Cell Wall Synthesis inhibitors Flashcards
Which are the cell wall synthesis inhibitors?
B-Lactams
Peptides
Fosfomycin
Bacitracin
Which agents fall under the B-Lactams?
Penicillins
Cephalosporins
Carbapenems
Monobactams
Which agents fall under the Peptides?
The Glycopeptides
Difference btwn gram +ive and -ive bacteria?
Gram +ive: contain a thick cell wall that consists of 40 layers of a peptidoglycan polymer. Retain Purple dye
Gram -ive: the peptidoglycan polymer is thin, is surrounded by a membrane and it also surrounds a periplasmic space. Retain Red dye
Process of Bavterial cell wall synthesis
Formation of sheets of amino sugars which are alternating reisdues of N-acetylglucosamine and N-acetyluramic acid( contains pentatpeptide side chains). Transpeptidase enzyme cross-links neighbouring amino sugar chains to form penta-glycine bridges between the side chains
Action of the B-Lactamsq
They inhibit the formation of the Peptidoglycin bridge by inhibiting the Transpeptidase enzyme
Are Penicillins Bacteriostatic or Bactericidal agents?
They are bactericidal agents–> kill bacteria
MOA of Penicillins
They inhibit the Transpeptidase enzyme during the Peptidoglycan synthesis by binding to the Cell wall (peptidoglycan) thus the enzyme cannot attach to it
–> cell wall gets defects= swelling of bacteria=lysis
In what state does the bacterial cell have to be in in order for the Penicillin to work?
It has to be actively growing/replicating/forming the cell wall
Bacterial Resistance against Penicillins
- Absence of cell wall: if there’s no cell wall then the penicillins cannot affect it.
- Metabolically inactive bacteria: if the bacteria is not actively growing (inherent resistance) they cannot affect it
- Altered Penicillin binding proteins: The Transpeptidase has altered its binding site
- Permeability barrier
- Some bacteria lack autolysins:
- Mutations can also reduce or eliminate activity
- B-Lactamase production–> cleaves the penicillin in surrounding media–> hydrolysis of B-Lactam ring–>inactivation
Action of B-Lactamases
cleave the B-Lactam bond to form an inactive acid
Penicilloic acid
What is a natural penicillin?
its produced by microorganisms that kill other microorganisms
Which are the natural penicillins
Penicillin G: Benzylpenicillin
Penicillin V: Phenoxymethylpenicillin
Characteristics of the Natural Penicillins
Both have a narrow spectrum i.e. target certain spectrum
Both are B-Lactamase sensitive therefore resistance develops easily
Spectrum/Clinical uses of Penicillin G
Gram +ive: Tonsillitis
Pneumonia
Gram -ive rod bacteria: Oropharyngeal infections (are sensitive to Penicillins)
Spiral-shaped bacteria: Syphillis
Gram +ive facultative anaerobes: Abscesses
Enterococci is less susceptible therefore used concurrently with Aminoglycosides
Which Bacteria have developed Resistance against Penicillin G
Gram -ive cocci: Meningitis
Gram -iive diplococci: Gonorrhoea
Grma =ive rod: tetanus, gangrene
Which is the 1st line treatment for Syphillis?
Penicillin G: IM injection
Against which bacteria is Penicillin G used as a Prophylaxis?
Streptococcal infections
Rheumatoid fever recurrence
Surgical/dental procedures on patients with valvular heart disorders
When is Penicillin G used as Initial Therapy?
for serious infections like infective Endocarditis, syphilis (depot prep benzathine penicillin G)
Difference between Penicllin G and V
Penicillin V is 2-4 times less active and potent than penicillin G
Spectrum/Clinical uses for Penicillin V
used mostly for treatment of less serioius infections like Streptococcal tonsillitis/pharyngitis
OR
used as follow-up antibiotic treatment after serious infections responded well to parenteral treatment
Which are the B-Lactamase resistant penicillins
Cloxacillin
Flucloxacillin
Spectrum/Uses of B-Lactamase resistant penicillins
used for treatment of mild B-lactamase positive Staphylococcal infections
Are less active than penicillin G–> much less potent
What are Broad spectrum Penicillins (aminopenicillins)
are broad spectrum penicillins with extended spectrum–> affect many gram +ive and -ive bacteria (gram -ive bacteria show widespread resistance)
Which are the B-Lactamase sensitive Aminopenicillins?
