antimicrobial pharmacology

what are antibiotics

evolved by bugs to fight each other

hijacked by man and now an arms race - resistance develops, new substances evolve

Man has synthesised new versions and developed ways to block resistance

Bugs fight back

More use = more selection pressure = more resistance

some are completely synthetic = completely chemical synthesised

substance produced by bugs/plants which are then modified to alter properties

pharmokinetics

action of animal on drug

pharmacodynamics

action of drug on animal

antibiotics = on the bacteria

mechanism of action

aim to prevent growth and/or survival of invading organisms while causing minimal damage to host

• using specific pathways that a mammal doesn’t have so doesn’t kill a mammal

selective toxicity = magic bullets

tend to target receptors or pathways unique to prokaryote cells

how do antibiotics work

distrupt cell wall production or function

• beta-lactams, penicillins, cephalosporins

distrupts cell membrane function

• ionophores

distrupts DNA function

• potential sulphonamides, fluroroquinolones, aminocoumarins

distrupt protein synthesis

• aminoglycosides, tetracyclines, macrolides, florphenicol

chemotherapeutic triangle

antibiotic classifications

how they affect bacteria - bacteriostatic or bacteriocidal

range of bacteria they affect

post-antibiotic effect

whether they are concentration or time dependent in how they kill bacteria

chemical structure and properties e.g molecular size, lipid solubility

Depend on concentration

• Gentamicin can be static, but cidal at 2-4x higher concentration

• Tetracyclins would be toxic given at bacteriocidal concentrations, so used at static dose.

Bacteriostatic may have a slow onset of “action” and require good host immune response as the drug do not clear the infection, the body does.

Should not give static drugs with cidal, as many cidal drugs require active growing cells. Will only get the static action.

bacteriostatic antibiotics

antibiotics that prevent replication but don’t kill susceptible bacteria

• number of organisms will stay the same

e.g tetracyclines, macrolides, sulphonamides alone

bacteriocidal

antibiotics that kill susceptible bacteria

• number of organisms will go down

e.g fluroquinolones, B-lactams, trimethoprim, potantiated sulphonamides

spectrum of activity

broad spectrum

• no need to diagnose

• select for resistance in wide population of organisms

narrow spectrum

• greater chance of failure

• will not select for resistance in enteric gram -ve organisms when treating gram +ve disease

penicillins = narrow spectrum

fluroquinolones = broad spectrum

broad vs narrow spectrum

empiric therapy

• infecting organisms not yet identified

• more broad spectrum use

definitive

• organisms identified and specific therapy chosen

• more narrow spectrum

prophylactic (preventative)

• prevent an initial infection or its recurrence after infection

currative treatment

treatment of sick animal or group of animals following diagnosis of infection and/or clinical disease

prophylactic treatment

veterinary medicines regulations 2024

Prophylactic use is defined as =

‘the administration of a medicinal product to an animal or group of animals before clinical signs of disease in order to prevent the occurrence of disease or infection.’

Clinical signs of disease include visible outward signs of disease as well as sub-clinical disease detected through laboratory testing, for example, somatic cell counts in milk and/or other pathology testing

routine use as - repeated, habityal use such as treating every batch of animals without attempts to reduce ongoing use of sntibiotics and/or without a proper evidence/ risk based assessment to determine whether antibiotic use is necessary

mataphylaxis treatment

Metaphylaxis treatment – which is mostly equivalent in human

medicine to “group prophylaxis”

“means the administration of the veterinary medicinal product to a group of animals after a diagnosis of clinical disease in part of the group has been established, with the aim of treating the clinically sick animals and controlling the spread of the disease to animals in close contact and at risk and which may already be sub-clinically infected

antibiotic classes and examples of antibiotics

try to use class D

how long does it need to be there for

mode of action

• time over MIC(minimal inhibitory concentration) dependent - peniclinis, cephalosporins, tetracyclines, macrolides

• concentration dependent - aminoglycerides

• area under curve dependent - fluroquinolones

ratio of plasma to tissue distrubution may not matter as long as enough gets to where it is needed - judged by MIC of organism

post-antibiotic effect - PAE

the ability of a drug to suppress or kill bacteria after the drug concentration has dropped below the MIC

highly dependent on antimicrobial and the pathogen

concentration dependent antibiotics

plateaus when you have maximium amount of antibiotic that you need

time dependent antibiotics

have to get it over a certain concentration for a certain amount of time

if you don’t then you have no effect

systemic availability of the drug

dosage

route of administration

dosing rate - some need to be spread out across multiple sites to work

access to site of infection

injectables

used for treatment of severe infections

may depend on availability and toxicity

advantages

• used for drugs poorly absorbed, inactive or inefective if given orally due to action of GI tract - poor blood supply, immunocompressed, dehydrated, GI infection

• IV route provides immediate onset of action and may get higher initial concentrations depending on tissue

• IM and SC routes may slow or delay onset of action - but can stay for longer

• client training and compliance to give injection

disadvantages

• can be painful

• cost

• aseptic technique required

• side effects - higher initial concentration in heart and other tissues

• must be soluble prep

• needle stick injury, sharps disposal safety and cost

intravenous administration

total dose enters systemic circulation

high concentration quickly declines

high concentration gradient from plasma to tissue

Drug molecules penetrate cellular barriers and enter cells via passive diffusion

Physiochemical properties, lipid solubility, degree of ionization (weak acids/bases) determine concentration obtained in the tissues, transcellular fluids (CSF, synovial and ocular) and glandular secretions (milk, saliva, prostatic)

