a guide to antibiotics

7/30/2019 A guide to antibiotics

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Pharmacology Antimicrobials

1

Antimicrobial pharmacologyPenicillins Natural penicillins

Penicillin V

Benzylpenicillin

Procaine penicillin

Benzathine penicillin

Synthetic, antistaphylococcal penicillins

Flucloxacillin

Dicloxacillin

Extended spectrum penicillins

Amoxicillin

Ticarcillin

Piperacillin

Drug Pharmacodynamics PharmacokineticsMechanism Organ effects Clinical use Toxicity and

interactions

Absorption and

distribution

Metabolism and

excretionPenicillin V

Benzyl-

penicillin

Procaine

penicillin

Benzathine

penicillin

Inhibition of cell wall

synthesisPenicillins bind to penicillin

binding proteins and inhibit

transpeptidation in

peptidoglycan synthesis and

therefore formation of cross-

links in the cell wall that

confer rigidity.

Active against gram

positive cocci, gram

negative cocci, some

anaerobes

Destroyed by beta

lactamases

Inactive against

enterococci, some

anaerobes, gram

negative rods

Streptococci

Meningococci

Enterococci

Pneumococci

Staphylococci

Treponema

pallidum

Bacillus anthracis

Clostridium

Dose10-50mg/kg/day in

3-4 doses orally or

IV

Resistance

mechanisms

Beta lactamases

Destroyed by beta

lactamases produced

by staphylococci,

haemophilus, E coli,

pseudomonas,

enterobacter

Alteration on

target penicillinbinding proteins.

Resistant organisms

have binding sites

with low affinity for

binding

particularly seen

with MRSA and

pneumococcus

Poor ability to

penetrate outer

membraneGram-negative

organisms

Allergy

Minor toxicities such as

nausea, vomiting, diarrhoea

Important cause of type I

hypersensitivity.

Type III hypersensitivity can

also occur.

5-8% claim penicillin allergy

but only 5-10% of these will

have a reaction.

High doses in renal failure

can causes seizures

Original penicillins

such as penicillin G

acid labile.

Penicillin V is acid

stable and well

absorbed orally but

has poor

bioavailability

Avoid administration

with meals

60% protein bound.

Penetrates tissues

very well except eye,

prostate and CNS

though penetration is

better if inflammation

is present.

Renal excretion

10% by filtration,

90% by tubular

secretion.

Half-life 30

minutes, increases

to 10 hours in renal

failure.

Dose adjustment

required in renal

failure

Frequent dosing

required

Flucloxacillin

Dicloxacillin

Beta lactam

antibiotic withresistance to

staphylococcal

beta-

lactamases.


synthesisPenicillins bind to penicillin


transpeptidation inpeptidoglycan synthesis and



confer rigidity.

Active against gram

positive cocci including

beta lactamase

producing staphylococci

Inactive against

enterococci, anaerobes,

gram negative.

Infections likely to

be due to beta

lactamse-

producing

staphylococci(>90%)

Dose

10-50mg/kg/day in

3-4 doses orally or

IV

Resistance

mechanisms

Beta lactamasesNot destroyed by

staphylococcal beta

lactamases.

Alteration on

target penicillin

binding proteins.

Resistant organisms

have binding sites

with low affinity forbinding.

Inability to

penetrate outer

membrane

Gram-negative

organisms

AllergyMinor toxicities such as


Important cause of type Ihypersensitivity.


also occur.



have a reaction.


can causes seizures

Small risk of hepatitis hence

introduction of dicloxacillin

Acid stable and well

absorbed orally.

Absorption impaired

by food.

Highly protein

bound.

Penetrates tissues


prostate and CNS



is present.

Hepatic

metabolism and

rapid renal

excretion10% by

filtration, 90% bytubular secretion.

No adjustment in

renal failure.


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interactions

Absorption and

distribution

Metabolism and

excretionAmoxicillin

Ampicillin

Piperacillin

Ticarcillin


synthesis

Penicillins bind to penicillin


transpeptidation in




confer rigidity.

