Inhibitors of cell wall synthesis Flashcards
What are the different classes of inhibitors?
β-Lactams, Peptides, Fosfomycin, Bacitracin
Why do cell wall synthesis inhibitors work?
Mammalian cells have no cell wall (selective toxicity) and all bacterial cells have a cell wall (gram positive or gram negative)
What is the difference between gram positive and gram negative bacteria?
Gram positive has a thick cell wall and gram negative has a thin cell wall
What is the MOA of penicilin?
The transpeptidase enzyme in the bacterium is inhibited to disrupt peptidoglycan synthesis. This causes cell wall defects and the ultimate swelling and rupturing of the bacterium
What causes bacterial resistance?
- Absence of a cell wall
- Metabolically inactive bacteria
- Altered penicillin binding proteins (pneumococci),
- Permeability barrier (e.g. Gram neg. bacteria (E.
coli) penicillin G cannot penetrate but ampicillin
can - Some bacteria lack autolysins
- Mutations can also reduce or eliminate activity
- β-lactamase production (penicillinase) →
hydrolysis of β-lactam ring → inactivation
What are the natural penicillins?
- Penicillin G (Benzylpenicillin)
- Penicillin V (Phenoxymethylpenicillin)
(Both have narrow spectrum and are β-
Lactamase sensitive)
What are the clinical uses for penicillin G (Benzylpenicillin)?
- Gram pos. cocci and anaerobes:
– Tonsillitis - Streptococcus pyogenes
– Pneumonia – Pneumococci - Gram neg. cocci:
– Meningitis - Neisseria meningitides - Gram neg. diplococci:
– Gonorrhea - Neisseria gonorrhoeae - Gram pos. rod bacteria:
– Tetanus, gangrene – Clostridium - Gram neg. rod bacteria:
– Oropharyngial infections - Bacteroides fragilis - Spiral-shaped bacteria:
– Syphilis – Treponema - Gram positive facultative anaerobes:
– Abscesses - Actinomyces - Enterococci less susceptible (add aminoglycoside)
- Prophylaxis:
– Streptococcal infections
– Prevention of rheumatic fever recurrence
– Surgical or dental procedures on patients with
valvular heart disorders - Penicillin G: initial therapy for serious infections
(infective endocarditis), syphilis (depot prep.
benzathine penicillin G)
What are the clinical uses for penicillin V (Phenoxymethylpenicillin)?
- 2 – 4 times less active than penicillin G
- Used mostly for the treatment of less serious
infections (streptococcal tonsillitis/pharyngitis)
Or - it is used as follow-up antibiotic treatment after
serious infections responded well to parenteral
treatment
What drugs are β-Lactamase resistant
penicillins?
– Methicillin, nafcillin, oxacillin, dicloxacillin (Not
available in SA)
– Cloxacillin
– Flucloxacillin
What are the uses of β-Lactamase resistant
penicillins?
- Slightly less active than penicillin G
- They are used for the treatment of mild -
lactamase positive staphylococcal infections
What are the two β-lactamase sensitive, broad spectrum penicillians (aminopenicillans)?
– Amoxicillin (amoxycillin)
– Ampicillin
What are the two extended spectrum aminopenicillans?
- β-lactamase resistant
– amoxicillin + clavulanic acid (co-amoxiclav) - Extend the spectrum
– ampicillin + cloxacillin in combination
What is the β-lactamase inhibitor?
Clavulanic Acid. It is produced by Streptomyces-moulds
What is the MOA of Clavulanic Acid?
Clavulanic acid binds covalently near or in the active site of the β-lactamase enzyme
- Most Gram neg. organisms are irreversibly inhibited by clavulanic acid
What are the clinical uses for Ampicillin?
Mostly Gram pos bacteria + H. influenza
What are the clinical uses for Amoxicillin?
