4. Intended learning outcomes
● Describe major classifications of antibacterial drugs
● Understand main mechanisms of bacterial drug
resistance
● Classify β-Lactams antibiotics based on their spectrum
of activity
● Describe mechanism of action, kinetics, mode of
resistance and major side effects of β-Lactams
● Describe mechanism of action, kinetics, mode of
resistance and major side effects of Macrolides
5. Case scenario
Mr J.W., aged 40 years, lives at home and was previously healthy. He saw his GP
in August, 5 days after returning from a conference abroad, where he had stayed in
a large hotel and indulged his passion for frequent whirlpool baths. He had
characteristic symptoms of pneumonia, including pleuritic chest pain and the
sudden development of fever and cough, producing yellow sputum. Physical
examinations and chest radiography supported the diagnosis.
1. Before the results of the microbiological test were available, what treatment would
you have commenced?
6. Definition …
Antimicrobial drugs → chemical substances (natural or synthetic) that
suppress the growth of, or kill, microorganisms (bacteria, fungi,
helminths, protozoa and viruses)
Antibacterial drugs
(Antibiotics)
7.
8. Classification …
According to their mechanisms
of action
● Inhibition of bacterial cell
wall synthesis → β-
lactams
● Increased permeability of
the bacterial cell
phospholipid membrane
● Impaired bacterial
ribosome function →
reversible inhibition of
protein synthesis →
macrolides
● Selective block of
bacterial metabolic
pathways
● Interference with
bacterial DNA or RNA
synthesis
9. Classification …
Bacteriostatic → inhibit bacterial growth but do not kill
the bacteria at plasma concentrations that are safe for
humans → natural immune mechanisms are required to
eliminate the bacteria.
Bacteriostatic drugs → less effective in
immunocompromised individuals or when the bacteria are
dormant and not dividing.
Bactericidal → kill bacteria at plasma concentrations
safe for humans
According to the concentration of antibiotic that can
be achieved safely in plasma without causing
significant toxicity.
11. Antimicrobial resistance …
Def .. the ability of bacteria to grow in the presence of a drug
that would normally kill them or inhibit their growth.
● Intrinsic (innate)
● Acquired resistance → due to modification of its genetic
structure (acquired resistance).
Mechanisms ..
1. Structural change in the target molecule for the
antibacterial drug
2. Production of enzymes that inactivate the
antibacterial drug
3. Decreased penetration of the antibacterial drug into
the bacterial cell
4. Acquisition of efflux pumps that actively transport the
antibacterial drug out of the bacterial cell
13. β-Lactam Antibacterials …
● Penicillins
● Cephalosporins
● Monobactams
● Carbapenems
All drugs in this class → have a β-lactam ring →
must be intact for them to be active
β-Lactam → susceptible to inactivation by
bacterial β-lactamases → split the β-lactam ring
Cephalosporins, monobactams &
carbapenems → have structural modifications →
show some resistance to β-lactamases.
14. β-Lactams Mech. of action …
1. β-lactam antibiotics → bind to penicillin-binding
proteins PBPs (transpeptidases) in bacteria, which is
required for the last step of the bacterial cell wall
synthesis (cross-linking of the peptidoglycan
layer) → inhibit transpeptidation reaction → inhibits
cell wall synthesis when bacterium divides →
exposure of the osmotically unstable cell membrane
→ bacterial cell swelling, rupture and death of the
bacterium.
2. In Gram positive bacteria → binding of β-lactam antibiotics
to other PBPs → ↑ activity of autolytic enzymes →
promotes lysis of the bacterial cell wall.
15. Bacterial resistance to β-Lactams
1. Production of β-lactamases → hydrolyse the β-lactam ring
There are hundreds of β-lactamases → produced by various
organisms
○ Methicillin sensitive Staph. aureus (MSSA) → release
extracellular β-lactamases.
○ Gram-negative bacteria → secrete β-lactamases
between the inner and outer cell membranes in the
periplasmic space.
○ Enterobacteria → release extended-spectrum β-
lactamases (ESBLs) → hydrolyse 3rd-generation
cephalosporins & monobactams
1. Mutation in PBP → PBP2A → do not bind β-lactam
antibacterials → gonococci and in meticillin-resistant S.
aureus (MRSA)
MRSA MSSA
17. b. Cephalosporins
Cephalosporins → more resistant to
hydrolysis by β-lactamases
Classified into 5 generations
As a rule …
● Successive generations → have ↑
activity against Gram-negative
bacilli.
