Principles of Antibiotic

Therapy

Definition -Antibiotic

An antibiotic is a substance produced by

various species of living microorganisms

(e.g. bacteria and fungi)

Inhibit pathogens by interfering with
intracellular processes

Term antibiotic includes synthetic
antimicrobial agents i.e. sulphonamides

Antibiotics do not kill viruses -not effective
in treating viral infections.
2

Selection of Antimicrobial Agent

Empiric therapy - prior to identification of

organism critically ill patients

Organisms susceptibility to the antibiotic

Patient factors - immune system,
renal/hepatic function

Effect of site of infection on therapy blood
brain barrier

Safety of the agent

Cost of therapy
3

Properties Influencing Frequency of

Dosing

Concentration dependent killing

antimicrobials including aminoglycosides =

significant increase in rate of bacterial killing as
the drug concentration increases

Time-dependent killing -lactams,

glycopeptides, macrolides, clindamycin &

linezoid dependent on the % of time that
blood concentrations remain above minimum
inhibitory concentration (MIC)
4

Properties Influencing Frequency of

Dosing

Post-antibiotic effect (PAE) persistent

suppression of microbial growth after levels

of antibiotic have fallen below MIC

Antibiotics with a long PAE aminoglycosides

and fluroquinolines

Minimum bacterial concentration (MBC) is

the lowest concentration of antibiotic that

kills 99.9% of bacteria
6

MIC
INHIBITS

Figure 30.2 (part 2)

Chapter 30 MENU >

MBC
KILLS

Figure 30.2 (part 3)

Chapter 30 MENU >

Chemotherapeutic Spectra

Narrow-spectrum Antibiotics:

Act on a single / limited group of micro-organisms;

e.g., isoniazid given for mycobacterium

Extended-spectrum Antibiotics:

Effective against gram-positive organisms and a

significant number of gram-negative organisms; e.g.,

ampicillin

Broad-spectrum Antibiotics:

Effective against a wide variety of microbial species;

e.g., tetracycline & chloramphenicol.

Can alter the nature of intestinal flora = super infection
9

Combinations of Antimicrobial Drugs

Advantages

Synergism; the combination is more effective

than either drug used separately; -lactams and

aminoglycosides

Infections of unknown origin

Disadvantages

Bacteriostatic (tetracycline) drugs may interfere

with bactericidal ( penicillin and cephalosporin)

drugs
10

Complications of Antibiotic Therapy

Resistance inappropriate use of antibiotics

Hypersensitivity penicillin

Direct toxicity aminoglycosides = ototoxicity

Super infections broad spectrum

antimicrobials cause alteration of the normal

flora; often difficult to treat
11

Drug Resistance
1.

Alteration of the target site of the antibiotic

One of the most problematic antibiotic resistances worldwide,

methicillin resistance among Staphylococcus aureus.

2.

Enzyme inactivation of the antibiotic

-lactam antibiotics (penicillins & cephalosporins) can be

inactivated by -lactamases.
3.

Active transport of the antibiotic out of the bacterial cell

(efflux pumps)

Removal of some antibiotics (i.e. tetracyclines, macrolides, &

quinolones)
4.

Decreased permeability of the bacterial cell wall to the

antibiotic

Alteration in the porin proteins that form channels in the cell

membrane Resistance of Pseudomonas aeruginosa to a variety

of penicillins and cephalosporins
12

Antibiotic
Resistance

4.

2.

1.

3.
13

Resistance - -lactamase

Some bacteria secrete an enzyme called -

lactamase which destroys the beta lactam

ring, rendering beta-lactam antibiotics
ineffective.