– Gram pos. spectrum similar to penicillin G, ↑
activity against enterococci and Listeria
– Gram neg. spectrum: H. influenzae, E. coli,
Proteus mirabilis, Salmonella & Shigella
* Amino side-chain is hydrophilic → penetration via porins in outer membrane of Gram neg. bacteria is easier
– Drug of choice for: otitis media, sinusitis lower RTI
– Soft tissue infections
– Cholecystitis, GIT infections (incl. thyroid)
– Urinary tract infections (possibility of resistance
developing)
– Prophylaxis to prevent infective endocarditis
What drugs are used as Antipseudomonal penicillins?
Piperacillin + tazobactam (β-lactamase inhibitor)
What bacteria are antipseudomonal penicillans most effective against?
Pseudomonas aeruginosa
What can be done to prolong the action of Penicillan G?
- Higher doses above the MIC
- Combine with probenecid (a uricosuric drug) (the excretion of penicillin takes place in the acid secretory system in the proximal convoluted tubule of the kidney, prebenecid (an acid) competes with this route and delays the excretion of penicillan)
- Depot formulation via intramuscular injection
* Anionic form (COO-) forms weak water-soluble
salts with compounds that contain positively
charged amino groups (procaine)
– Release of penicillin G from this depot
formulation → a longer time period
* Inflammation → ↑ Penetration into CSF and
synovial fluid
What are the limitations of penicillin G?
- Narrow spectrum antibiotic
- Acid labile
- β-lactamase sensitive
What are the side effects of penicillin G?
- Antibodies formed → hypersensitivity reactions
(skin rashes → anaphylactic shock) → 5 – 10%
occurrence - Cross-hypersensitivity between all penicillins
- Very high concentrations → administered rapidly via IV or intrathecal injections → neurotoxic effects e.g. convulsions
What are the side effects of β-Lactamase resistant antibiotics?
- As for penicillin G
- Cloxacillin not many side effects, well tolerated
- Mild GIT disturbances & hypersensitivity effects
- Neutropenia & agranulocytosis described
- Flucloxacillin → cholestatic hepatitis
What are the side effects of Extended-spectrum β-lactam antibiotics?
- Superinfections are possible especially by Candida and Clostridium difficile (Antibiotic associated colitis – especially ampicillin)
- Rashes (toxin) rather than allergic reaction
- Reduce efficacy of combined oral contraceptive
- GIT effects
- Infectious mononucleosis (amoxicillin)
What effect does Ampicillin have on the GIT?
Weak oral absorption ampicillin → more destruction of the microflora in the gastrointestinal tract (causes diarrhea)
What are the side effects of Co-amoxiclav (Augmentin®)?
- Gastrointestinal discomfort, diarrhea, nausea and vomiting → high dosages
- Hepatitis and cholestatic jaundice → clavulanic
acid - Amoxicillin and clavulanic acid must also be used with caution during lactation → excreted in
mothers milk
What are the side effects of Piperacillin?
- Same as penicillin G
- Potential → bleeding diathesis
What caution must be taken with aminoglycosides and penicillins?
Do not combine probenicid in same infusion, syringe or IV line
What are the drug interactions of extended spectrum penicillins?
– Allopuranol (skin rash)
– Combined oral contraceptive pill
What general cautions are associated with penicillins?
- Elderly
- Neonates (extended dose intervals)
- C/I when allergic
- Flucloxacillin - porphyria
What are Cephalosporins?
Broad-spectrum semi-synthetic antibiotics
Contain a β-lactam ring → cross-hypersensitivity
reactions may occur with penicillins
What is an advantage of Cephalosporins over penicillins?
Inherent greater stability against -lactamases as
compared to the penicillins
What bacteria are resistant to all cephalosporins?
Enterococci are resistant to all cephalosporins
What drugs are in the 1st generation of Cephalosporins and what are their uses?
- 1 st generation: Cefalexin, Cefazolin, Cefadroxil
Uses: Streptococci, Staphylococci
What drugs are in the 2nd generation of Cephalosporins and what are their uses?