● Moving from the 1st to 3rd
generations → ↓ Gram-positive
activity & moving from 3rd to 5th
generations → progressively ↑
Gram-positive activity again
19. c. Carbapenems & Monobactams
Monobactams (Aztreonam)
● Spectrum of activity → limited to Gram-negative bacteria, including Pseudomonas, Neisseria meningitidis , N. gonorrhoeae and H.
influenzae.
● No cross-allergenicity with the penicillins → given to people with penicillin allergy
Carapenems
● Ertapenem, imipenem, meropenem
● Extremely broad spectrum of activity → Gram-positive cocci + Gram-negative bacilli + P. aeruginosa + many anaerobic bacteria.
● Only ertapenem is inactive against Pseudomonas.
● Imipenem is rapidly hydrolysed by dihydropeptidase in the kidneys → is always given in combination with the dihydropeptidase inhibitor
cilastatin → Imipenem-Cilastin.
● Meropenem is available in combination with β-lactamase inhibitor vaborbactam
20. Pharmacokinetic
notes
Drug Route of administration Elimination
Penicillins
Narrow-Spectrum Penicillins
Penicillin G Oral or parenteral Renal (TS)
Penicillin V Oral Renal (TS)
Anti Staph penicillins
Flucloxacillin Oral or parenteral Renal (TS)
Dicloxacillin Oral Renal (TS)
Nafcillin Oral or parenteral Biliary
Broad spectrum penicillins
Amoxicillin Oral Renal (TS)
Ampicillin Oral or parenteral Renal (TS)
and biliary
Extended spectrum penicillins
Piperacillin Parenteral Renal (TS)
Drug Route of administration Elimination
Cephalosporins
1st generation
Cefazolin Parenteral Renal (TS)
Cephalexin Oral Renal (TS)
2nd generation
Cefotetan Parenteral Renal (TS)
Cefoxitin Parenteral Renal (TS)
Cefprozil Oral Renal (TS)
Cefuroxime Oral or parenteral Renal (TS)
3rd generation
Cefdinir Oral Renal (TS)
Cefotaxime Parenteral Renal (TS)
Ceftazidime Parenteral Renal (GF)
Ceftriaxone Parenteral Biliary
4th generation
Cefepime Parenteral Metabolized
5th generation
Ceftaroline Parenteral (IV) Renal (GF)
Drug Route of
administration
Elimination
Aztreonam Parenteral Metabolized
Carbapene
ms
Parenteral Renal (TS)
Vancomycin Oral or parenteral Renal (GF)
21. Side effects of β-Lactams
● GIT → Nausea, vomiting → most common with oral preparations
Diarrhoea (Clostridium difficile -related colitis) → a result
of disturbance of normal colonic flora → especially with broad-
spectrum penicillins.
● Allergic reactions → common (5% of exposed individuals).
Manifestations →
Urticaria, wheeze and anaphylaxis (IgE-
mediated reactions);
Vasculitis and serum sickness (immune
complex-mediated reactions).
Nonspecific maculopapular rash, and the rare
serious Stevens–Johnson syndrome (T-cell-
mediated allergy)
Cross-allergenicity → with cephalosporins is < 2%;
with carbapenems is < 1%;
no cross-allergenicity with monobactams.
● Aminopenicillins → frequently produce a nonallergic
maculopapular rash in people with glandular fever (infectious
mononucleosis with Epstein-Barr virus)
Not associated with other types of penicillin..
● Encephalopathy → excessively high concentrations in the CSF →
occurs in severe renal failure or after mistaken intrathecal injection
● Cholestatic jaundice → flucloxacillin or clavulanic acid
Penicillins
Safest
of
all
antibiotics.
● GIT → same as penicillins
→ more common with
cephalosporins
● Allergic reactions → A
history of IgE-mediated
reaction to penicillin (e.g.
anaphylaxis, wheeze,
urticaria) → contraindicates
use of cephalosporins.
● Allergic reactions
● Neurotoxicity
with seizures, →
more common
with imipenem
Cephalosporins
Carbapenems
22. Vancomycin
Mech. of action → it binds to the terminal D-Ala-D-Ala portion of
pentapeptide side chain → block transpeptidation and inhibit cross-linking
of peptidoglycan → interfere with cell wall synthesis
Spectrum → narrow spectrum → only against Gram-positive bacteria,
particularly MRSA.
Uses → usually reserved for
● Ttt of serious Gram-positive bacterial infection
● Ttt of bacterial endocarditis not responding to other treatments.
● Ttt of C. difficile colitis → given orally
23. Side effects of vancomycin …
● Nephrotoxicity → ↑ if used in combination with other nephrotoxic drugs
(aminoglycosides).