Amoxicillin (amoxycillin)
Ampicillin
VERY SENSITIVE THEREFORE RESISTANCE DEVELOPS EASILY
Which are the B-Lactamase resistant Aminopenicillins
Amoxicillin+Clavulanic acid (co-amoxiclav)
Which are the Aminopenicillins that extend the spectrum
Ampicillin+Cloxacillin in combination
Ampicillin is sensitive to B-Lactamase theredore combining it with an agent that in insensitive to B-Lactamase–> can target both types of bacteria
What is Clavulanic acid
its a B-Lactamase inhibitor
MOA of Clavulanic acid
it binds covalently and irreversibly near or in the acitve site of B-Lactamases = inhibition
Most gram -ive organsims are ireeversibly inhibited by it
Spectrum/Clinical uses of Ampicillin
most gram +ive bacteria+ Influenza
*most gram -ive bacteria are resistant to it
Spectrum of Amoxicillin
gram +ive spectrum similar to Pen G= incr. activity against Enterococci and Listeria
Gram -ive spectrum: H.influenza, E.coli, Proteus mirabilis, Salmonella & Shigella
Amoxicillin is drug of choice in
Otis media
Sinusitis lower RTI
Clinical Uses of Amoxixllin
Soft tissue infections
Cholecystitis, GIT infections (incl. thyroid)
UTIs
Prophylaxis to prevent infective Endocarditis
What are Antipseudomonal penicillins
They are extended spectrum antibodies.
Which are the Extended Spectrum Antipseudomonal penicillins
Piperacillin+Tazobactam(B-Lactamase inhibitor
Antipseudomonal pencillins are effective against
Most effective against Pseudomonas Aeruginosa
MOA of Antipseudomonal penicillins
They act synergistically with Aminoglycosides for empiric treatment of serious Pseudomonas infections
Which is the 1st line treatment for P.aeruginosa
Aminoglycosides
Ways to prolong action of Penicillin G
- Higher dosages=plasma level above MIC
- Combined with Probenecid: Probenecid competes with the Penicillin for the excretory route–> delayed excretion of penicillin= incr. T1/2
- Depot Formulations via IM injection: slow release of pencillin over time–> prolonged time spent in blood
- Inflammations: incr. penetration into CSF and synovial fluid
What are the Limitations to Penicillin G?
- Narrow spectrum: affects gram +ive
- Acid Labile
- B-Lactamase sensitive
S/Es of Pencillin G
-Antibodies formed: Penicillin G forms metabolites and if a patient develops a Hypersensitivity rxn antibodies form against those metabolites.
-Cross hypersensitivity between all penicillins: if you are allergic to one avoid the rest.
-Since its given at {very high} via IV or intrathecal injections, may cause Neurotoxic convulsions (eg. convulsions)
S/Es of B-Lactamase Resistant antibiotics/penicillins
-Cloxacillin is generally well-tolerated
–> mild GIT disturbance and hypersensitivity rxns
- Neutropenia and agranulocytosis
-Flucloxacillin–> precipitates Cholestatic hepatitis
S/Es of Extended Broad spectrum B-Lactam antibiotics/penicillins
-Superinfections esp. by Candida+ C.Difficule (antibiotic ass. colitis esp. Ampicillin)
-Rashes (toxin) rather than allergic rxn
-Reduce efficacy of COC pill
-GIT effects
-Infectious mononucleosis (amoxicillin)
S/E of Ampicillin
Weak oral absorption of ampicillin–> more destruction of microflora of GIT (causes diarrhea)
S/Es of Co-amoxiclav
High doses: GIT discomfort, diarrhea, N+V
Hepatitis and Chloestatic Jaundice–> Clavulanic acid
Amoxicillin and Clavulanic acid must be used with caution during Lactation–> excreted in mothers milk
SEs of Piperacillin
Same as Penicillin G
May cause potentiala bleeding diathesis
General SE in all Pencillins
Formulations as Na or K salts in high doses –> use in care in patients with cardiac and renal disease (may cause fluid retention, Hypocalcemia, hypernatremia, may precipitate arrythmias)
DIs of Pencillin
Probenecid
Must not combine Aminoglycosides and penicillins in same syrung, infusion/IV= deactivate each other
DIs of Extended Spectrum Penicillins
Allopurinol: skin rash which is not an allergic rxn
COC pill: reduced efficacy
Cautions/CIs of Penicillin
Elderly + neonates: kidney functions are not optimal, require dose adjsutment
CI when allergic
Flucloxacillin: porphyria (genetic diseae where enzymes that produce Hb are not functioning optimally)
What are Cephalosporins
they are broad spectrum semi synthetic antibiotics
They are derived form B-Lactams
Structure of Celphalosporins
Contain a B-Lactam ring
–> therefore, cross hypersensitivity rxns with penicillins may occur
How are Cephalosporins better that Penicillins