Solution - add clavulanic acid - a lactamase inhibitor - i.e. co-amoxiclav
(Augmentin) or the combination of
piperacillin and tazobactam (Tazocin).
14

Resistance
Decreased Permeability of the Drug

Prevents the drug reaching the target

penicillin binding proteins (PBPs)

Presence of an Efflux pump also reduces the

amount of the intracellular drug

15

Classifying Antimicrobial Agents

Mode of action
BACTERICIDAL (kills the bug)
BACTERIOSTATIC (stops the bug multiplying)
Spectrum of activity
BROAD (e.g. effective a variety of gram-neg & gram-pos bacteria)
NARROW (e.g. effective only against gram-neg or gram-pos
Mechanism of action / site of action;


Inhibitors of cell metabolism; (Sulfonamides, Trimethoprim)


Cell wall inhibitors; (-Lactam, Vancomycin)


Protein synthesis inhibitors; (Tetrecyclines, Aminiglycosides,
Macrolides, Clindamycin, Chloramphenicol)


Nucleic acid inhibitors; (Floroquinolones, Rifampin)


Cell membrane inhibitors; (Isoniazid, Amphotericin B)
16

Classification of Antimicrobials by Site

of Action

Figure 30.13 (still)

17

Chapter 30 MENU >

Wolters Kluver

1. CELL WALL INHIBITORS

Interfere with the synthesis of the bacterial cell

wall

Little or no effect on bacteria that are not growing
and dividing
-lactam group
Penicillins
Cephalosporins
Carbapenems
Monobactams
-lactam inhibitors +
antibiotic combinations
18

Other antibiotics

Vancomycin
Bacitracin
Daptomycin
Telavancin

Antimicrobial Agents
Affecting Cell Wall
Synthesis
Figure 31.1 (still)

19

Chapter 31 MENU >

PENICILLINS (bactericidal)

Most widely effective and least toxic

Limited use - increased resistance

Mechanism of action

Inactivates various proteins on bacterial

cell wall

20

Administration and Fate of

PENICILLIN
Routes of Administration
Oral only Pen V, Amoxicillin &
amoxicillin combined with clavulanic
acid
IV / IM- Tiracillin, piperacillin,
ampicillin with sulbactam, tiracillin
with clavulanic acid and piperacillin
with tozobactam
Others oral, IV or IMI
Absorption
Decreases by food in the stomach
administer before meals 30-60min
Distribution to bone and CSF
insufficient
Excretion - Kidneys

Figure 31.7 (still)

21

Chapter 31 MENU >

Adverse Effects of Penicillin

Figure 31.9 (still)

22

Chapter 31 MENU >

CEPHALOSPORINS (bactericidal)

Semi-synthetic antibiotics

-lactam antibiotics closely related functionally

and structurally to penicillins

Mode of action - inhibit the synthesis of the cell
wall

More resistant than penicillins to certain
lactamases

Classified as 1st, 2nd, 3rd and 4th generation based
on spectrum of antimicrobial activity
23

Mechanism of Action

Bactericidal, inhibit cell wall synthesis.

Cephalosporins are also beta-lactams so can be

degraded by beta-lactamase secreting bacteria.

Good to know:

Classified by generation, based on general features

pertaining to activity;

The higher the generation, the broader the
spectrum. E.g. ceftriaxone (3rd generation) is
effective against more gram negative bacteria than
cephalexin (1st generation).
24

 Gram +ve and moderate

Gram ve activity
Act as penicillin G
substitutes
Resistant to staph
penicillinase

Figure 31.10 (part 1)

25

Chapter 31 MENU >

Greater activity against

Gram -ve organisms;
H influenza
Enterobacter aerogenes
Neisseria species
Activity against gram +ve
organisms is weaker
Some agents with activity
against anaerobes

Figure 31.10 (part 2)

26

Chapter 31 MENU >

 Activity against Gram +ve

organisms
Increased activity against
Enterobacteriaceae and
pseudomonas aeruginosa
Important in the treatment
of infectious diseases
Inferior to 1st generations
in activity against MSSA
(meticillin-sensitive
S.Aureus)
Figure 31.10 (part 3)

27

Chapter 31 MENU >

4th Generation Cephalosporins

Spectrum similar to 3rd

Generation

Have increased stability

Cefepime ;

28

Administration and fate

of cephalosporins
Resistance same as
that for penicillins

Figure 31.11 (still)

Chapter 31 MENU >

29

Most Common Side Effects

Cephalosporins

30

Diarrhoea
Nausea
Abdominal pain
Vomiting
Headache
Dizziness
Skin rash
Fever
Abnormal liver tests
Vaginitis