Similar spectrum to

penicillin but better

penetration of gram

negative bacteria,

though still sensitive to

beta lactamases

Streptococci

Meningococci

Pneumococci

(particularly active

therefore 1st choice for

respiratory infection)

Staphylococci

Treponema pallidum

Bacillus anthracis

Clostridium

(not enterobacter)

Ampicillin effective for

Shigella

Ampicillin not active

against

E coli

Proteus

Haemophilus

Klebsiella

Pseudomonas

Enterobacter

Citrobacter

Serratia

Ticarcillin is also active

against

Pseudomonas

Enterobacter

Piperacillin is also

active against

Klebsiella

Dose

10-50mg/kg/day in

3-4 doses orally or

IV

Resistance

mechanisms

Beta lactamasesDestroyed by beta

lactamases produced

by staphylococci,

haemophilus, E coli,

pseudomonas,

enterobacter

Alteration on

target penicillin

binding proteins.Resistant organisms

have binding sites

with low affinity for

binding

particularly seen

with MRSA and

pneumococcus

Increased ability to

penetrate outermembrane

Allergy

Minor toxicities such as


Important cause of type I

hypersensitivity.


also occur.



have a reaction.


can causes seizures

Acid stable and well

absorbed orally.

Highly protein

bound.

Penetrates tissues


prostate and CNS



is present.

Hepatic

metabolism and

rapid renal

excretion10% by

filtration, 90% by

tubular secretion.

No adjustment in

renal failure.

Half life 1 hour

Clavulinic acid Resemble beta lactam

molecules and protect

against many beta lactamases

Active against beta

lactamases produced by

Haemophilus

Neisseria gonorrhoea

Salmonella

Shigella

E coli

Klebsiella

Legionella

Bacteroides

Not active against beta

lactamases produced by

Enterobacter

Citrobacter

Serratia

Pseudomonas


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Cephalosporins 1st generation cephalosporins

Cefadroxil

Cefazolin

Cephalexin

Cephalothin

Cephadrine

2nd generation cephalosporins

Cefaclor

CefuroximeCefoxitine

3rd generation cephalosporins

Ceftriaxone

Cefotaxime

Cephtazidime


interactions

Absorption and

distribution

Metabolism and

excretionCefadroxil

Cefazolin

Cephalexin

Cephalothin

Cephadrine

1stgeneration

cephalosporin


synthesisCephalosporins bind to

penicillin binding proteins

and inhibit transpeptidation

in peptidoglycan synthesisand therefore formation of

cross-links in the cell wall

that confer rigidity.

Gram positive cocci

plus

E coli

Klebsiella

Proteus

Anaerobic cocciPeptococcus

Peptostreptococcus

Not active against

Listeria

MRSA

Haemophilus

Pseudomonas

Some proteus

Enterobacter

Serratia

Citrobacter

Surgical

prophylaxisUncomplicated UTI,

skin and soft tissue

infection

Dose

10-50mg/kg/day

AllergyCross allergy between

penicillins and

cephalosporins is 5-10% -

withhold in anaphylaxis

only.

Toxicity

Local irritation.

Superinfection.

Well absorbed orally Renal excretion

10% by filtration,

90% by tubular

secretion.

Half-life 30minutes, increases

to 10 hours in renal

failure.

Dose adjustment

required in renal

failure

Cefaclor

Cefuroxime

Cefoxitin

2nd generation

cephalosporin


synthesisCephalosporins bind to



in peptidoglycan synthesisand therefore formation of



Gram positive cocci

plus

E coli

Klebsiella

Proteus

Anaerobic cocciPeptococcus

Peptostreptococcus

Plus extended gram

negative cover against

Haemophilus

Some serratia

Not active against

Listeria

MRSA

Pseudomonas

Some proteus

Enterobacter

Some serratia

Citrobacter

LRTI, otitis media,

sinusitis

Also used for

surgical infections

Cefuroxime less

effective than 3rd

generation agents

for meningitis

Dose10-50mg/kg/day


penicillins and



only.