-They have inherent greater stability against B-Lactamases–> B-Lactamases can’t inactivate them as easuly as they do the penicillins
-Resistance against Cephalosporins is much less than penicillins
Which bacteria is resistant to all Cephalosporins
Enterococci
Which are the 1st gen. Cephalosporins
Cefalexin (oral)
Cefazolin (IV)
Cefadroxil (oral)
1st gen Cephalosporins are effective agains
Gram +ive only
–> Streptococci
–> Staphylococci
Which are the 2nd gen Cephalosporins
Cefuroxime (oral + IV)
Cefamandole (IV)
Cefoxitin (IV)
Cefprozil (don’t need to know)
2nd gen Cephalosporins are effective against
Gram +ive,
E coli
Klebsiella
Proteus
H.influenza
Enterobacter
WHich are the 3rd gen Cephalosporins
Cefotaxime (IV)
Ceftriaxone (IV)
(Cefixime, Ceftazidime, Cefpodoxime)
3rd gen. Cephalosporins are active against
Gram +ive
H.influenza
N.gonorrhoea
Salmonella spp
some are active against P.aeruginosa
Which are the 4th gen Cephalosporins
Cefepime
Cefpirome
4th gen Cephalosporins are active against
same as 3rd gen=active against Both Gram +ive and -ive
Esp. P.aeruginosa
Which are the 5th gen Cephalosporins
Ceftaroline (IV)
5th Gen Cephalosporins are active against
MRSA+MR S.Epidermidis
Gram -ive
What happens as the generation no. of Cephalosporins increase
Their resistance to B-Lactamase increases
Mechanism of Bacterial resistance in Cephalosporins
- Bacteria become impermeable to drug
- Alterations in PBS
- Autolysins cannot be activated
- B-Lactamase sensitive
Pharmacokinetics of Cephalosporins
(Excretion)
Mainly via urine therefore if Probencid is added their T1/2 can increase
*Except Ceftriaxone: 40% is eliminated via hepatic
Which gen of Cephalosporins can treat Meningitis
3rd gen as they can penetrate well into CSF
Which Cephalosporin is 1st line treatment of Meningitis
Ceftriaxone
Which Cephalosporin is a Prodrug?
Ceftaroline and it’s metabolized by plasma phosphatases.
SEs of Cephalosporins
-Hypersensitivity rxns: anaphylactic shock, fever, skin rashes, nephritis, Granulocytopenia, Hemolytic anemia
-Some patients who are allergic to penicillin can tolerate them
*if get anaphylaxis due to P, then avoid Cs
-decr. effectiveness of Oral Contraception
-Nephrotoxicity: concurrent admin with aminoglycosides/vancomycin
-Phlebitis (Cs with IV admin)
-Neurotoxicity: at high doses/renal impairment
Which Cephalosporin causes Alcohol Intolerance as SE
Cefamandole: its chemical structure interferes with Acetaldehyde Dehydrogenase
DIs of Cephalosporins
Alcohol: Cefamandole
Warfarin
NSAIDs
COC
Probenecid: incr. T1/2
Cephalosporins and aminoglycosides in same container may chemically inactivate each other
Ceftriaxone: not to be admin at same time as Ca IV containing solutions (>48 hrs) esp. in neonates <28 days
Cautions/CIs of Cephalosporins
Anaphylactic shock
Allergy
Ceftriaxone:in neonates with Hyperbilirubinaemia
Which are the Carbapenems
Imipenem (never given alone)
Meropenem
Ertapenem
MOA of Carbapenems
Bactericidal and inhibit cell wall synthesis
Spectrum of Carbapenems
very broad: affects gram +ive and -ive and anaerobic+aerobic
Which bacteria are Carbapenems not active against?
Methcillin-resistant staphylococci
How is Imipenem given
with Cilastatin (which is an enzyme inhibitor that blocks renal metabolism of Imipenem)
Which Carbapenem can cross BBB
Meropenem: can treat Meningits
Clinical uses of Imipenem
Severe nosocomial infections
(septicemia, endocarditis, LRT, genitourinary tract, intra-abdominal, bone and joint, skin and soft tissue)
Clinical uses of Meropenema
Alternative treatment for bacterial meningitis
PK of Carbapenems
Mostly IV admin
Eliminated via Kidneys
Ertapenem: single day dosing, IV or IM, T1/2 of 3.8hrs
General SEs of Carbapenems
Hypersensitivity rxns
GIT effects
Haematological abnormalities
Incr. Liver enzymes
incr. serum creatinine and blood urea
IV: pain, erythema, thrombophlebitis
SEs of Imipenem
CNS effects: induces seizures at high dosages
Red discolouration of urine in children
Cautions/CIs of Carbapenems
Allergy
CNS disorders/seizures
Renal Impairment
Which are the Monobactams
Aztreonam
MOA of Monobactams
Bactericidal: affect cell wall synthesis
Spectrum of Monobactams
Good activity against aerobic gram -ive only
(E.coli, P.aeuroginosa, Enterobacter, Citrobacter, Proteus Mirabilis, H.influenza)
Are Monobactams susceptible to B-Lactamases
They are stable to many B-Lactamses therefore they cannot be cleaved easily
Do Monobactams have cross-sensitivity?