Individuals
hypersensitive to
penicillins may also be
hypersensitive to
cephalosporins
Like almost all
antibiotics, may cause
mild or severe cases of
pseudomembranous
colitis

OTHER -LACTAM ANTIOBIOTICS

Carbapenems:

Imipenem broad spectrum of activity

against Gram +ve and Gram ve aerobic

and anaerobic bacteria

Meropenem Important for empirical

mono therapy of serious infections

31

Other -Lactam Antiobiotics

Monobactams

Activity restricted to Gram ve aerobic
bacteria

Aztreonam

32

-LACTAMASE INHIBITORS

-lactamase inhibitors

clavulanic acid sulbactam and

tazobactam

Do not have significant

antibacterial activity

Bind to and inactivate the -

lactamases protect the

antibiotics

Formulated in combination with
-lactamase sensitive antibiotics

Clavulanic acid and amoxicillin
33

Growth of E. Coli in presence of

amoxicillin with and without
clavulanic acid

VANCOMYCIN;
Tricyclic glycopeptide
Effective against multiple
drug resistant organisms
(MRSA) & enterococci
Resistance is becoming a
problem

Figure 31.17 (still)

34

Chapter 31 MENU >

Enterococcus faecium
Enterococcus faecalis

Vancomycin Adverse Effects Serious problem

Figure 31.18 (still)

35

Chapter 31 MENU >

DAPTOMYCIN

Cyclic lipopeptide linezolid and quinupristin /

dalfopristin

Treatment of infections caused by resistant
gram +ve

MRSA methicillin S. Aureus

MSSA - methillin susceptible S. Aureus

VRE - vancomycin- resistant enterococci

Daptomycin is bactericidal

Concentration dependent

Inactivated by surfactant never used in

treatment of pneumonia

36

Adverse Effects

Constipation

Nausea

Headache

Myalgias

Insomnia

Increased hepatic transaminases

Elevation of creatine phosphokinases
37

TELAVANCIN

Semi-synthetic lipoglycopeptide

antibiotic

Synthetic derivative of Vancomycin

Treatment of complicated skin and
skin structure infections caused by
resistant gram +ve organisms
including MRSA
38

Mechanism of
Action
Inhibits bacterial cell
wall synthesis
Also involves
disruption of
bacterial cell
membrane
Bactericidal against
MRSA
Figure 31.20 (still)
Chapter 31 MENU >

Cautions & Adverse Effects Telavancin

Prolonged QT
interval

Figure 31.21 (still)

Chapter 31 MENU >

2. PROTEIN SYNTHESIS INHIBITORS

Target the bacterial
ribosome
High levels of drugs i.e.
Chloramphenicol or the
tetracyclines may
cause toxic effect
Interaction with the
host mitochondrial
ribosomes
41

TETRACYCLINES
Antibacterial spectrum

Broad-spectrum bacteriostatic

antibiotic

Effective against:

Gram+ve and Gram-ve bacteria

Organisms other than bacteria

42

Tetracyclines drug of choice

43

Absorption

Adequately but
incomplete oral
absorption

Taking with dairy
foods decreases
absorption

44

Resistance

Widespread
resistance limits
clinical use

Administration
of
Tetracyclines

Figure 32.5 (still)

Chapter 32 MENU >

Distribution
Liver, kidneys, liver
and skin
Bind to tissue
undergoing
calcification; bones
and teeth, tumours
with high calcium
Penetrate most body
fluids

Tetracycline - Adverse Effects

Figure 32.6 (still)

46

Chapter 32 MENU >

Adverse effects have restricted their usefulness

GLYCYLCYCLINES
(Pronunciation: gli-sil-s-klns)

