3. Major divisions of bacteria-Gram + and –
Reflect the important differences in the structure of their cell
wall for action of many antibiotics
Gram positive cell wall
Simple in structure (15-50nm thick)
Has peptidoglycan (50%), acidic polymer (40-45%)-makes the
wall polar with negative charge and ‘protein and
polysaccharides’ (5-10%)
The polymer favors penetration of ionized molecules and
positively charged molecules eg streptomycin
4.
5.
6. Gram negative cell wall
Is much more complex. It comprises of
Periplasmic space-contains enzymes and other components
Peptidoglycan layer (2nm, 5%). Linked to outwardly projecting
lipoprotein molecules
Outer membrane-has lipid bilayer that contains protein
molecules (outside) and lipoprotein (inside) linked to
peptidoglycan layer. Other proteins form water filled trans
membrane channels (porins) through which hydrophilic
antibiotics can move freely.
7. Complex polysaccharides-forms important components of the
outer surface. They differ between bacteria and responsible for
their antigenicity. They are the source of endotoxin which
activates the complement system in inflammation.
Difficulty in penetrating this complex is the reason why some
antibiotics are ineffective against gram negative bacteria. Eg P.
Auroginosa has extraordinary resistance against antibiotics
The wall also hinders penetration of benzylpenicillin, fucidic
acid, bacitracin, vancomycin, meticilin, novobiocin and
rifampicin
13. PENICILLINS
They are effective and widely used antibiotics
However they can be destroyed by bacterial amidases and
beta-lactamases.
Penicillins combined with other antibiotics remain
crucially important in antibacterial chemotherapy.
14. Mechanism of action
Work by interfering with synthesis of bacterial wall
peptidoglycan
After attaching to the penicillin binding protein on the
bacteria they inhibit transpeptidation enzymes which cross-
link peptide chain attached to peptidoglycan backbone.
Final bactericidal effect is due to inactivation of inhibitor
of autolytic enzymes in the cell wall.
This leads to lysis of the bacterium.
15.
16. Types of penicillins and their action
Naturally occurring penicillins-benzylpenicillin (PG) and its
congener including phenoxymethylpenicillin (PV). PG is the
choice for many infections. Its disadvantages are poor absorption
through the gut and its susceptibility to lactamases.
Semisynthetic penicillin-They have side chains attached to
penicillin nucleus. They include beta-lactamase resistant
penicillin eg meticillin, temocillin, flucloxacillin
Broad spectrum penicillin-eg. Ampicillin and amoxicillin
17. Extended spectrum penicillin-example ticarcillin and
piperacillin which have antipseudomonal activity.
Amoxicillin and ticarcillin are sometimes given in
combination with beta-lactamase inhibitor as clavulanic
acid.
18. Pharmacokinetics
Absorption varies depending on stability in acidic environment
and adsorption on the food substances.
Parenteral preparations are also available
They have wide distribution in tissues. They reach the joints,
pleural and pericardial cavities, saliva, milk and across the
placenta. They cross BBB when the meninges are inflamed eg in
meningitis
Elimination is mainly by kidneys through secretion
20. Unwanted side effects
The main unwanted effects are hypersensitivity reactions caused by
the degradation products of penicillin, which combine with host
protein and become antigenic. Skin rashes and fever are common; a
delayed type of serum sickness occurs infrequently.
Much more serious is acute anaphylactic shock which, although rare,
may be fatal.
When given orally, penicillins, particularly the broadspectrum type,
alter the bacterial flora in the gut. This can be associated with
gastrointestinal disturbances and in some cases with suprainfection
by other, penicillin insensitive, microorganisms leading to problems
such as pseudomembranous colitis (caused by C. difficile
21. CEPHALOSPORINS AND CEPHAMYCINS
Cephalosporins N and C, which are chemically related to
penicillin, and cephalosporin P, a steroidal antibiotic that
resembles fusidic acid, were first isolated from
Cephalosporium fungus.
Cephamycins are beta-lactam antibiotics produced by
Streptomyces and are closely related to cephalosporins
They have similar mechanism of action as penicillin.
Semi-synthetic broad spectrum cepharosporins have been
produced by addition of side chains to cepharosporin c nucleus.
22. Original members of the group such as cefradine, cefalexin and
cefadroxil have largely been replaced with ‘second-generation’ drugs
such as cefuroxime and cefaclor, or ‘third-generation’ drugs such as
cefotaxime, ceftazidime, cefixime, cefpodoxime and ceftriaxone.