● Thrombophlebitis at the site of i.v infusion.
● Rapid i.v injection or infusion of vancomycin → histamine release → ↓ BP,
wheezing, urticaria, upper body flushing & itching → the ‘red man’ syndrome.
● Ototoxicity → uncommon → usually starts with tinnitus.
Therapeutic monitoring of the trough plasma concentrations of vancomycin and
dose adjustment → ↓ risk of toxic effects.
Not absorbed orally → given by i.v infusion
25. Macrolides
Erythromycin, clarithromycin, azithromycin
Mech. of action → bind reversibly to the 50S
subunit of the bacterial ribosome → inhibit
peptidyl transferase & block translocation of
the aminoacyl-tRNA from the A site to the P site
→ preventing elongation of the polypeptide
chain → interfere with bacterial protein synthesis
26.
27. Macrolides → spectrum of activity
● Erythromycin → has a similar spectrum of activity to amoxicillin + Legionella + atypicals
(Mycoplasma, Chlamydia, Campylobacter and Bordetella pertussis).
Used to treat infections in people who are allergic to β-lactams.
● Clarithromycin & Azithromycin > erythromycin → ↑ activity against H. influenzae &
mycobacterium avium
● Clarithromycin → part of the multidrug treatment of H. pylori
28. Macrolides → side effects
● GIT → common → Epigastric discomfort, nausea, vomiting and diarrhoea
→ erythromycin.
● Rashes.
● Cholestatic jaundice → with erythromycin estolate → if treatment is continued
> 2 week.
● Prolongation of the Q –T interval → predispose to ventricular arrhythmias.
● Drug interactions → erythromycin and clarithromycin inhibit P450 drug-
metabolising enzymes (CYP3A4, CYP2D6) → ↑ plasma concentration of other
drugs metabolised by these enzymes, including warfarin, carbamazepine,
cyclosporine and simvastatin.
● CI →
a. Patients with hepatic dysfunction → these drugs accumulate in the liver
→ esp. Erythromycin & azithromycin
b. Patients with proarrhythmic conditions or concomitant use of
proarrhythmic agents.
30. Case scenario
Mr J.W., aged 40 years, lives at home and was previously healthy. He saw his GP
in August, 5 days after returning from a conference abroad, where he had stayed in
a large hotel and indulged his passion for frequent whirlpool baths. He had
characteristic symptoms of pneumonia, including pleuritic chest pain and the
sudden development of fever and cough, producing yellow sputum. Physical
examinations and chest radiography supported the diagnosis.
1. Before the results of the microbiological test were available, what treatment would
you have commenced?
31. Selection of an antibiotic for the treatment of a particular infection is largely based on …
1. Host factors → pregnancy, drug allergies, age and immune status, and the presence of renal
impairment, hepatic insufficiency, abscesses, or indwelling catheters and similar devices.
2. Drug factors
○ Antimicrobial spectrum of activity →
■ Based on laboratory tests (microbial culture and sensitivity) or
■ Based on knowledge of the most common organisms causing various types of
infections and the preferred drugs for these organisms (empiric selection) → may be
used to treat serious infections until lab test results are available or to treat minor upper
respiratory and urinary tract infections
○ Pharmacokinetic Properties → oral bioavailability, peak serum concentration, distribution to
particular sites of infection, routes of elimination, and t1/2.
○ Adverse Effect Profile
32. Answer …
The most common cause of community-acquired pneumonia is S. pneumoniae, but
other ‘atypical’ organisms could be involved.
In Mr J.W., who was previously well, a recent stay in a hotel abroad might indicate
the involvement of Legionella species, which multiply in warm water – for example,
in the tanks of air-conditioning systems. The incubation time is 5 to 10 days.
Co-amoxiclav (amoxicillin and clavulanic acid) plus a macrolide should be given
orally before the diagnosis is confirmed → treatment should be reviewed as soon
as the microbiology sensitivities are known.
33. True / False
1. Broad-spectrum penicillins can promote colonic infection with C. difficile.
2. Penicillins act by inhibiting peptidyl transferase activity.
3. The antipseudomonal penicillin ticarcillin is resistant to β-lactamase.
4. Cefotaxime is a third-generation cephalosporin.
5. Individuals allergic to penicillins are also allergic to cephalosporins.
6. Imipenem is rapidly metabolised in the kidney.
7. Meropenem is bacteriostatic at normal doses.
8. Erythromycin commonly causes gastrointestinal disturbances.
9. Vancomycin is active against β-lactamase-producing Gram-positive bacteria.