Tigecycline a derivative of minocycline

Similar to tetracycline

Broad-spectrum activity against

Multidrug-resistant Gram +ve pathogens

Some Gram ve organisms

Aerobic organisms

Treatment of complicated skin and soft tissue

infections and complicated intra-abdominal

infections

Mechanism of action bacteriostatic
47

GLYCYLCYCLINES Adverse Effects

Associated with nausea and vomiting and

other adverse effects similar to tetracyclines

Drug interactions

Inhibits the clearance of warfarin

Oral contraception with Glycylcyclines

less effective

48

AMINOGLYCOSIDES

Similar antimicrobial spectrum to Macrolides

Relatively toxic but still useful in treatment of

infections caused by anaerobic Gram ve bacteria

Ototoxicity = main limitation

Inhibit bacterial protein synthesis

Have a PAE

Good to know: Only available IV

Not absorbed by gut

49

Aminoglycosides

Antibacterial spectrum effective in

combination for empirical treatment of

aerobic Gram ve bacilli infections
Pseudomonas aeruinosa

Combines with a -lactam i.e.
Vancomycin Aminoglycosides and
bactericidal amikacin,gentamycin,
tobramycin and streptomycin
50

Figure 32.9 (still)

Chapter 32 MENU >

Adverse Effects of Aminoglycosides

Figure 32.10 (still)

Chapter 32 MENU >

MACROLIDES (bacteriostatic)

May also be bacteicidal

Large group of antibacterials

Low toxicity

Similar spectrum of activity

PAE antibacterial activity continues after

concentrations have dropped

Good to know: Take on an empty stomach

53

Macrolides Antibacterial Spectrum

Erythromycin effective against the

same organisms as penicillin G

Clarithromycin - spectrum of activity
similar to erythromycin also Chlamidia,
Legionella, Moraxella & Ureaplasma
species & Helicobacter pylori

54

Macrolides Antibacterial Spectrum

Azithromycin less active to strep and

staph. More active against H. Influenzae,

Moraxella catarrhalis.

Preferred therapy for urethritis caused by

chlamydia trachomatis.

Also activity against Mycobacterium aviumintracellularae complex in patients with AIDS

Telithromycin (ketolite) spectrum similar

55

to azithromycin, resistance lower = more

effective

Therapeutic Applications of Macrolides

Most strains of staphylococci in hospitals are resistant

Figure 32.12 (still)
Chapter 32 MENU >

Macrolides
Absorption
food interferes with
absorption
IV = increased
thrombophlebitis
Distribution
High in all body fluids &
prostatic fluids - except
CSF

Figure 32.13 (still)

Chapter 32 MENU >

Elimination
Erythromycin &
telithromycin interfere with
metabolism of drugs such
as theophylline &
carbamazepine

Macrolides - Adverse Effects

Interactions
Erythromycin, telithromycin and clarithromycin inhibit
metabolism of a number of drugs = toxic accumulation
Figure 32.15 (still)
Chapter 32 MENU >

OTHERS

Chrolamphenical - Chrolomycetin

Clindamycin- Cleocin, Dalacin C

Linezolid - Zyvox

Quinupristin / dalfopristin -

Synercid

59

Chloramphenicol

Active against a wide range of

Gram +ve and Gram ve organisms

High toxicity bone marrow
toxicity

Restricted for life-threatening
infections where no alternative
exists
60

Chloramphenicol - Spectrum

Broad spectrum antibiotic

Active against bacteria, Rickettsia,

Mot affected against - Pseudomonas

Aeruginosa and chlamydiae

Excellent activity against anaerobes

Both bactericidal and Bacteriostatic

61

Adverse Effects

Figure 32.18 (still)

Chapter 32 MENU >

Clinical use limited to life

threatening infections serious
side effects, GI upsets,
overgrowth of Candida albicans
Anaemias haemolytic
anaemia
Gray baby syndrome poor
feeding, depressed breathing,
cardiovascular collapse,
cyanosis and death
Interactions blocks the
metabolism of warfarin,
phenytoin, tolbutamide &
chlopropamide = increased
effects of the drugs
Bone Marrow depression

CLINDAMYCIN

Mechanism of action same as

erythromycin

Treatment of infections caused by
anaerobic bacteria Bacteriodes
fragilis (infections associated with
trauma) & MRSA

Resistance same as erythromycin
63

Clindamycin

Administration
Well absorbed by oral
route
Adequate levels not
achieved in the brain
Penetration into bone good
Accumulation of drug in
patients with compromised
renal function or hepatic
failure

Figure 32.20 (still)

