Antimicrobial agents

1. ANTIMICROBIAL THERAPY
A. L. YIAILE

2. General principles of antimicrobial therapy
• Antimicrobial agents are among the most
commonly used and misused of all drugs.
• The inevitable consequence of their widespread
use has been the emergence of antibiotic-
resistant pathogens
• Reducing inappropriate antibiotic use is thought
to be the best way to control resistance.

3. • There are different microorganisms such as:
Bacteria
Viruses
Fungi
Protozoas
 Helminthes
• Antimicrobial agents act by the principle of
selective toxicity whereby they cause harm to
the invading organism with minimal harm to the
host/man.

4. ANTIBIOTICS/ANTI-INFECTIVE AGENTS
Introduction to antibiotics
• Infection is the invasion and multiplication of
microorganisms in body tissues.
• Infectious diseases comprise a wide spectrum of
illnesses caused by a wide range of bacteria.
• These antibacterial substances are derived from
fungi and bacteria e.g. penicillin from fungi.
• There are different groups of antibacterial agents
based on molecular structure.
• Members of each group have a comparable
pharmacokinetics and pharmacodynamics

5. Classification of antibiotics
• Beta-lactam antibiotics
• Tetracyclines
• Aminoglycosides
• Macrolides
• Quinolones
• Azoles
• Antimycobacterial
agents
• Sulphonamides
• Lincosamides
• Unclassified antibiotics
like chloramphenical,
Spectinomycin and
vancomycin.

6. Beta-lactam antibiotics
All are β -lactam compounds, so named because of
their unique four-membered lactam ring as a basic
chemical structure.
They are further subdivided into:
• Penicillins
• Cephalosporins
• Others e.g. carbapenenerms and monobactams

8. Penicillins
• The first antibiotics to be discovered in 1929.
They were produced by growing of the
penicillium moulds in deep tanks.
• According to the variety of fungus and the
composition of the medium, either
benzylpenicillin (penicillin G) or
phenoxymethylpenicillin (penicillin V) results.
• Different semi-synthetic penicillin’s have been
made by adding various chains to the basic
penicillin nucleus (6-aminopenicillanic acid).
• Penicillins have different anti bacterial spectrums
which are the basis for further subdivision.

9. • Natural penicillins include Penicillin G;
Procaine, Penicillin V, Benzathine.
• These antibiotics were the first agents in the
penicillin family to be introduced for clinical use.
• The natural penicillins are based on the original
penicillin-G structure.
• They are effective against gram-positive strains of
streptococci, staphylococci, and some gram-
negative bacteria such as meningococcus

10. • These have greatest activity against gram-
positive organisms, gram-negative cocci, and
non– b lactamase producing anaerobes.
• However, they have little activity against
gram-negative rods, and they are susceptible
to hydrolysis by β-lactamases.

11. Classification of penicillins
Penicillins can be classified into:
1. Narrow spectrum (natural penicillins) e.g. benzyl
penicillin, phenoxymethyl penicillin, phenethicillin.
2. Antistaphylloccoccal penicillins: these are also
called beta-lactamase resistant penicillins or
penicillinase-resistant penicillins): e.g. nafcillin,
Cloxacillin, flucloxacillin, Methicillin.
3. Broad spectrum penicillins: e.g. Ampicillin,
amoxicillin, baccampicillin, pivampicillin,
talampicillin and mezlocillin.
4. Antipseudomonal (Extended spectrum penicillin)
e.g. Carbecillin, Carfecillin, Ticarcillin, Temocillin,
Aziocillin and Piperacillin.

12. Mechanism of action
• Beta-lactam antibiotics inhibit the growth of
sensitive bacteria by inactivating enzymes located
in the bacterial cell membrane, which are
involved in the third stage of cell wall synthesis.
• Beta-lactams inhibit a family of related enzymes
involved in different aspects of cell wall synthesis.
• Beta-lactam antibiotics are generally bactericidal
against organisms that they inhibit.
• The mechanism of bacterial cell killing is an
indirect consequence of the inhibition of bacterial
cell wall synthesis.

13. Pharmacodynamics
• Penicillins inhibit cell growth by inhibiting transpeptidation
reaction of bacterial cell wall sysnthesis.
• Transpeptidation causes cross linkage of peptide chains
inhibiting synthesis of the peptidoglycan layer of cell wall
which protects the bacterial cell wall from lysis.
• The cells weak wall becomes incapable of withstanding the
osmotic gradient between its interior and its external
environment so that it swells and explodes.
• Thus penicillins are bactericidal agents effective against
multiplying bacteria (dividing cells) as resting bacteria do
not make new cell walls.
• Some bacteria can produce beta- lactamase enzyme which
opens the beta-lactam ring of penicillin and inactivates
them.