Toxicity

Local irritation.

Cefaclor associated with

serum-sickness like reaction

Superinfection.

Renal excretion

10% by filtration,

90% by tubular

secretion.

Half-life variable

Dose adjustment

required in renal

failure

CeftriaxoneCefotaxime

Cephtazidime

3rdgeneration

cephalo-sporin

with

a similar

structure and

mechanism of

action to

penicillin.

Inhibition of cell wallsynthesisCephalosporins bind to



in peptidoglycan synthesis

and therefore formation of



Broad-spectrumantibiotic.

Extended coverage of

gram-negative

organisms compared

with first and second

generation.

Citrobacter

Serratia

Haemophilus

Neisseria

Particularly

pseudomonas.

Less active against

gram-positive

organisms.

Not active against

enterococci or listeria.

Treatment of seriousinfections by

susceptible

organisms.

Treatment of serious

infection if

organism unknown.

Especially useful for

CNS infection.

Treatment of

penicillin resistant

infections including

MRSA and

gonorrhoea

Dose10-50mg/kg/day.

Ceftriaxone suitable

for once daily

dosing.


penicillins and



only.

ToxicityLocal irritation.

Superinfection.

Intravenous dosing.Good tissue

penetration,

especially into CNS.

Half-life 7-8 hours.

Metabolised by

liver and excreted

in bile.

No dosing

adjustment required

in renal failure


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interactions

Absorption and

distribution

Metabolism and

excretionImipenem

Meropenem

Carbapenems

Structurally related to beta

lactams


synthesisBinds to penicillin binding

proteins and inhibit

transpeptidation in




confer rigidity.

Broad spectrum

Resistant to most beta

lactamases

Not active against

Enterococcus

Clostridium difficile

Burkholderia

Infections due to

resistant organisms

Highly active

against resistant

pneumococci and

enterobacter

Toxicity

Minor toxicities including


and skin rashes


can causes seizures

Inactivated by

dehydropeptidases

in renal tubules

therefore

administered with

cilastatin

Vancomycin Inhibition of cell wall

synthesisBinds to peptidoglycan and

inhibits transglycosylase

therefore preventing

peptidoglycan elongation

and cross-linking that

confers rigidity.

Active against gram

positive bacteria

(plus flavobacterium)

Bactericidal

Synergistic with

gentamicin

Sepsis or

endocarditis due to

MRSA

Dose10-50mg/kg/day

intravenous

Resistance

mechanisms

Alteration of

binding site.

ToxicityMinor reactions in 10%

Phlebitis

Histamine release (red

man/red neck syndrome)

Ototoxicity and

nephrotoxicity, especially if

administered with

aminoglycoside

Poorly absorbed

orallyused orally

for the treatment of

resistant clostridium

difficile

90% filtered by

kidney

Dose adjustment

required in renal

failure

Not removed by

haemodialysis

Teicoplanin Inhibition of cell wall

synthesis

Binds to peptidoglycan and

inhibits transglycosylase

therefore preventing

peptidoglycan elongation

and cross-linking that confer

srigidity.

Active against gram

positive bacteria

(plus flavobacterium)

Synergistic with

gentamicin

Sepsis or

endocarditis due to

MRSA

DoseOnce daily dosing

Can be given IM

Poorly absorbed

orallyused orally

for the treatment of

resistant clostridium

difficile

90% filtered by

kidney

Dose adjustment

required in renal

failure


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5


interactions

Absorption and

distribution

Metabolism and

excretionChloram-

phenicol

Potent inhibition of

microbial protein synthesis

Reversibly binds to 50S

subunit of bacterial ribosome

Bacteristatic

Broad spectrum

Not effective for

chlamydia

Effectively obsolete

as a systemic drug

due to other less

toxic agents

Eye infectionsdue

to broad spectrum

and good tissue

penetration

Not effective for

chlamydia

Dose

50-100mg/kg/day

(neonates

metabolise the drug

less wellgive

25mg/kg)