Resistance to this group of drugs has increased because of plasmid-
encoded or chromosomal beta-lactamase.
Nearly all Gram-negative bacteria have a chromosomal gene coding
for a beta-lactamase that is more active in hydrolyzing cephalosporins
than penicillins
Resistance also occurs when there is decreased penetration of the
drug as a result of alterations to outer membrane proteins, or
mutations of the binding-site proteins.
23. Pharmacokinetics
Some cephalosporins may be given orally, but most are given parenterally,
intramuscularly (which may be painful) or intravenously. After absorption, they are
widely distributed in the body and some, such as cefotaxime, cefuroxime and
ceftriaxone, cross the blood–brain barrier. Excretion is mostly via the kidney, largely
by tubular secretion, but 40% of ceftriaxone is eliminated in the bile.
Side effects
Hypersensitivity reactions, very similar to those seen with penicillin, may occur,
and there may be some cross sensitivity; about 10% of penicillin-sensitive
individuals will have allergic reactions to cephalosporins.
Nephrotoxicity has been reported (especially with cefradine), as has drug-induced
alcohol intolerance. Diarrhoea is common and can be due to C. difficile
25. Other beta-lactam antibiotics
They were produced to deal with beta-lactamase producing
microorganisms resistant to penicillins.
Carbapenems-imepenem is an example. Has very broad
spectrum of action and acts the same way as the b-lactams.
Active against many aerobic and anaerobic G-and G+
organisms. However, many of the meticillin-resistant’
staphylococci are less susceptible, and resistant strains of P.
aeruginosa have emerged during therapy. Other drugs in the
grou are meropenem and etarpenem.
26. Monobactams-The main monobactam is aztreonam which is resistant
to most b-lactamases. It is given by injection.
Aztreonam has an unusual spectrum of activity and is effective only
against Gram negative aerobic bacilli such as pseudomonads,
Neisseria meningitidis and Haemophilus influenzae. It has no action
against Gram-positive organisms or anaerobes.
Unwanted effects are, in general, similar to those of other b-lactam
antibiotics, but this agent does not necessarily cross-react
immunologically with penicillin and its products, and so does not
usually cause allergic reactions in penicillin-sensitive individuals.
27. Glycopeptides. Vancomycin is a glycopeptide antibiotic, and
teicoplanin is similar but longer lasting. Vancomycin acts by inhibiting
cell wall synthesis It is effective mainly against Gram-positive
bacteria and has been used against MRSA. Vancomycin is not
absorbed from the gut and is only given by the oral route for
treatment of gastrointestinal infection with C. difficile. For parenteral
use, it is given intravenously.
The clinical use of vancomycin is limited mainly to
pseudomembranous colitis (a clostridial infection sometimes
associated with antibiotic therapy) and the treatment of some
multiresistant staphylococcal infections. It is also valuable in severe
staphylococcal infections in patients allergic to both penicillins and
cephalosporins, and in some forms of endocarditis.
28. Unwanted effects include fever, rashes and local phlebitis
at the site of injection. Ototoxicity and nephrotoxicity can
occur, and hypersensitivity reactions are occasionally seen.
Daptomycin is a new lipopeptide antibacterial with a
similar spectrum of actions to vancomycin. It is usually
used, in combination with other drugs, for the treatment
of MRSA.
30. SULFONAMIDES
Their discovery dates back to 1930s
Discovered from prontosil (prodrug) which was metabolized to
sulfanilamide (active product)
Since then many sulfonamides were developed but most lost
their usefulness due to resistance.
The remaining commonly used are sulfamethoxazole (usually
combined with trimethoprim as co-trimoxazole), sulfasalazine
and sulfadiazine.
31. Mechanism of action
Sulfanilamide is a structural analogue of p-aminobenzoic acid
(PABA) which is the precursor for synthesis of folic acid needed
for DNA and RNA synthesis in bacteria.
Sulfonamides compete with PABA for the enzyme
dihydropteroate synthetase. Increasing [PABA] overcomes the
effect of sulfonamides.
PABA esters used as local anaesthetics (eg. Procaine)
antagonize the effect of sulfonamides
32.
33.
34. Sulfonamides are in action bacteriostatic
Their action is lost in pus and products of tissue breakdown due
to presence of thymidine and purine which are directly utilized
by bacteria to form DNA and RNA
Resistance to drug is plasmid mediated resulting in forming
enzymes insensitive to the drug
35. Pharmacokinetics
They have good oral absorption except for sulfasalazine
Have risk of sensitization or allergic reaction when given
topically
Metabolized in the liver to form acetylated product (inactive)
Have wide distribution in the body. Can cross inflammatory
exudates, BBB and placenta.
