitations of clinical use of Penicillin G include:
1. Drug undergoes rapid breakdown by acid inside stomach hence, NOT
2. Drug rapidly excreted from kidney, via TUBULAR SECRETION thus, has
SHORT DURATION OF ACTION!
3. Drug covers mainly GRAM-POSITIVE BACTERIA 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 can cause severe hypersensitivity reactions!!
To overcome above shortcomings of Penicillin G newer penicillins have been
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 thus can be
- 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 can make it long-acting
- BENZATHINE PN G longest-acting penicillin!
- PROBENECID if given with Penicillin G tubular secretion of latter will be
- Since Pn G has WIDE THERAPEUTIC INDEX 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,
d. Strategy to overcome resistance issues with Penicillin G:
- Beta-lactamase inhibitors if added to Penicillin G causes inhibition of
bacterial enzyme penicillins escape degradation!
- Administration of PENICILLINASE-RESISTANT PENICILLINS, like
CLOXACILLIN OXACILLIN, NAFCILLIN, DICLOXACILLIN &
e. Strategies, to prevent risk of hypersensitivity with Pn G:
- Hypersensitivity reactions can occur with ANY PENICILLIN
- PENICILLINS most common drugs responsible for ANAPHYLACTIC SHOCK
- If a person is severely allergic to any penicillin NO BETA-LACTAM
ANTIBIOTIC SHOULD BE ADMINISTERED TO THAT PERSON!!(Except
- To prevent severe allergic reactions INTRA-DERMMAL SKIN TESTING can
HOW TO REMEMBER NAMES OF ACID-RESISTANT
USE THE CODE “VODKA”!!
“V”: Penicillin V
“A”: Amoxicillin, ampicillin!!
HOW TO REMEMBER THE NAMES OF PENICILLINASE-
USE THE CODE: “CONDOM”!!
HOW TO REMEMBER NAMES OF EXTENDED-
USE THE CODE: “ACT MAP”!!
“A”: Ampicillin, amoxicillin
“T” : Ticarcillin
All extended-spectrum penicillins effective against Gram-
negative bacteria like E.coli, salmonella, shigella(except
CT-MAP Penicillins effective against PSEUDOMONAS!!
MAP-penicillins effective against KLEBSIELLA!!
- 1 gram of PENICILLIN equivalent to 1.6 million units
- Gastric acid breaks down penicillins results in reduced oral bioavailability
- Pn G used ORALLY only for those infections, in which clinical experience has
- AMPICILLIN & NAFCILLIN excreted partly in bile
- Benzyl penicillin is given by i.m injection
- Drug has short t1/2 thus given 6-12 hourly
- Procaine & benzathine penicillin are LONG-ACTING(due to slow release)
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
- DOC for NEUROSYPHILIS: Aq. Pn G(Since benzathine Pn has little CNS
- Given also, for GRAM(+) cocci, MENINGOCOCCI, etc
- Most staphylococci & gonococci are now resistant
- Effective against ANAEROBES (except Bacteroides)!
B. METHICILLIN, NAFCILLIN, OXACILLIN & CLOXACILLIN:
- Although mainly given for S.aureus infections resistant organisms have been
- MRSA developed, due to formation of ALTERNATIVE PBPs possess less
affinity for drugs
- In cases of MRSA treatment of choice is VANCOMYCIN/ TEICOPLANIN
- In case of VANCOMYCIN resistance(VRSA) treatment of choice is
C. AMPICILLIN, AMOXICILLIN:
- Wide-spectrum, penicillinase-sensitive antibiotics
- In addition to Gram (+) organisms they are also effective against:
iii. Hemophilus organisms!
- Activity of above drugs 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.
D. PIPERACILLIN, TICARCILLIN, CARBENICILLIN, AZLOCILLIN,
- Possess activity against GRAM-NEGATIVE RODS (including Pseudomonas
- Used along with BETA-LACTAMASE INHIBITORS & along with
- UREIDOPENICILLINS highly effective against KLESIELLA species!!
HOW TO REMEMBER IMPORTANT USES OF
USE THE CODE : “LAST MAN”!!!
“L” : Leptospira
“S”: Streptococcus, staphylococcus(non-penicillinase
“T”: Treponema, Tetanus(also gas gangrene!)
“AN”: Anthrax(Ciprofloxacin is also 1st line agent!)
TOXICITY ISSUES WITH PENICILLINS:
1. HYPERSENSITIVITY REACTIONS:
- Serum sickness
- It is MANDATORY to conduct INTRA-DERMAL SENSITIVITY TESTING before
- If a patient develops hypersensitivity reaction to Penicillins ALL OTHER
BETA-LACTAM ANTIBIOTICS are CONTRAINDICATED(except
2. AMPICILLIN if used in patients with viral diseases like “infectious
mononucleosis” can cause development of MACULOPAPULAR SKIN RASHES!