Resistance

mechanisms

Decreased

permeability

Production of

chloramphenicol

acetyltransferasethat inactivates the

drug

Toxicity

GIT

Nausea, vomiting, diarrhoea

Bone marrowCommonly causes dose

related reversible bone

marrow suppression

Rare idiosyncratic aplastic

anaemia (1 in 30000)

Neonates

Grey baby syndrome

InteractionsInhibition of hepatic

microsomal enzymes

prologed half life and

increased concentrations of

phenytoin and warfarin

Well absorbed orally

Widely distributed

Good tissue

penetration

Metabolised by

liver and excreted

by kidney

Dose adjustment

required in hepatic

failure

Tetracyclines

Doxycycline

Minocycline





Enter microorganisms by

diffusion and active transport

Broad spectrum

Active against

Rickettsiae,

Chlamydiae,

Mycoplasma,

Vibrio

Also active against

some protozoa

Mycoplasma,

Chlamydia,

rickettsia, vibrio

Malaria prophylaxis

Acne

Marine infections

Dose100mg twice daily

Resistance

mechanisms

Decreased

intracellular

accumulation due to

impaired active

transport

Decreased binding

to ribosome due to

production of

inhibitory proteins

Enzymatic

inactivation

(note resistance is

common)

Contraindications

Children under 8

years

Toxicity

GIT


Bacterial overgrowth

Liver toxicity

ATN

Bones and teethTooth discolouration due to

chelation with calcium

Other

Photosensitivity

InteractionsEnzyme inducers such as

phenytoin and

carbamazepine reduce half

life by 50%


Absorption not

impaired by food

Impaired by divalent

cations and dairy

products

40-80% protein

bound

Widely distributed

except CNS

Metabolised by

liver, excreted in

urine and bile.

Bile concentration

10 times serum

concentration

Dose reduction

required in renal

failure

Doxycycline is

excreted by non-

renal mechanism

and therefore is

drug of choice in

renal failure

Half life 12-16

hours


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6


interactions

Absorption and

distribution

Metabolism and

excretionMacrolides

Erythromycin

Semi-synthetic

Roxithromycin

Clarithromycin

Azithromycin





Concentrated in polymorphs

and macrophages

Bacteristatic at low

concentrations, bactericidal

at high concentrations

Broad spectrum

Gram positive

(strep>>staph)

Gram negative

Neisseria

Bordetella

Rickettsia

Treponema

Campylobacter

Chlamydia

Mycoplasma

Legionella

Less active against

haemophilus and

staphylococcus

Clarithromycin more

active against

mycobacterium avium

intracellulare

Erythromycin

Atypical pneumonia

Skin and soft tissue

infections

Alternative to

penicillin in allergy

STI (Chlamydia

only)

Dose

Erythromycin

10-50mg/kg/day in

4 divided doses

Semi-synthetic

macrolides have

longer half lives

therefore less

frequent dosing.

Azithromycin and

Roxithromycin

suitable for once

daily dosing

Resistance

mechanisms

Decreasedintracellular

accumulation due to

decreased

permeability

Decreased binding

to ribosome due to

modification of the

binding site by

methylase (accounts

for 90% of

resistance)

Enzymatic

inactivation by

enterobacter

Toxicity

GIT


Acute cholestatic hepatitis

(semi-synthetic macrolides

better tolerated)

Interactions

Erythromycin and

clarithromycin

Inhibition of cytochrome

P450 resulting in increased

concentrations of

theophylline, warfarin,

antihistamines

Causes increased

bioavailability of digoxin

Semi-synthetic macrolides

relatively free of above

effects due to less avid

binding to P450

Erythromycin base

combined with

stearate or ester

confers acid stability

Widely distributed

except CNS

Erythromycin

Metabolised by

liver, excreted in

bile

No adjustment

necessary for renal

impairment.