they do not have any cross-sensitivity with Penicillins or Cephalosporins s their structure is different completely (can be used in penicillin allergic rxns)
Admin and PK of Monobactams
IV or IM (T1/2 1.5-2hrs)
Mainly eliminated via kidneys in unchanged form
SEs of Monobactams`
Injection site rxns
Rash
Rarely toxic epidermal necrolysis
GIT SEs
Drug-induced Eosinophilia: their no.s incr. peripherally
Which are the Glycopeptides
Vancomycin
Tecicoplanin
When is Vancomycin used
ONLY reserve antibiotic used for treatment of life threatening infectionsS
Spectrum of Vancomycin
Gram +ive bacteria Only
Vancomycin use is restricted to?
Cloxaclilin-resistant Staphylococci and penicillin-resistant enterococci
Vancomycin is an alternative agent for?
Prophylaxis and treatment of Endocarditis in penicillin allergic patients
When is oral Vancomycin used
GIT infections (pseudomembranous colitis)
–> Clostridium Difficule
Does Vancomycin share cross-resistance with other antibiotics
no, because its structure is very different from other antibiotics
MOA of Vancomycin
Bactericidal
Inhibits cell wall synthesis: attaches to D-alanine-D-alanine end of Peptidoglycan Pentapeptide
–>Transglycosylation is inhibited: peptidoglycan cross-linkages do not form
= weakened cell wall that swells and lyses of bacterium occurs
PK of Vancomycin
Poory absorbed via oral admin
IM admin is painful
ONLY via slow IV infusion
ONLY orally for C.Dofficule
Excreted 80-90% unaltered via glomerular filtration in urine
SEs of Vancomycin
Fever and skin rashes
Admin too rapidly via IV=release of histamine–> blushing of neck and face known as RED MAN SYNDROME
Ototoxic and Nephrotoxic: RARE
Nephrotoxic in geriatric patients
TDN essential in elderly, children, impaired renal function
DIs of Vancomycin
Ototoxic and Nephrotoxic drugs: aminoglycosides+ some Cephalosporins
Cautions/CIs of Vancomycin
Renal Impairement
ELderly patients
Neonates/young infants
Hearing abnormalities
Pregnancy
MOA of Teicoplanin
Bactericidal
Inhibits cell wall synthesis: attaches to D-alanine-D-alanine end of Peptidoglycan Pentapeptide
–>Transglycosylation is inhibited: peptidoglycan cross-linkages do not form
= weakened cell wall that swells and lyses of bacterium occurs
Spectrum of Teicoplanin
Gram +ive bacteria Only
PK of Teicoplanin
IM (painful), IV, T1/2: 45-70hrs thus taken ONCE DAILY
SEs of Teicoplanin
Same as Vancomycin, lower incidence of RED MAN Syndrome, allergy: cross-sensitivity with Vancomycin
Spectrum of Fosfomycin
Broad Spectrum
Gram +ive and -ive
Synergism with B-Lactams, aminoglycosides or Quinolones
MOA of Fosfomycin
Interferes with formation of N-acetylmuramic acid
–> inhibits early stage in bacterial cell wall synthesis
Bactericidal
Resistance mechanism in Fosfomycin
limited due to inadequate transport of drug into cell
PK of Fosfomycin
Oral: absorption delayed by food=take 2hrs before food
T1/2: 4hrs
Excreted in breast milk: can affect baby
Excreted in urin: therapeutic levels (1-3 days)
Uses of Fosfomycin
- Single dose therapy for acute uncomplicated lower urinary tract infection (sensitive E.Coli)–> woman and female>5yrs
- Prophylaxis in diagnostic and surgical transurethral procedures in adult men
SEs of Fosfomycin
GIT disturbance: taken on empty stomach
Skin rashes
DIs of Fosfomycin
Metoclopramide prevents its absorption and conversion into its active form–>
decr. serum and urinary conc. of fosfomycin
Caution in Fosfomycin
Pregnancy and Lactation
CI in Fosfomycin
Renal Failure