Often in the form of a salt (pH varies) at high concentration = IV preparations must be given slowly or via infusion

route of administration

IM or SC

absorption following injection

• formulation of drug - concentration is important

• vascularity of injection site - lateral neck preffered site in large animals - consider scaring and meat quality

• physiochemical properties

>20ml volumes should not be used in one site of a cow

rapidly absorbed with peak plasma levels ~1hr

route of administration - injectables

IM or SC

withdrawl periods

• varies with formulation of drug and between animal species due to metabolism

• parental preps should be formulated to not cause local tissue damage when given IM = tissue damage may lead to persistence of drug residues, hide damage

tissue damage at injection site

route of administration - oral administration

lots of dosage forms - incl medicating water and feed

dissolution will dictate rate of drug absorption

monogastric versus ruminants - diluted rumen and may be metabolised by organism/ select for resistance/kill them

systemic availability

• fraction of dose which reaches systemic circulation unchanged - bioavailability

• influenced by - stability in gastric contents, susceptibitlity to inactivation, physiochemical properties(passive diffusion across epithelial barrier)

drugs then go into hepatic portal venous blood to liver which is main organ for drug metabolism

metabolism of drug before it reaches systemic circulation

pre-systemic metabolism = 1st pass effect

• gut lumen - bacterial

• mucosal epithelium

• liver

• effect of liver blood flow and metabolic rate

important for activating some drugs

other factors

• presence of food or binding to food can affect it

• decreases systemic availability for following drugs - most penicillins, oral sephalosporins, trimethroprim/sulphonamide combinations, tetracyclines

• doxycycline and erythrocoplasmacin systemi availability increased after food in dogs

• in horses systemic availability for drugs decreased by feeding therefore recomended to not feed for up to 2 hrs following administration

drug distribution systemically

determined by blood flow to tissues

ability to penetrate cellular barriers

rate is dependent upon

• perfusion - lipophilic drugs - fluroquinolones, macrolides, lincosamides

• diffusion - ionised or polar drugs

binding of drug to plasma protein also limits immediate availability

selective binding e.g aminoglycerides to phospholipid rich inner ear and kidney cortex tissues = small fraction of total drug but can result in toxicity

volume distribution

= reflection of amount left in blood stream after drug has been absorbed

• if drug held in blood stream it will have a small volume of distribution

• if very little drug remains in blood stream has a large volume of distribtuion

plasma protein binding

can affect

• tissue penetration

• volume of distribution

• half-life

• elimination

reduces free fraction of drug available for bacterial killing

reveraible

PP binding important for some drugs and allows them to be long acting - good for B-lactams

cefovecin ~97% PP binding in dogs and 99% in cats

excreted unchanged in urine - only unbound fraction

halflife of antimicrobials

time required for plasma concentration to half after reaching pseudo-equilibrium distribution

The larger the volume of distribution, the longer it takes to clear the drug, at a constant rate of clearance

important for dosing intervals

synergism

= potentiation of 1 drug action by another

may be due to preventing drug metabolism or blocking bacterial metabolism in different ways

concentration deendent

• do pharmo-kinetics match in theses species

phase of bacterial of bacterial life cycle when active

• growth

• biofilms

possible antagonism if concentrations wrong

inhibition of L-form to enable activity

• they have just a cell membrane and no cell wall

half life vs clearnace

clearance = ability to eliminate drug

half-life - overall elimination during terminal phase which depends on both clearance and distrubtuion

drug elimination

various routes by which drugs can be eliminated

most important = kidney, liver

less important = bile, sweat, milk, faeces for oral antibiotics with poor absorption

drug clearnace

most drugs are cleared from plasma in 2 ways by metabolism in liver and by being eliminated(unchanged) through kidneys

fraction unchanged(fu) represents the proportion cleared by kidneys while 1-fu represents fraction cleared by metabolism

drug elimination via liver

depends on

• blood flow to liver

• activity of enzyme in liver - influenced by milk yield or work animal is doing

liver enzymes will chemically alter the drug to form metabolites which may

• inactivate

• equally or more active than the parent

Metabolites are eventually eliminated via the kidney as they are usually more water soluble

Factors which may reduce elimination via the liver

• elderly have poorer blood flow

• neonates have a low liver enzyme activity

• some drugs reduce liver enzyme activity

• extensive liver damage (cirrhosis, liver fluke)

antibiotics mechanisms of action

cell wall inhibitors - penicillins, cephalosporins, polymixins, bacitracin

protein synthesis inhibitors - aminoglycerides, macrolide, tetracyclines

DNA metabolism - sulfonamides, potentiated sulfonamides, fluroquinolones, metronidazole

penicillins classes of agents

1. Natural: penicillin G, penicillin V

2. ß-Lactamase Resistant: cloxacillin

3. Aminopenicillins: amoxicillin, ampicillin

4. Extended Agents: ticarcillin, carbenicillin

5. Augmented Agents: amoxicillin + clavulanate

penicillins common properties

1. cleared by kidneys (filtered + tubule transport)

2. does NOT enter CNS (meningitis)

3. weak acids; 50% plasma protein bound

penicillins side effects

Immune-mediated reactions: autoimmune haemolytic anemia and immune-mediated thrombocytopenia (Type II hypersensitivities), anaphylaxis (Type I hypersensitivity).

Procaine reactions (e.g. CNS stimulation). hyperexcitability , muscle tremors, ataxia, apnea and cardiac arrest. No treatment.

Can inhibit protein binding or renal excretion of other acidic drugs