2nd generation: Cefuroxime, Cefprozil, Cefamandole, Cefoxitin
Uses: Streptococci, Staphylococci, E. coli, Klebsiella, Proteus, H. influenzae,
Enterobacter
What drugs are in the 3rd generation of Cephalosporins and what are their uses?
3rd generation: Cefotaxime, Ceftriaxone, Cefixime, Ceftazidime, Cefpodoxime
Uses: Gram pos. + H. influenzae, N.
gonorrhoeae, Salmonella spp,
some active against P.
aeruginosa
What drugs are in the 4th generation of Cephalosporins and what are their uses?
4th generation: Cefepime, Cefpirome
Uses: As for 3rd generation (Gram
pos. + Gram neg.) especially P. aeruginosa
What drugs are in the 5th generation of Cephalosporins and what are their uses?
5th generation: Ceftaroline
Uses: MRSA+MR S. Epidermidis + Gram
Neg organisms
What causes bacterial resistance to cephalosporins?
- Bacteria become impermeable to drug
- Alterations in PBS
- Autolysins cannot be activated
- β-Lactamase (cephalosporinases) sensitive
How is Ceftriaxone eliminated?
40% hepatic elimination
How are cephalosporins excreted?
Excreted mainly via glomerular filtration
and tubular secretion (can use probenecid to
increase t1/2 except ceftriaxone)
How is Ceftaroline fosamil metabolised?
metabolised by plasma phosphatases
What is the general rule for 1st generation cephalosporins?
First generation is most effective against Gram pos. organisms
What is the general rule for 4th generation cephalosporins?
Fourth generation is similar to 1st generation & effective against Gram neg. Organisms
What is the general rule for 5th generation cephalosporins?
Fifth generation active against MRSA and MR S.
Epidermidis + Gram neg. Organisms
What are the side effects of cephalosporins?
- Hypersensitivity reactions e.g.
– anaphylactic shock, fever, skin rashes, nephritis, granulocytopenia and hemolytic anemia - Chemical structure differs enough from penicillins → some people can tolerate them
- The occurrence of cross-hypersensitivity → 2%
- Some can also cause alcohol intolerance
(cefamandole) - Effectiveness of oral contraception ↓
- Nephrotoxicity, especially when administered with aminoglycosides or vancomycin
- Phlebitis can occur (IV)
- Neurotoxicity at high doses or renal impairment
What are the drug interaction of cephalosporins?
- Alcohol (cefamandole)
- Warfarin
- NSAIDs
- Combined oral contraceptive pills
- Probenecid
- Cephalosporins & aminoglycosides in same
container may chemically inactivate each other - Ceftriaxone – Not to be administered at same time as Ca2+- containing solutions (>48 h)
What are the cautions associated with cephalosporins?
Anaphylactic shock (penicillins)
Allergy
Ceftiaxone CI in hyperbilirubinaemic neonates
(prematures)
What drugs are Carbapenems?
Imipenem + cilastatin, Meropenem, Ertapenem
What is the spectrum of Ertapenem?
narrower spectrum, single daily
dosing, IV & IM
What is the MOA of carbapenems?
Bactericidal, same as penicillins
What is the spectrum of carbapenems?
Very broad spectrum (Gram pos., Gram
neg. & anaerobic bacteria)
What do carbapenems not work against?
Not active against methicillin-resistant
staphylococci
What are the clinical uses for Imipenem?
Severe nosocomial infections
(septicaemia, endocarditis, lower respiratory tract, genitourinary tract, intra-abdominal, bone & joint, skin & soft tissue)
What are the clinical uses for Meropenem?
Alternative treatment for bacterial
meningitis (good penetration into CSF)
How are carbapenems administrated?
Mostly IV
How are carbapenems eliminated?
Kidneys
What are the side effects of carbapenems?
- Similar to other β-lactams (hypersensitivity
reactions, GIT effects, haematological
abnormalities, CNS effects (seizures at high
dosages of imipenem)), ↑ liver enzymes, ↑ serum
creatinine & blood urea - Red discolouration of urine in children (Imipenem)
- IV: pain, erythema & thrombophlebitis
What are the cautions of carbapenems?
