Antibiotic principles

Principles of Antibiotic

Therapy

1

Definition -Antibiotic

� An antibiotic is a substance produced by

various species of living microorganisms

(e.g. bacteria and fungi)

� Inhibit pathogens by interfering with � 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

�Organism’s susceptibility to the antibiotic

� Patient factors - immune system, renal/hepatic functionrenal/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 – β-lactams, glycopeptides, macrolides, clindamycin & linezoid – dependent on the % of time that blood concentrations remain above minimum inhibitory concentration (MIC)

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5

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 �Antibiotics with a long PAE – aminoglycosides

and fluroquinolines

� Minimum bacterial concentration (MBC) is

the lowest concentration of antibiotic that

kills 99.9% of bacteria

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MIC

INHIBITS

Figure 30.2 (part 2)

Chapter 30 MENU >7

MBC

KILLS


Chapter 30 MENU >8

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 � 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

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Combinations of Antimicrobial Drugs

� Advantages

� Synergism; the combination is more effective

than either drug used separately; β-lactams and

aminoglycosides

� Infections of unknown origin� Infections of unknown origin

� Disadvantages

� Bacteriostatic (tetracycline) drugs may interfere

with bactericidal ( penicillin and cephalosporin)

drugs

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Complications of Antibiotic Therapy

� Resistance – inappropriate use of antibiotics

� Hypersensitivity – penicillin

Direct toxicity – aminoglycosides = ototoxicity� Direct toxicity – aminoglycosides = ototoxicity

� Super infections – broad spectrum antimicrobials cause alteration of the normal flora; often difficult to treat

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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

� β-lactam antibiotics (penicillins & cephalosporins) can be inactivated by β-lactamases.

3. Active transport of the antibiotic out of the bacterial cell 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

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Antibiotic Resistance

2.

4.

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1.

3.

Resistance - β-lactamase

� Some bacteria secrete an enzyme called β-

lactamase which destroys the beta lactam

ring, rendering beta-lactam antibiotics

ineffective. ineffective.

� Solution - add clavulanic acid - a β-

lactamase inhibitor - i.e. co-amoxiclav

(Augmentin) or the combination of

piperacillin and tazobactam (Tazocin).

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Resistance –

Decreased Permeability of the Drug

� Prevents the drug reaching the target

penicillin binding proteins (PBPs)

� Presence of an Efflux pump also reduces the � Presence of an Efflux pump also reduces the

amount of the intracellular drug

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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; (β-Lactam, Vancomycin)

� Protein synthesis inhibitors; (Tetrecyclines, Aminiglycosides,

Macrolides, Clindamycin, Chloramphenicol)

� Nucleic acid inhibitors; (Floroquinolones, Rifampin)

� Cell membrane inhibitors; (Isoniazid, Amphotericin B)

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Classification of Antimicrobials by Site

of Action

Figure 30.13 (still)

Chapter 30 MENU >Wolters Kluver17

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

β-lactam group Other antibiotics

Penicillins Vancomycin

Cephalosporins Bacitracin

Carbapenems Daptomycin

Monobactams Telavancin

β-lactam inhibitors +

antibiotic combinations18

Figure 31.1 (still)

Chapter 31 MENU >

Antimicrobial Agents

Affecting Cell Wall

Synthesis

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PENICILLINS (bactericidal)

� Most widely effective and least toxic

� Limited use - increased resistance

� Mechanism of action

� Inactivates various proteins on bacterial

cell wall

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Administration and Fate of

PENICILLIN Routes of Administration• Oral only –Pen V, Amoxicillin &

amoxicillin combined with clavulanicacid

• IV / IM- Tiracillin, piperacillin, ampicillin with sulbactam, tiracillinwith clavulanic acid and piperacillinwith tozobactam

• Others oral, IV or IMI

Figure 31.7 (still)

Chapter 31 MENU >21

• 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

Adverse Effects of Penicillin

Figure 31.9 (still)

Chapter 31 MENU >22

CEPHALOSPORINS (bactericidal)

� Semi-synthetic antibiotics

� β-lactam antibiotics closely related functionally

and structurally to penicillins

� Mode of action - inhibit the synthesis of the cell

wallwall

� More resistant than penicillins to certain β –

lactamases

� Classified as 1st, 2nd, 3rd and 4th generation – based

on spectrum of antimicrobial activity

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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:� 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).

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• Gram +ve and moderate Gram –ve activity

• Act as penicillin Gsubstitutes

• Resistant to staph


Chapter 31 MENU >

• Resistant to staph penicillinase

25

Greater activity against Gram -ve organisms;• H influenza• Enterobacter aerogenes• Neisseria species

Activity against gram +ve


Chapter 31 MENU >

Activity against gram +ve organisms is weaker

Some agents with activity against anaerobes

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• Activity against Gram +ve organisms

• Increased activity against Enterobacteriaceae and pseudomonas aeruginosa


Chapter 31 MENU >

• Important in the treatment of infectious diseases

• Inferior to 1st generations in activity against MSSA (meticillin-sensitive S. Aureus)

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4th Generation Cephalosporins