36. Unwanted side effects
Serious side effects which necessitate stopping the drug are
hepatitis, hypersensitivity reactions (SJS, TEN, fever,
anaphylactoid reactions), bone marrow depression and AKI due
to IN or crystalluria.
Mild to moderate side effects include nausea, vomiting,
headache and mental depression
37. Clinical uses
Co-trimoxazole for P. Carinii
Combined with pyrimethamine for drug resistant malaria and
toxoplasmosis.
Sulfasalazine for IBD (sulfapyridine and aminosalicylate comb)
Silver sulfadiazine for infected burn
Sexually transmitted infections (trachoma, chancroid and
chlamydia)
Rarely used for RTI and UTI
38. TRIMETHOPRIM
Mechanism of action
Is related to anti-malaria pyrimethamine both being folate
antagonists.
It resembles pteridine moiety of folate and therefore inhibiting
dihydrofolate reductase. Bacterial enzyme is highly sensitive to
trimethoprim than the equivalent human enzyme.
It is bacteriostatic and is active against many bacteria and
protozoa.
Usually combined with sulfonamides for potentiation of activity
39.
40.
41. Pharmacokinetics
Is well absorbed from the GIT and widely distributed in tissues
in body fluids
Reaches high concentration in lungs, kidney and CSF
Is a weak base hence elimination increased in low urine PH.
44. TETRACYCLINES
Is the broad acting antibiotic
The group includes tetracycline, demeclocycline, minocycline,
doxycycline, oxytetracycline, tigelcycline
They are taken by active transport by susceptible bacteria
They are bacteriostatic by inhibiting formation of proteins
45.
46. Antibacteria spectrum
Have very wide antimicrobial activity. They act against
gram+, gram-, mycoplasma, rickettsia, chlamydia, protozoa
(amoeba). Minocycline is active against N-meningitides
Their usefulness has been decreased by development of
resistance transmitted through plasmids
47. Pharmacokinetics
Are given orally, but can also be given parenterally
Minocycline and doxycycline are virtually completely absorbed
Absorption of others is irregular and incomplete. It is improved
by food
Tetracycline chelates with metals (aluminum, calcium, iron and
magnesium) to form non-absorbable complexes.
Hence their absorption is decreased when taken with milk, iron
preparations and some antacids.
48. Clinical uses
Chlamydia, rickettsial, lyme, anthrax and brucellosis
Second choice for leptospira and mycoplasma
RTI eg. Exacerbation of chronic bronchitis and community
acquired pneumonia
Acne
Demeclocycline has activity against ISADH
Doxycycline can be used in renal impairment due to its once
daily dosing
49. Unwanted side effects
Commonest is GIT disturbance due to direct irritation and later by
modification of gut flora.
Vitamin B complex deficiency
Dental hypoplasia and bone deformity. Also staining. Should not be
given to pregnant and breasting women as well as children.
Demeclocycline-phototoxicity, minocycline-vestibular disturbance
High dose-reduced protein synthesis to cause renal damage
Long term use may lead to bone marrow disturbance.
50. AMPHENICOLS
Principal agent in the group is chloramphenicol
It inhibits protein synthesis by binding to 50s ribosome
Has wide spectrum of activity (G+, G-, Rickettsiae)
Mostly bacteriostatic, but kills H-influenza
Resistance is to due to formation of chloramphenicol
acetyltransferase which is plasmid mediated.
51.
52. Pharmacokinetics
Is rapidly and completely absorbed in the GIT
Reaches peak plasma concentration in 2 hours
Widely distributed in tissues in the CSF
10% excreted in the kidneys unchanged, the rest
deactivated in the liver.
53. Clinical uses
Reserved for serious infections due to its serious adverse
effects. The infections include H-influenza resistant to other
drugs, meningitis in whom penicillin can be used etc
Topically for bacterial conjunctivitis. Is safe and effective
For typhoid fever.
54. Side effects
Pancytopenia due to bone marrow depression (most
important and unwanted side effect)
Should be used with great care in newborns closely
monitoring plasma concentration (fear of grey-baby
syndrome)
hypersensitivity
GIT disturbance
55. AMINOGLYCOSIDES
They have a complex chemical structure.
Include gentamycin, amikacin, tobramycin, streptomycin
They are similar in properties and toxicity
Penetration into the cell is by the oxygen dependent active
transport by a polyamine carrier system.