Half life 1.5 hours

Synthetic

macrolides

metabolised by

liver and excreted

in bile and urine

therefore dose

adjustment in renal

failure is

recommended


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interactions

Absorption and

distribution

Metabolism and

excretionAmino-

glycosides

Gentamycin

Tobramycin

Netilmycin

Irreversible inhibition of

protein synthesis

Aminoglycoside enters the

bacteria by passive diffusion

via porin channels across the

outer membrane (this process

is aided by penicillins)

Aminoglycoside is then

actively transported into the

cytoplasm

Binds to 30S subunit of

bacterial ribosome

Bactericidal

Gram negative

Pseudomonas

Proteus

Enterobacter

Klebsiella

Serratia

E coli

Some gram positive

activity

Streptococci and

enterococci are

relatively resistant

No action against

anaerobes

Tobramycin is more

active against

pseudomonas

Gram negative

sepsis

Endocarditis

Dose5mg/kg/day if

normal renal

function

4mg if creatinine

clearance 80ml/min

3mg if creatinine

clearance 50ml/min

2mg if creatinine

clearance


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interactions

Absorption and

distribution

Metabolism and

excretionSulfonamides

Sulpha-

methoxazole

Anti-folate

Sulphonamides are structural

analogues of para-

aminobenzoic acid that bind

to dihydropteroate synthase

and competitively inhibit

folic acid synthesis

Bacteriostatic

Bacteriocidal when given

with trimethoprim

Broad spectrum

Gram positive and gram

negative actions

Includes Chlamydia

Stimulates growth of

Rickettsia

Used in combination

with trimethoprim in

the treatment of

urinary tract

infection,

respiratory tract

infections and in

episodes of

resistance

Resistance common

Use is limited by

toxicity

Very cheap

therefore extensive

use in 3rd world

Resistance

mechanisms

Some bacteria

utilise exogenous

folate therefore are

not susceptible

Decreased

intracellular

accumulationreduced

permeability

Decreased binding

to dihydropteroate

synthase

Resistance is

common

Toxicity

5% of patients have side

effects


Fever

Exfoliative dermatitis

Photosensitivity

Stevens Johnson syndrome

GITSulfonamides may

precipitate in urine and may

cause obstruction

MarrowAplastic anaemia

ContraindicationsPorphyria

Orally active (slow)

Sulfamethoxazole

chosen due to its

similar half life to

trimethoprim

Wide distribution

Metabolised in liver

and excreted in

urine.

Metabolised

impaired in slow

acetylators

Dose adjustment

required in renal

insufficiency

Half life 10-12

hours

Trimethoprim Anti-folate

Inhibition of dihydrofolate

reductase

Synergistic effect when

given with sulphonamide due

to sequential action in folate

synthesis

Broad spectrum

Especially

E coli

Enterobacter

Proteus

Neisseria

Salmonella

Klebsiella

Haemophilus

Not active against

Pseudomonas

Mycoplasma

Mycobacterium

Treponema

Used in combination

with trimethoprim in

the treatment of

urinary tract

infection,

respiratory tract

infections, skin

infections

Resistance

mechanisms

Some bacteria

utilise exogenous

folate therefore are

not susceptible

Decreased

intracellular

accumulation due to

reduced

permeability

Decreased binding

to dihydrofolate

reductase

ToxicityNausea, vomiting, diarrhoea

GIT

Sulfonamides may

precipitate in urine and may

cause obstruction

MarrowMegaloblastic anaemia

Contraindications

Porphyria

Concentrated in

prostate, vagina.,

kidney and lungs

Metabolised in liver

and excreted in

urine.

Dose adjustment

required in renal

insufficiency

Half life 10-12

hours


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interactions

Absorption and

distribution

Metabolism and

excretionQuinolones

the important

quinolones are

synthetic

fluorinated

analogues of

nalidixic acid.