3. METHICILLIN can cause ACUTE INTERSTITIAL NEPHRITIS
4. NAUSEA & DIARRHEA with oral drugs like AMOXICILLIN & AMPICILLIN
5. AMPICILLIN incompletely absorbed causes increased suppression of
normal microbial flora can cause higher incidence of DIARRHEA!
6. AMPICILLIN can also cause PSEUDOMEMBRANOUS COLITIS
7. PROCAINE PENICILLIN given in high doses can cause SEIZURES &
8. OXACILLIN can cause HEPATITIS
9. NAFCILLIN can cause NEUTROPENIA
10. CARBENICILLIN given in high dose can cause BLEEDING!
- Most cephalosporins excreted via kidney through TUBULAR SECRETION
- CEFOPERAZONE & CEFTRIAXONE secreted in the BILE
- Nephrotoxicity of cephalosporins enhanced with concurrent use of LOOP
SPECIAL USES & IMPORTANT FEATURES OF
A. FIRST-GENERATION CEPHALOSPORINS:
- Active against Gram(+) cocci, including STAPHYLOCOCCI
- MRSA is resistant to cephalosporins as well!
- DOC for SURGICAL PROPHYLAXIS : CEFAZOLIN!
B. SECOND-GENERATION CEPHALOSPORINS:
- Has less activity against Gram(+) organisms(compared to 1st generation)
- Extended Gram(-) coverage
- Drugs active against BACTEROIDES FRAGILIS(anaerobe):
- CEFUROXIME attains higher CSF levels (compared to other 2nd generation
drugs) thus, can be used for BACTERIAL MENINGITIS!(Ceftriaxone is
preferred as empirical, though).
- LORACARBEF chemically similar to CEFACLOR
C. THIRD GENERATION CEPHALOSPORINS:
- Active against GRAM-NEGATIVE ORGANISMS(resistant to other BETA-
- Penetrate BBB easily (except CEFOPERAZONE & CEFIXIME)
- Third-generation drugs, active against PSEUDOMONAS:
ii. Ceftazidime(most active, when used along with aminolglycosides!)
- CEFTAZIDIME DOC for MELIOIDOSIS (caused by Burkholderia
- CEFTIZOXIME has maximum activity against BACTEROIDES!
- CEFOTAXIME metabolized to an active metabolite (desacetyl-cefotaxime)
• FIRST-CHOICE DRUG for:
b. Salmonellosis(including typhoid)
c. E.coli sepsis
d. Proteus species
g. Bacterial meningitis(empirical therapy).
• Long-term use of > 2g/day of CEFTRIAXONE can result in :
a. Biliary sludging syndrome
b. Cholelithiasis(due to drug precipitation in bile).
D. FOURTH-GENERATION CEPHALOSPORINS:
- Possess activity against Gram(-ve) organisms(including PSEUDOMONAS),
resistant to 3rd generation ones!
- Efficacy against G(+) cocci similar as that of 3rd generation ones!
- Inactive against ANAEROBES!
E. FIFTH-GENERATION CEPHALOSPORINS:
- Indicated for CAP & MRSA infections
- Ceftolozane & ceftobiprole also effective against PSEUDOMONAS!!
TOXICITY ISSUES WITH CEPHALOSPORINS:
1. Hypersensitivity reactions
2. Drugs, containing METHYLTHIOTETRAZOLE group can cause
HYPOPROTHROMBINEMIA & DISULFIRAM-LIKE REACTION with
ALCOHOL, that include:
3. CEFTAZIDIME can cause NEUTROPENIA!!
4. LORACARBEF in high doses can cause SEIZURES!
Active against GRAM-NEGATIVE RODS(including Pseudomonas)
Inactive against Gram-positive organisms/anaerobes
T1/2 prolonged in renal failure
ONLY BETA-LACTAM ANTIBIOTIC, that can be used in patients having
SEVERE ALLERGY TO PENICILLINS/ CEPHALOSPORINS(since it is not
• Have wide activity against:
a. Gram (+) cocci
b. Gram (-) rods
MEROPENEM most active against PSEUDOMONAS
ERTAPENEM least active against PSEUDOMONAS
CARBAPENEMS BETA-LACTAMASE RESISTANT!!
For activity against Pseudomonas infections carbapenems should be given in
combination with AMINOGLYCOSIDES!!
DOC for :
iii. Acinobacter species
• Since CARBAPENEMS are the ONLY BETA-LACTAM ANTIBIOTICS that are
efficacious against ESBL(Extended Spectrum Beta-Lactamases) they are also
DOC for ESBL-producing bacteria!!
IMIPENEM rapidly inactivated by RENAL DEHYDROPEPTIDASE I thus
given in combination with CILASTATIN(cilastatin inhibits this enzyme)!