Have minimal action against anaerobes
It is bactericidal and its activity is enhanced by agents
which interfere with cell wall synthesis
57. Resistance
Is mainly due to formation of inactivating microbial enzymes.
Sometimes resistance is due to failure of penetration which is
overcome by concomitant use of penicillins
Antibacterial spectrum
Active against most aerobic G- and some G+. Mostly used for
enteric G- organisms and in sepsis. May be given with penicillin
in streptococcal infections as well as Listeria and P.Aeruginosa
Amikacin has the widest antimicrobial activity.
58. Pharmacokinetics
They are highly polar and only given IM or IV
Can cross placenta but cannot cross the BBB
More than 50% excreted unchanged by kidneys hence rapid
accumulation to toxic level in renal impairment situations
59. Side effects
Serious, dose related toxic effects, include ototoxicity and
nephrotoxicity.
Ototoxicity is due to progressive damage and eventually destruction of
sensory cells in the cochlea especially for neomycin and amikacin
(auditory disturbance and deafness) and vestibular, especially for
gentamycin and streptomycin (ataxia, vertigo and loss of balance)
Ototoxicity is potentiated by simultaneous use of other ototoxic agents
such as loop diurets
Nephrotoxicity is due to damage of the tubules and is reversible upon
stopping the drug.
Rare but serious side effect is paralysis due to neuromuscular block.
Occurs especially when administered together with neuromuscular
blocking agent
60. MACROLIDES
The main macrolide and related antibiotics are
erythromycin, clarithromycin and azithromycin. Spiramycin
and telithromycin are of minor utility.
They inhibit protein synthesis by effecting translocation
They bind to the 50S ribosome
61.
62. Antimicrobial spectrum
Erythromycin-spectrum like that of penicillin and hence used
as alternative in sensitive patients. Is active against G+ and
spirochaetes but not G- with few exceptions. Resistance develops
due to alteration of erythromycin binding site controlled by
plasmid.
Azithromycin is less active against G+ but more active against
legionella, H-influenza and toxoplasma gondii.
Clarithromycin is also active against H-influenza, MAI, leprosy
and H-Pylori.
63. Pharmacokinetics
They are given orally. Erythromycin can be given IV
Diffuse readily in tissues except for BBB and have poor
penetration into the synovial fluid
They enter and get concentrated in phagocytes.
Erythromycin is partly inactivated in the liver, azithromycin
resist inactivation and clarithromycin is converted to active
metabolites.
They inhibit P450 increasing availability of some drugs such as
theophylline
Main route of excretion is bile
64. Unwanted side effects
Gastrointestinal disturbance
With erythromycin, the following have also been reported:
Hypersensitivity reactions such as rashes and fever,
transient hearing disturbances and, rarely, following
treatment for longer than 2 weeks, cholestatic jaundice.
Opportunistic infections of the gastrointestinal tract or
vagina can occur.
66. QUINOLONES
Include broad spectrum agents; ciprofloxacin, levofloxacin,
ofloxacin, norfloxacin and moxifloxacin as well as a narrow-
spectrum drug used in urinary tract infections—nalidixic
acid.
These agents inhibit topoisomerase II (a bacterial DNA
gyrase), the enzyme that produces a negative supercoil in
DNA and thus permits transcription or replication
67.
68. Antibacterial spectrum and clinical use
The fluoroquinolone ciprofloxacin is the most commonly used and typical of
the group
It is a broad-spectrum antibiotic, effective against both Gram-positive and
Gram-negative organisms, and also against the Enterobacteriaceae (the
enteric Gram-negative bacilli), including many organisms resistant to
penicillins, cephalosporins and aminoglycosides.
And also against H. influenzae, penicillinase-producing N. gonorrhoeae,
Campylobacter spp. and pseudomonads.
Of the Gram-positive organisms, streptococci and pneumococci are only
weakly inhibited, and there is a high incidence of staphylococcal resistance.
Ciprofloxacin should be avoided in MRSA infections.
69. Clinically, the fluoroquinolones are best reserved for infections with
facultative and aerobic Gram-negative bacilli and cocci.
Resistant strains of S. aureus and P. aeruginosa have emerged
Clinical use
Norfloxacin and ofloxacin- for complicated UTI and gonorrhoea
P. aeruginosa respiratory infection in patients with cystic fibrosis
Invasive external otitis due to P. aeruginosa
Eradication of salmonella typhi
Cervicitis (ofloxacin) and prostatitis (norfloxacin)
70. Pharmacokinetics
Well absorbed orally
Accumulate in certain tissues; kidney, lungs and prostate
All quinolones are concentrated in phagocytes. Most fail to cross the
blood–brain barrier, but ofloxacin does so.