14. MECHANISMS OF BACTERIAL RESISTANCE
• Three general mechanisms of bacterial resistance
to antibiotics, including the beta-lactams, have
been well characterized:
Decreased penetration to the target site;
Alteration of the target site;
Inactivation of the antibiotic by a bacterial
enzyme

15. Pharmacokinetics
• Benzylpenicillin is destroyed by Gastric acid hence it
is parenterally administered while
Phenoxymethylpenicillin can be orally given as it
resists destruction by the gastric acid.
• Metabolism of penicillins takes place in the liver
with half life of less than 2 hours.
• They have poor lipid solubility hence they do not
cross the blood brain barrier in significant amounts.
• Distribution occurs in body fluids and tissues with a
few exceptions.
• They are polar hence extracellular concentrations
exceed the intracellular.

16. • They distribute into the cerebral spinal fluid if the
meninges are inflamed.
• Metabolism takes place in the liver and
elimination takes place mainly through the kidney
by glomerular filtration and active tubular
secretion.
• Elimination can be delayed by concurrently giving
probenecid which competes for the transport
mechanism.
• Used for example when high plasma
concentrations are required.

17. Benzyl penicillin (penicillin G):
• Penicillin G is gastric Acid unstable and is used
where high plasma concentrations are required.
• Maximum blood concentrations reached after 15
minutes of administration.
• The half life is 0.5 hours hence reasonably spaced
doses have to be large to maintain a therapeutic
concentration.
• High doses can be maintained by use of
probenecid which reduces renal secretion

18. Benzyl penicillin (penicillin G):
• It is generally active against gram positive and
gram negative cocci, hence indicated for
treatment of conditions such as: actinomycosis,
gonococcus infections, throat infection, Otitis
media, streptococcal endocarditis, meningococcal
meningitis.
• Most staphylococci are resistant to pen. G because
they produce ß - lactamase which inactivates
penicillins.

19. Cloxacillin:
• Has a half life of 30 minutes.
• It is indicated for infections due to penicillinase
producing staphylococci especially skin infections
soft tissue infections e.g. Cellulitis, otitis externa,
impetigo etc.
• The dosage: Adults- by oral 500mg Q.i.d i.e.
every 6 hrs at least 30 minutes before meals
because food decreases absorption.
• It is given by IM 250mg every 4-6 hrs, IV injection
or infusion 500mg every 4-6hrs.

20. • The dose may be increased in severe infections.
• A child less than 2yrs should get a quarter adult
doses by any of the routes.
• Children 2-10 years should receive half of the
adult dose.

21. Ampicillin:
• This is in the class of broad spectrum penicillins.
• Is gastric acid stable, it is moderately (50%) absorbed
orally as food interferes with its absorption.
• The drug is concentrated in the bile and it undergoes
entero hepatic recycling.
• Approximately 1/3 of the administered dose appears
in the urine unchanged. The half life is one hour.
• Almost all staphylococcal aureus, 50% of E. coli and
15% of haemophillus influenza are now resistant.
• Indications include urinary tract infections, Otitis
media, sinusitis, chronic bronchitis, invasive
salmonellosis and gonorrhea.

22. Side effects:
• Diarrhea quite common with ampicillins,
Macular rashes resembling measles/
rubella rashes-discontinue treatment,
nausea.
• The dosage: Adult oral 0.25 to 1gm 6
hourly at least 30min before food.
• Different doses are used in treatment of
different conditions.

23. • Gonorrhea- 2-3.5g is administered as a
single dose with probenecid.
• Urinary tract infections: 500mg every 8 hrs.
It is given by 1M or IV injection or infusion.
• Meningitis 500mg 4-6 hourly is given.
• For children under the age of 10 years give
half the adult dose by any route.

24. Amoxicillin:
• This is in the class of broad spectrum penicillins.
• It’s a derivative of ampicillin and differs by only one
hydroxyl (OH) group. Have similar antibacterial
spectrum as ampicillin.
• When given orally it is absorbed better than ampicillin.
• Absorption is not affected by the presence of food in
the stomach.
• Half life is 1 hour
• Side effects: Diarrhea is less frequent with the use of
amoxicillin than ampicillin by 12%.
• Indications: urinary tract infections, Otitis media,
sinusitis, chronic bronchitis, invasive salmonellosis and
gonorrhea.