Additional benefits of CILASTATIN when given with IMIPENEM:
a. Cilastatin increases t1/2 of imipenem
b. Cilastatin prevents formation of nephrotoxic metabolite
• Main ADRs of IMIPENEM-CILASTATIN combination:
b. GI distress.
• MEROPENEM, DORIPENEM & ERTAPENEM not metabolized by RENAL
DEHYDROPEPTIDASE less risk of SEIZURES!!
• ERTAPENEM very long-acting!!
Refer to “enzymes, that HYDROLYZE beta-lactam
antimicrobials, by acting on BETA-LACTAM ring”
There are 2 basic types of BETA-LACTAMASE
A. MOLECULAR CLASSIFICATION(AMBER
- Based on STRUCTURE(amino acid sequence)
- Classified into 4 categories: A,B,C & D
- Class “A”, “D” & “C” enzymes require serine residue to
- Class “B” enzymes require ZINC IONS hence also
known as “METALLO-BETA LACTAMASES”!
B. FUNCTIONAL CLASSIFICATION(BUSH
- 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
BETA-LACTAMASE MOLECULAR GROUP INHIBITED BY SUBSTRATES
CEPHALOSPORINASE C NONE Cephalosporins,
A/D CA & TZB
PENICILLINASE A CA & TZB Penicillin G & early
ESBL A CA & TZB Penicillins,
CARBENICILLINASE A CA & TZB Cloxacillin, oxacillin
OXACILLINASE A/D CA & TZB Cloxacillin, oxacillin,
B EDTA Carbapenems
EXTENDED-SPECTRUM BETA-LACTAMASES: A BRIEF
- Enzymes , that offer resistance to MOST BETA-LACTAM antibiotics (Penicillins,
- Mainly found in G(-ve) organisms, like KLEBSIELLA & E.coli
- Important features include:
a. Can be inhibited by CLAVULANIC ACID/TAZOBACTAM
b. Can hydrolyze:
c. Cannot hydrolyze:
- CEFAMYCINS(Cefoxitin, cefotetan, cefmetazole)
d. CARBAPENEMS DOC for infections caused by bacteria producing ESBL!!
1. Clavulanic acid
• More active against PLASMID-ENCODED BETA-LACTAMASES(produced by
gonococci & E.Coli), than against INDUCIBLE CHROMOSOMAL BETA-
LACTAMASES(produced by PSEUDOMONAS & ENTEROBACTER)!
• AMOXICILLIN combined with clavulanic acid
• AMPICILLIN combined with SULBACTAM
• PIPERACILLIN combined with TAZOBACTAM
CEFTAZIDIME-AVIBACTAM combination FDA-approved for :
a. Complicated UTI (including PYELONEPHRITIS)
b. Complicated intra-abdominal infections
• MEROPENEM-VABORBACTAM new combination, approved for
- Drug inhibits “bacterial transglycosylase enzyme” prevents CHAIN
ELONGATION causes inhibition of bacterial cell-wall synthesis
- Narrrow-spectrum antibiotic
- Mainly effective against G(+ve) organisms, including MRSA, pneumococci &
- Generally administered via i.v route
- Excreted unchanged in urine
- Rapid i.v infusion of high doses of Vancomycin results in RED MAN
SYNDROME(diffuse flushing, due to HISTAMINE release)
- Vancomycin not absorbed from GIT thus higher concentration of drug can
reach the colon thus it can BE USED ORALLY FOR THE TREATMENT OF
Toxic effects of vancomycin include:
• Dose should be reduced in RENAL FAILURE
• In VANCOMYCIN RESISTANCE(to S.aureus & Enterococci) terminal
ALANINE-ALANINE is replaced by ALANINE-LACTATE(of peptidoglycan)
this reduces affinity of drug for TRANSGLYCOSYLASE.
• Vancomycin is DOC for:
2. Corynebacterium jeikeium
3. Serious infection in PENICILLIN-ALLERGIC PATIENTS!!
- 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!!
- Newer glycopeptide
- Used for MRSA infections!
- Approved for COMPLICATED SKIN & SKIN STRUCTURE INFECTIONS
- Effective against MRSA
- Other than that of vancomycin MOA it also DISRUPTS MEMBRANE
POTENTIAL of susceptible organisms!!
- Given as ONCE-WEEKLY DRUG
- Same mechanism as vancomycin
- Additional benefits: Effective against MRSA & VRSA!!!!
Causes NEUROTOXICITY(tremors, seizures)
Can also precipitate NEUROPSYCHIATRIC
One of the second-line agent for treatment of
- Basically, drugs that inhibit BACTERIAL CELL-WALL SYNTHESIS has been
- Summarized names/classes of drugs include:
a. BETA-LACTAM ANTIBIOTICS(Penicillins, cephalosporins, monobactams,
b. GLYCOPEPTIDE ANTIBIOTICS