�Spectrum similar to 3rd

Generation

�Have increased stability �Have increased stability

�Cefepime ;

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Administration and fate

of cephalosporins

• Resistance same as

that for penicillins


Chapter 31 MENU >

that for penicillins

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Most Common Side Effects –

Cephalosporins

• Diarrhoea

• Nausea

• Abdominal pain

• Vomiting

• Headache

• Individuals

hypersensitive to

penicillins may also be

hypersensitive to

cephalosporins• Headache

• Dizziness

• Skin rash

• Fever

• Abnormal liver tests

• Vaginitis

cephalosporins

• Like almost all

antibiotics, may cause

mild or severe cases of

pseudomembranous

colitis

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OTHER β-LACTAM ANTIOBIOTICS

Carbapenems:

�Imipenem – broad spectrum of activity

against Gram +ve and Gram –ve aerobic

and anaerobic bacteria and anaerobic bacteria

�Meropenem – Important for empirical

mono therapy of serious infections

31

Other β-Lactam Antiobiotics

Monobactams

�Activity restricted to Gram –ve aerobic

bacteria

�Aztreonam�Aztreonam

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β-LACTAMASE INHIBITORS

� β-lactamase inhibitors –

clavulanic acid – sulbactam and

tazobactam

� Do not have significant

antibacterial activityantibacterial activity

� Bind to and inactivate the β-

lactamases – protect the

antibiotics

� Formulated in combination with

β-lactamase sensitive antibiotics

� Clavulanic acid and amoxicillin

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Growth of E. Coli in presence of amoxicillin with and without clavulanic acid

VANCOMYCIN;

• Tricyclic glycopeptide

• Effective against multiple

drug resistant organisms

(MRSA) & enterococci


Chapter 31 MENU >

(MRSA) & enterococci

• Resistance is becoming a

problem• Enterococcus faecium

• Enterococcus faecalis34

Vancomycin Adverse Effects – Serious problem


Chapter 31 MENU >35

DAPTOMYCIN� Cyclic lipopeptide – linezolid and quinupristin /

dalfopristin

� Treatment of infections caused by resistant gram +ve�MRSA – methicillin S. Aureus�MSSA - methillin susceptible 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

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Adverse Effects

�Constipation

�Nausea

�Headache

Myalgias�Myalgias

� Insomnia

� Increased hepatic transaminases

�Elevation of creatine phosphokinases

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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

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Mechanism of Action• Inhibits bacterial cell

wall synthesis• Also involves

disruption of


Chapter 31 MENU >

disruption of bacterial cell membrane

• Bactericidal against MRSA

Cautions & Adverse Effects Telavancin

Prolonged QT interval


Chapter 31 MENU >

interval

2. PROTEIN SYNTHESIS INHIBITORS

•Target the bacterial ribosome

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

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TETRACYCLINES –

Antibacterial spectrum

�Broad-spectrum bacteriostatic

antibiotic

�Effective against:

� Gram+ve and Gram-ve bacteria� Gram+ve and Gram-ve bacteria

�Organisms other than bacteria

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Tetracyclines – drug of choice

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Absorption

� Adequately but

incomplete oral

absorption

� Taking with dairy

foods decreases

absorptionabsorption

Resistance

� Widespread

resistance limits

clinical use44

Administration of

Tetracyclines

Distribution –• Liver, kidneys, liver

Figure 32.5 (still)

Chapter 32 MENU >

• 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)

Chapter 32 MENU >46 Adverse effects have restricted their usefulness

GLYCYLCYCLINES

(Pronunciation: gli-sil-sī-klēns)

� Tigecycline – a derivative of minocycline

� Similar to tetracycline

� Broad-spectrum activity against

� Multidrug-resistant Gram +ve pathogens

� Some Gram –ve organisms� Some Gram –ve organisms

� Aerobic organisms

� Treatment of complicated skin and soft tissue

infections and complicated intra-abdominal

infections

� Mechanism of action – bacteriostatic

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GLYCYLCYCLINES Adverse Effects

� Associated with nausea and vomiting and

other adverse effects similar to tetracyclines

� Drug interactions� Drug interactions

� Inhibits the clearance of warfarin

�Oral contraception with Glycylcyclines –

less effective

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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� Inhibit bacterial protein synthesis

� Have a PAE

� Good to know: Only available IV

� Not absorbed by gut

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Aminoglycosides

�Antibacterial spectrum – effective in

combination for empirical treatment of

aerobic Gram –ve bacilli infections –

Pseudomonas aeruinosa

Combines with a β-lactam i.e. �Combines with a β-lactam i.e.

Vancomycin Aminoglycosides and

bactericidal amikacin,gentamycin,

tobramycin and streptomycin

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Figure 32.9 (still)

Chapter 32 MENU >

Adverse Effects of Aminoglycosides


Chapter 32 MENU >

MACROLIDES (bacteriostatic)

� May also be bacteicidal

� Large group of antibacterials

� Low toxicity

� Similar spectrum of activity

PAE – antibacterial activity continues after � PAE – antibacterial activity continues after

concentrations have dropped

� Good to know: Take on an empty stomach

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Macrolides – Antibacterial Spectrum

�Erythromycin – effective against the

same organisms as penicillin G

�Clarithromycin - spectrum of activity

similar to erythromycin also Chlamidia, similar to erythromycin also Chlamidia,

Legionella, Moraxella & Ureaplasma

species & Helicobacter pylori

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Macrolides – Antibacterial Spectrum

� Azithromycin – less active to strep and

staph. More active against H. Influenzae,

Moraxella catarrhalis.