25. The dosage:
• The adult dose by oral is 250mg every 8 hours which
can be doubled in severe infections.
• Children up to 10 years of age get 125mg 8 hourly.
• This is doubled in severe infections. In severe or
recurrent purulent respiratory infections, 3g is given
every 24 hours.
• Adults get 500mg 8 hourly by IM route while
children get 50-100 mg/kg daily in divided doses.
• If administered by IV route or infusion, adults get
500mg every 8 hrs which is increased to 1gm every 6
hrs.
• Children get 50- 100mg/kg daily in divided doses.

26. • Amoxicillin (250Mg or 500mg) can be combined
with clavulanic acid (125mg) to make
Co-amoxiclav. (Augmentin)
• Clavulanic acid itself has no significant
antibacterial activity but binds to beta lactamase
and thereby competitively inhibits its activity
hence protecting the penicillin.
• This potentiates its action against bacteria which
owe their resistance to production of beta
lactamases.

27. • Active against beta lactamase producing bacteria
that are resistant to amoxyllin, which include:
Staphylococcus aureus (most strains), 50 % of E-
coli strains, 15% if H. influenzae strains, klebsiella
spp.
• Dosage for c0-amoxclav (Augmentin) is one
tablet 8 hourly for adult. Double the dose in
severe infections.
• Child 6-12 years give 5mls every 8hrs; doubled in
severe infections.

28. ADVERSE EFFECTS OF PENICILLINS
• IgE-mediated allergic reactions ;
• Type I, IgE-mediated reactions present with
various combinations of pruritus, flushing,
urticaria, angioedema, wheezing, laryngeal
edema, hypotension, and/or anaphylaxis.

29. Serum sickness
• Serum sickness is a late allergic reaction
characterized by fever, rash (usually urticarial),
adenopathy, arthritis and occasionally
glomerulonephritis.
• It is associated with circulating immune
complexes and has been reported with all of
the beta-lactam antibiotics.

30. Dermatologic reactions
• A variety of rashes occur with the beta-lactam
antibiotics, of which morbilliform rash is the
most common.
• Erythema multiforme is an acute eruption
characterized by distinctive target lesions and
diagnostic histology
• when the mucosal surfaces are involved as well,
the reaction is termed the Stevens-Johnson
syndrome.
• Exfoliative dermatitis is a severe skin disorder
with generalized erythema and scaling.

31. Neurologic reactions
• Among the antibiotics, the penicillins are the
most common to cause encephalopathy.
• Penicillin neurotoxicity is characterized by a
change in the level of consciousness with
generalized hyper reflexia , myoclonus and
seizures.
• This syndrome occurs with high-dose penicillin
therapy, particularly if excretion is delayed by
underlying renal disease, or if pre-existing
neurologic disease is present.

32. Gastrointestinal reactions
• Diarrhea is a frequent nonspecific complication
of antibiotic therapy, especially with certain oral
antibiotics such as ampicillin or amoxicillin.

33. Hepato-biliary reactions
• The semisynthetic penicillins, such as oxacillin
and nafcillin, may cause hypersensitivity hepatitis
accompanied by fever, rash, and eosinophilia

34. Renal reactions
• Glomerulonephritis may be seen in association
with hypersensitivity angiitis or serum sickness
following administration of beta-lactam
antibiotics.
• The cephalosporin antibiotics may potentiate the
renal toxicity

35. CEPHALOSPORINS
Cephalosporins are the most frequently prescribed
class of antibiotics.
• They are structurally and pharmacologically related
to the penicillins.
• Like the penicillins, cephalosporins have a beta-
lactam ring structure that interferes with synthesis of
the bacterial cell wall and so are bactericidal.
• Cephalosporins have a wider spectrum of activity
than penicillins hence they are more expensive.
• All cephalosporins have similar antibacterial
spectrum although individual agents have differing
activity against certain organisms.

36. Classification of Cephalosporins
• Cephalosporins are grouped into "generations"
based on their spectrum of antimicrobial activity.
• The first cephalosporins were designated first
generation while later, more extended spectrum
cephalosporins were classified as second
generation cephalosporins.

37. • Each newer generation of cephalosporins has
significantly greater gram-negative antimicrobial
properties than the preceding generation, in
most cases with decreased activity against gram-
positive organisms.
• Fourth generation cephalosporins, however, have
true broad spectrum activity.
• The newer agents have much longer half-lives
resulting in the decrease of dosing frequency.