Nalidixic acid

Norfloxacin

Ciprofloxacin

Ofloxacin

Sparfloxacin

DNA gyrase inhibitors

Block relaxation of

positively supercoiled DNA

required for normal

transcription and replication

of bacteria.

Active against a variety

of gram negative and

gram-positive bacteria.

Nalidixic acid

Doesnt achieve

systemic levels

therefore only used for

urinary tract infections.

NorfloxacinLeast active

Ciprofloxacin

Particularly active

against gram-negative

cocci and bacilli

including enterobacter,

pseudomonas, neisseria,

haemophilus and

campylobacter.

Less effective against

gram-positive organisms

especially streptococci.

Ofloxacin

Sparfloxacin

Improved gram-positiveaction. Longer half-life.

Anaerobes are generally

resistant though

intracellular organisms

are susceptible.

Generally reserved

for use on resistant

organisms.

Urinary tract

infections

especially with

multi-drug resistant

bacteria and

pseudomonas.

Respiratory tract

infections

especially

pseudomonas and

cystic fibrosis.

Gonococcal

infection.

Bacterial

gastroenteritis

Joint and soft tissue

infections.

Resistancemechanisms

Uncommon point

mutation in the

quinolone-binding

region.

Dose

Ciprofloxacin

500mg bd.

Well tolerated.

General

Nausea

Diarrhoea

Headache

Rash

May damage growing

cartilage therefore not

recommended in children

unless no other drug

available or suitable

Little data on pregnancy.

Excreted in breast milk.

InteractionsEnzyme inducerincreases

the metabolism of phenytoin


with greater than

80% bioavailability.

Concentrates in

prostate and kidney.

Half-life 3-4 hours.

Excreted renally

therefore

accumulates in

renal failure.


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10


interactions

Absorption and

distribution

Metabolism and

excretionMetronidazole Antiprotozoal agent with

potent anti-anaerobic actions

Reduction of the nitro group

produces toxic metabolites

Only active against

obligate anerobes

Bacteroides

Fusobacterium

Clostridium

Anaerobic

streptococci

Trichomoniasis

Giardiasis

Amoebiasis

Toxicity

General


Metallic taste

Dry mouth

Headache

Disulfiram-like effect with

alcohol

Pancreatitis

CNSAtaxia, seizures

Interactions

Potentiates the effect of

warfarin

Reduced half life if taken

with enzyme inducers

phenytoin, phenobarbitone

Increased half life if taken

with enzyme inhibitors

cimetidine


Also given rectally

and intravenously

Metabolised by

liver

Half life 7 hours

May accumulate in

hepatic dysfunction


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interactions

Absorption and

distribution

Metabolism and

excretionAcyclovir Antiherpes agent

Selectively activated by

phosphorylation in infected

cells only.

Acyclovir triphosphate

inhibits vial DNA synthesis

Active against

HSV1 and HSV2

Varicella zoster

Genital and labial

herpes

Herpes encephalitis

DoseOral

200mg 5 times daily

Intravenous

10mg/kg every 8

hours

Toxicity

Well tolerated

Nausea, vomiting

Headache

Rapid intravenous

administration may be

associated with renal

insufficiency and

neurological toxicity

Oral, topical and

intravenous

formulations

Well absorbed orally,

low bioavailability,

hence frequent

dosing

Distributed to most

tissues

Cleared by

glomerular

filtration and

tubular secretion.

Half life 3-4 hours

Dosage adjustment

required for renal

impairment


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12

Disinfectants and

antiseptics

Disinfection

chemical orphysical process that inhibits or kills micro-organisms

Antiseptic

a disinfectant with sufficiently low toxicity to allow use directly on skin,

mucous membranes and wounds

Sterilisation

a process to remove all microorganisms, spores and viruses

Autoclaving

sterilisation using pressurised steam at 120ofor 20 minutes

a guide to antibiotics

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