- Allergy
- CNS disorders/seizures
- Renal impairment
What drug is a monobactum?
Aztreonam
What is the MOA of Aztreonam?
Bactericidal, same as penicillins
What is the spectrum of aztreonam?
Good activity against aerobic Gram neg.
bacteria only (E. coli, P. aeruginosa, Enterobacter,
Citrobacter, Proteus mirabilis, H. influenzae)
Is aztreonam cross sensitive to other penicillans or cephalosporins?
No. Can use in pts with penicillin allergy
How is aztreonam eliminated?
Kidneys, unchanged
What are the side effects of aztreonam?
- Injection site reactions
- Rash
- Rarely toxic epidermal necrolysis
- Gastrointestinal side effects
- Drug-induced eosinophilia
When is vancomycin indicated?
Reserve antibiotic used for the treatment of life threatening infections
What is the spectrum of vancomycin?
– Gram pos bacteria only
– Use restricted to cloxacillin-resistant staphylococci
& penicillin-resistant enterococci
– Alternative agent for prophylaxis &
treatment of endocarditis (penicillin-allergic
patients)
– Gastrointestinal tract infections
(pseudomembranous colitis) → Clostridium
difficile
– No cross-resistance with other antibiotics
What is the MOA of vancomycin?
Bactericidal
* Inhibits cell wall synthesis → attaching to the D-
alanine-D-alanine end of a peptidoglycan
pentapeptide
* Transglycosylation is inhibited → peptidoglycan
cross-linkages do not form
* Result → weakened bacterial cell wall → lyses of the bacterium
How is vancomycin administered?
IV or orally for pseudomembranous collitis
What are the side effects of vancomycin?
- Fever and skin rashes
- Administered too rapidly → release of
histamine → blushing of the neck and face
known as “red-man-syndrome” - Ototoxic and nephrotoxic (rare)
- Nephrotoxic in geriatric patients
- Therapeutic drug monitoring essential (elderly,
children, impaired renal function)
What are the DI of vancomycin?
Ototoxic and nephrotoxic drugs (e.g. aminoglycosides
What are the cautions of vancomycin?
- Renal Impairment
- Elderly patients
- Neonates/young infants
- Hearing abnormalities
- Pregnancy
What drug is similar to vancomycin? (same MOA, indications)
Teicoplanin
What are the side effects of Teicoplanin?
Same as vancomycin, lower
incidence of “red man” syndrome, allergy
(cross sensitivity with vancomycin)
What is the spectrum of fosfomycin?
Broad spectrum
What is the MOA of fosfomycin?
- Interferes with formation of N-acetylmuramic
acid - Inhibits early stage in bacterial cell wall
synthesis - Bactericidal
What causes resistance to fosfomycin?
inadequate transport of drug into cell
What is the spectrum of fosfomycin?
Gram pos. and neg., synergism with β-
lactams, aminoglycosides or quinolones
Pharmacokinetics of fosfomycin
– Oral → absorption delayed by food (take 2 hrs before
meal)
– Plasma half life ~ 4 h
– Fosfomycin trometamol → prodrug → levels in urine (30
– 60%)
– Excreted in breast milk
– Excreted in urine → Therapeutic levels (1-3 days)
What are the uses of fosfomycin?
- Single-dose therapy for acute uncomplicated
lower urinary tract infections (sensitive E. Coli)
→ woman and female children > 5 years - Prophylaxis in diagnostic and surgical
transurethal procedures in adult men
What are the side effects of fosfomycin?
GIT disturbances, skin rashes
What are the drug interactions of fosfomycin?
Metoclopramide → ↓ serum & urinary
concentrations of fosfomycin (avoid)
What are the cautions for fosfomycin?
1.C/I in renal failure
2.Caution → pregnancy & lactation