38. Classification of cephalosporins
First generations
• These are generally active against gram positive
bacteria. They have moderate activity against gram
negative organisms.
• They include:
Cephalexin
Cefadroxil
 Cefazolin
Cephaloridine
Cephalothin
Cephapirin
Cephradine

39. Second generations
They include;
• Cefaclor
• Cefuroxime
• Cefoxitin
• Cefprozil
• Cephamandole/Cefamandole
• Cefotetan
• Cefonicid
• Cefprozil
• Ceforanide
• Carbacephem

40. Second generation
• They have a greater gram-negative spectrum e.g.
H. influenza and N. gonorrhea, E. coli, Shigella.
• But also to some extent gram positive organisms
e.g. clostridium, staphylococcus, streptococcus,
pneumococcal.
• They are also more resistant to beta-lactamase.
• They are useful agents for treating upper and
lower respiratory tract infections, sinusitis and
otitis media.

41. Third generation:
• e.g. Ceftriaxone, cefixime, ceftizone, moxalactam,
cefperazone, Cefotaxime, ceftazidine, cefodizime,.
• They are generally active against gram positive
and gram negative bacteria.
• They are especially better than 2nd generation or
first generation against gram negative bacteria.
Fourth generation: e.g. cefepime and cefditoren
and loracarbef.
• These are very good against both gram positive
and gram negative bacteria.

42. Pharmacodynamics
• Cephalosporins are bactericidal agents and have
the same mode of action as other beta-lactam
antibiotics.
• All bacterial cells have a cell wall that protects
them.
• Cephalosporins disrupt the synthesis of the
peptidoglycan layer of bacterial cell walls, which
causes the walls to break down and eventually
the bacteria dies.

43. Pharmacokinetics
• Usually given parenterally, though few may be
given orally e.g. cephalexin, cephradine and
cefadroxil.
• Have wide distribution because of lipid solubility.
• They are metabolized in the liver with half life of
1-4 hours.
• They are excreted unchanged in urine especially
by tubular secretion.
• Dosage reduced for patients with renal
impairment.
• Active excretion in the kidney can be blocked by
probenecid.

44. Indications:
Resistance is occurring due to chromosomal beta
lactamase (especially gram –ve bacteria) and
mutations of binding sites proteins.
But still they are good for septicemia, pneumonia,
meningitis, biliary tract infections, peritonitis,
urinary tract infections, and sinusitis.

45. Unwanted effects:
• Most common is hypersensitivity, 10% of
patients who are sensitive to penicillin are also
sensitive to cephalosporin i.e. cross-allergy
involving about 10% of patients.
• Hemorrhage due to interference with blood
clotting factors.
• Use of cephalosporin for more than two weeks
causes thrombocytopenia, neutropenia, and
interstitial nephritis and abnormal liver function
tests.

46. Drug interactions
• Cephalosporins interact with alcohol to produce
disulfuram- like effects.
• Therefore, you need to counsel the client to avoid
taking alcohol when taking cephalosporins.
• High ceiling diuretics like furosemide and torsemide
when administered together with cephalosporins are
likely to cause nephrotoxicity.
• This same effect may be caused when used with
aminoglycosides.
• Oral anticoagulants like warfarin when administered
together with cephalosporin may cause bleeding. This
is because both interfere with clotting factors.

47. Ceftriaxone (Rocephin):
• Has longer half life than other cephalosporins hence
it will require to be administered once daily.
• It is indicated for such conditions as serious
infections e.g. septicemia, pneumonia, meningitis,
UTI, RTI, skin and soft tissue infections.
• Also used for surgical prophylaxis.
• It’s contraindicated in penicillin sensitivity
• Should be administered with caution in renal
impairment.
• Calcium ceftriaxone may appear as precipitate in
urine or as gall stones.
• Ceftriaxone is also contra-indicated in infants under 6
weeks.

48. Cefuroxime (zinacef):
• Indications are similar to those for ceftriaxone but
cefuroxime is more active against haemophilus
influenza and neisseria gonorrheae.
• More widely used. Half life1-5 hours.
• Caution and contraindication is just like
ceftriaxone.
• Dosage orally is for adults 250mg daily in most
infections e.g. RTI e.g. bronchitis.
• This is doubled in severe lower RT infections,
pneumonia, and haemophilus influenza infection.
• It’s very good against Neisseria gonorrhea-1g as a
single dose.