�Preferred therapy for urethritis caused by �Preferred therapy for urethritis caused by

chlamydia trachomatis.

�Also activity against Mycobacterium avium-

intracellularae complex in patients with AIDS

� Telithromycin (ketolite) – spectrum similar

to azithromycin, resistance lower = more

effective55

Therapeutic Applications of Macrolides


Chapter 32 MENU >

Most strains of staphylococci in hospitals are resi stant

Macrolides• Absorption

• food interferes with absorption

• IV = increased thrombophlebitis

• Distribution• High in all body fluids &


Chapter 32 MENU >

• High in all body fluids & prostatic fluids - except CSF

• Elimination• Erythromycin &

telithromycin interfere with metabolism of drugs such as theophylline & carbamazepine

Macrolides - Adverse Effects


Chapter 32 MENU >

Interactions –Erythromycin, telithromycin and clarithromycin inhibit metabolism of a number of drugs = toxic accumulation

OTHERS

�Chrolamphenical - Chrolomycetin

�Clindamycin- Cleocin, Dalacin C

�Linezolid - Zyvox�Linezolid - Zyvox

�Quinupristin / dalfopristin -

Synercid

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Chloramphenicol

�Active against a wide range of

Gram +ve and Gram –ve organisms

�High toxicity – bone marrow

toxicitytoxicity

�Restricted for life-threatening

infections where no alternative

exists

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Chloramphenicol - Spectrum

�Broad spectrum antibiotic

�Active against bacteria, Rickettsia,

�Mot affected against - Pseudomonas

Aeruginosa and chlamydiae Aeruginosa and chlamydiae

�Excellent activity against anaerobes

�Both bactericidal and Bacteriostatic

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Adverse Effects• 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,


Chapter 32 MENU >

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 anaerobic bacteria – Bacteriodes

fragilis (infections associated with

trauma) & MRSA

�Resistance same as erythromycin

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Administration• Well absorbed by oral

route• Adequate levels not

achieved in the brain• Penetration into bone -

good

Clindamycin


Chapter 32 MENU >

Accumulation of drug in patients with compromised renal function or hepatic failure

Side EffectsFatal pseudomembraneouscolitis

• Reserved for Vancomycin-resistant Enterococcusfaecium (VRE)

• Active against Gram +ve cocciincluding those resistant to other antibiotics, including MRSA

Quinupristin / Dalfopristin


Chapter 32 MENU >

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


Chapter 32 MENU >

• Rash• Thrombocytopenia• Inhibits MAO activity• Precipitate serotonin

syndrome in patients taking SSRI’s

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 resistanceof resistance

� Interfere with absorption

� Antacids containing aluminium or magnesium

� Dietary substances containing iron or zinc

� Calcium , milk or yogurt

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Newer compounds , Ciprofloxacin & ofloxacin,• Greater potency• Broader spectrum of antimicrobial

activity• Greater efficacy against resistant

organisms• Active against Gram–ve bacilli &

cocci, mycobacteria, mycoplasmas

Figure 33.5 (still)

Chapter 33 MENU >

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


Chapter 33 MENU >

with sulphonamides is synergistic

Adverse effects :• Nephrotoxicity• Hypersensitivity• Haemopoeitic disturbances• Kernicterus• Displaces warfarin & Methotrexate

from binding sites

Therapeutic application of Cotrimoxazole (sulfamethoxazole plus trimethoprim)


Chapter 33 MENU >

Adverse Effects Cotrimoxazole


Chapter 33 MENU >

4. ANTIMYCOBACTERIALS

Figure 34.1 (still)

Chapter 34 MENU >


Chapter 34 MENU >

5. ANTIFUNGAL DRUGS

� Amphotericin B

� Flucytosine

� Ketoconazole

� Flucanozole� Flucanozole

� Itraconazole

� Variconazole

� Posaconazole

� Echinocandins

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Drugs for Cutaneous and Mycotic

Infections

� Terbinafine

� Neftifine

� Butenafine

� Griseofulvin� Griseofulvin

� Nystatin

� Imidazole

� Ciclopirox

� Tolnaftate

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The Top Ten Rule

1. All cell wall inhibitors are Beta-lactams

(penicllins, cephalosporins etc) except

vancomycin.

2. All penicllins are water soluble except nafcillin.

3. All protein synthesis inhibitors are bacteriostatic, 3. All protein synthesis inhibitors are bacteriostatic,

except for the aminoglycosides

4. All cocci are gram positive, except Neisseria spp.

5. All bacilli are gram negative, except anthrax,

tetanus, botulism and diphtheria bugs

6. All spirochaetes are gram negative

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The Top Ten Rule7. 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 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.

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Health & Medicine

Antibiotic principles