Aluminium and magnesium antacids interfere with the absorption of
the quinolones.
Elimination of ciprofloxacin and norfloxacin is partly by hepatic
metabolism by P450 enzymes (which they can inhibit, giving rise to
interactions with other drugs) and partly by renal excretion.
Ofloxacin is excreted in the urine.
71. Unwanted side effects
In hospitals, infection with C. difficile may prove hazardous but
otherwise unwanted effects are infrequent, usually mild and
reversible. The most frequent manifestations are
Gastrointestinal disorders and skin rashes.
Arthropathy has been reported in young individuals.
Central nervous system symptoms (headache and dizziness)
have occurred, as have, less frequently, convulsions associated
with central nervous system pathology or concurrent use of
theophylline or a non-steroidal anti-inflammatory drug.
73. Metronidazole
It was introduced as antiprotozoa
It is also active against anaerobic bacteria such as
bacteroides and clostridia species and some streptococci
It is effective in the treatment of pseudomembranous
colitis and serious anaerobic infection
It has disulfiram like action and so should not be taken
with alcohol.
74.
75. Streptogramins
Quinupristin and dalfopristin are cyclic peptides,
They inhibit protein synthesis by binding to 50S ribosome
For most effect they are used in combination and are active against most gram
positive bacteria
Dalfopristin changes the structure of ribosome facilitating binding of quinupristin.
Used in the treatment of serious bacterial infection where no other antibiotic is
suitable.
They are active against MRSA and vancomycin resistant enterococcus faeceum.
Must be given IV due to high fast pass effect.
Unwanted side effects include anthragia, myagia, nausea, vomiting and diarrhea
Resistance against streptogramins does not seem to be a problem
76.
77.
78. Clindamycin
Is the lincosamide active against gram positive cocci including
penicillin resistant staphylococcus and many anaerobes such as
bacteriodes.
It is used in treatment of staphylococcal infection in bones and
joints
Also given topically for staphylococcal conjunctivitis
Acts in the same way as chloramphenicol and macrolides
Unwanted side effects include GI disturbance and
pseudomembranous colitis due C.dificile (treated by
metronidazole and vancomycin)
79.
80. Oxazolidinones
It is the true new antibacterial by the novel MOA
It acts by inhibiting protein synthesis by inhibiting binding of
N-formylmethionyl-tRNA to 70S ribosome.
Linezolid is the first member of this class and is active against
many gram positive bacteria and particularly important in
treatment of MRSA, penicillin resistant streptococcus
pneumonia and vancomycin resistant enterococci.
Most gram negative organisms are not susceptible
Unwanted effects include thrombocytopenia, diarrhoea, nausea
and, rarely, rash and dizziness.
Linezolid is a non-selective inhibitor of monoamine oxidase,
and appropriate precautions need to be observed
81.
82.
83. Fusidic acid
Is a narrow spectrum steroid antibiotic active mainly against
gram positive bacteria.
Is well absorbed in the gut and widely distributed in tissues.
Some is excreted in bile and some is metabolized
Can be combined with other antistaphylococcal agents against
sepsis and topical infections eg. Eyes
Unwanted effects such as gastrointestinal disturbances are
fairly common. Skin eruptions and jaundice can occur.
Resistance occurs if it is used systemically as a single agent.
84.
85. Nitrofurantoin
Is synthetic and active against a range of G+ and G-s
Development of resistance and cross-resistance is rare
Unknown mechanism of action and its rapidly and completely
absorbed from the gut.
Is rapidly excreted by the kidneys. Its use is confined to
treatment of UTI
Unwanted effects such as gastrointestinal disturbances are
relatively common, and hypersensitivity reactions involving the
skin and the bone marrow (e.g. leukopenia) can occur.
Hepatotoxicity and peripheral neuropathy have also been
reported.
86.
87.
88. Polymixins
Polymixin antibiotics in use are polymixin B and colistin (polymixin
E).
They have cationic detergent properties and exert their antibacterial
action by disrupting the outer cell membrane
They have a selective, rapidly bactericidal action on Gram-negative
bacilli, especially pseudomonads and coliform organisms. They are not
absorbed from the gastrointestinal tract. Clinical use of these drugs is
limited by their toxicity and is confined largely to gut sterilization and
topical treatment of ear, eye or skin infections caused by susceptible
organisms.
Unwanted effects may be serious and include neurotoxicity and
nephrotoxicity