Chapter 32 MENU >

Side Effects
Fatal pseudomembraneous
colitis

Quinupristin / Dalfopristin

Figure 32.21 (still)

Chapter 32 MENU >

Reserved for Vancomycinresistant Enterococcus

faecium (VRE)
Active against Gram +ve cocci
including those resistant to
other antibiotics, including
MRSA
Primary use treatment of
E.faecium infections + VRE
strains
Adverse Effects
Venous irritation,
Arthralgia & myalgia,
Hyperbilirubinaemia, drug
interactions

LINEZOLID
Adverse effects
GI upset
Diarrhoea
Headaches
Rash
Thrombocytopenia
Inhibits MAO activity
Precipitate serotonin
syndrome in patients
taking SSRIs
Figure 32.24 (still)
Chapter 32 MENU >

3. NUCLEIC ACID INHIBITORS QUINOLONES

Not recommended for children

May prolong QT interval, not to be used in patients

with arrhythmias

Limited therapeutic utility and rapid development
of resistance

Interfere with absorption

Antacids containing aluminium or magnesium

Dietary substances containing iron or zinc

Calcium , milk or yogurt
67

Figure 33.5 (still)

Chapter 33 MENU >

Newer compounds, Ciprofloxacin &

ofloxacin,
Greater potency
Broader spectrum of antimicrobial
activity
Greater efficacy against resistant
organisms
Active against Gramve bacilli &
cocci, mycobacteria, mycoplasmas
& rikettsiae
Some cases better safety profile
than older quinolones
Respiratory quinolones
Levofloxacin, gemifloxacin &
moxifloxacin
Active against Gram +ve, typical,
atypical & anaerobic pathogens

Therapeutic Applications of Fluroquinolones

Figure 33.4 (still)

Chapter 33 MENU >

Adverse Reactions to Floroquinolones

Figure 33.7 (still)

Chapter 33 MENU >

Sulfonamides Cell Membrane

Inhibitors

Seldom prescribed on their own

Resistance limits spectrum of
antimicrobial activity
Trimethoprim -similar activity to
sulphonamides in combination
with sulphonamides is synergistic

Figure 33.10 (still)

Chapter 33 MENU >

Adverse effects:
Nephrotoxicity
Hypersensitivity
Haemopoeitic disturbances
Kernicterus
Displaces warfarin & Methotrexate
from binding sites

Therapeutic application of Cotrimoxazole

(sulfamethoxazole plus trimethoprim)

Figure 33.14 (still)

Chapter 33 MENU >

Adverse Effects Cotrimoxazole

Figure 33.16 (still)

Chapter 33 MENU >

4. ANTIMYCOBACTERIALS

Figure 34.1 (still)

Chapter 34 MENU >

Figure 34.10 (still)

Chapter 34 MENU >

5. ANTIFUNGAL DRUGS

Amphotericin B

Flucytosine

Ketoconazole

Flucanozole

Itraconazole

Variconazole

Posaconazole

Echinocandins
76

Drugs for Cutaneous and Mycotic

Infections

Terbinafine

Neftifine

Butenafine

Griseofulvin

Nystatin

Imidazole

Ciclopirox

Tolnaftate
77

The Top Ten Rule

1. All cell wall inhibitors are Beta-lactams

2.
3.
4.
5.
6.
78

(penicllins, cephalosporins etc) except

vancomycin.
All penicllins are water soluble except nafcillin.
All protein synthesis inhibitors are bacteriostatic,
except for the aminoglycosides
All cocci are gram positive, except Neisseria spp.
All bacilli are gram negative, except anthrax,
tetanus, botulism and diphtheria bugs
All spirochaetes are gram negative

The Top Ten Rule

Tetracylcines and macrolides are used for
intracellular bacteria
8. Beware pregnant women and tetracylcines,
aminoglycosides, fluoroquinolones and
sulfonamides.
9. Antibitoics beginning with 'C' are particularly
associated with pseudomembranous colitis i.e.
Cephalosporins, Clindamycin and Ciprofloxacin.
10. While the penicillins are the most famous for
causing allergies, a significant proportion of people
with penicillin allergies may also react to
cephalosporins. These should therefore also be
avoided.
7.

79

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81