Please enable JavaScript.
Coggle requires JavaScript to display documents.
Therapeutics: Antimicrobials - Coggle Diagram
Therapeutics: Antimicrobials
Aim
target site of infection
maintain an effective inhibitory or lethal concentration
Important considerations in farm animal veterinary practice
Cost
primary cost of the medicine
ease and frequency of administration
duration of treatment e.g. cost of withdrawal time
is the treatment appropriate in light of the prognosis
'dying is not a problem, but suffering is'
Theoretical antimicrobial decision process
1) site of infection is located and identity of infecting organism established by culture
2) the minimal inhibitory concentration (MIC) of each antimicrobial agent for the infecting organism is identified
3) An initial selection is made based on susceptibility of the organism and knowledge of the agent's ability to penetrate the site of infection and achieve the dose at non-toxic dose rates
4) The dose rates, route of administration, and frequency of administration required to achieve these concentrations should be considered
5) selection of drug, consider cost, ease of administration, withholding periods, potential toxicity and efficacy.
Practical antimicrobial decisions
often require treatment before c+s etc.
due to economic reasons and client care
case example: mastitis in dairy cows
cows immediately given intramammary treatment
but sterile sampling of clinical mastitis cases and follow up c+s can allow for the day to day farm mastitis treatment protocol to be assessed for accuracy and success in terms of pathogen prevalence and antibiotic sensitivity on the farm
on farm culture (OFC)
is becoming more commonplace
in 12-24hr can identify gram positive v gram negative pathogens in mastitic cows
treatment is delayed until the OFC result and those animals with G-ve results typically receive no AM tx
this is based on the principle that the majority of coliform mastitis cases self resolve without the need for AM tx
common things happen commonly
parachute mastitis in recently calved cows is commonly associated with infection by coliform, but also associated with staphylococci and streptococcus organisms or more rarely trueperlla progenies or pasteurella multocida
treatment must be initiated immediately to save gland or even the cow
Approaches for treatment when no certainty of the pathogen
direct therapy at most prevalent or likely agent
if disease could be associated with many different organisms with different susceptibilities and clinical experience suggests that there is not just a single predominant infectious agent
broad spectrum AM agent
change to more specific agent once susceptibility/pathogen determined
Amoxicillin
trimethoprim-potentiated sulphonamides
Empirical choice
advantages
quicker and cheaper
disadvantages
more likely to have wrong antibiotics (up to 50% of cases)
more likely to have wrong dosing regimen
potential for waste of time and money
potential for resistance (50% of isolates resistant to antibiotics commonly used empirically)
Susceptibility based choice
advantages
very likely to have the right antibiotic
more likely to have correct dosing regimen
save time and money if wrong antibiotics are chosen empirically
disadvantages
takes 24-48h
cost
one or two members of each class tested (assumption of similar results with other members)
lab protocol may not accurately represent reality
Route of administration
Intravenous injections
attain high and immediate blood and tissue levels
use for septicaemia and other life threatening diseases
concentrations much higher than same dose of IM or oral
greater diffusion concentrations are achieved at sites of infection
Intramuscular injection
most common route for Abs in food producing animals
when possible always abide by licensed routes
avoid in meat producing animals
esp. with irritant preparations
lesions can be detected at slaughter 12m after the IM injection of long acting tetracyclines
if must be given:
muscles of neck
but consider health and safety of this
site of IM administration can influence rate of absorption, the bioavailability and the subsequent pharmacokinetics of the administered antibiotics
in cattle and horses: injection in neck gives more favourable pharmacokinetic parameters than in the gluteal or shoulder muscles
differences in the spread of the injected drug within and between the muscles and differences in blood supply
Subcutaneous injection
providing not deposited in a fat depot, provides a reasonable alternative to IM injection (esp with concerns regarding lesions associated with IM)
Oral
generally restricted to
pre-ruminant animals, young foals and pigs
blood and tissue levels considerably less than parenterally - therefore dose usually 2-5x higher
less realisable as absorption characteristics vary with volume of ingesta, which variably bind the orally administered drug
oxytetracycline and trimethoprim have much lower bioavailability to calves when administered in milk, rather than in water, due to high degree of binding to milk
almost all Abs are excreted by the kidney and the urine usually contains high levels of them
Duration of treatment
therapy should be continued for at least 3-5 day period or longer if there is evidence of chronic infectious disease with localisation
treatment continued one day beyond the return of body temp
esp. if bacteriostatic abs are being used
chronic pyogenic processes require treatment for a 2-4w period or even longer.
Availability
all pneumonia treatments need to be able to work in acidic pus environment
• The law requires farmers to keep specific records of medicines used in food producing animals
• Records must be kept for a
minimum of 5 years
from the date of administration of a product (Vet
practices also need to keep proof of sale documentation for 5 years)
• 1 – Proof of purchase – product name, batch number, date acquired, quantity acquired and
name and address of supplier (All provided by vets)
• 2 – At time of Administration – Name of product, date of each administration, quantity
administered, withdrawal period, ID of animals treated
• 3 – Disposal if product not used for treatment must also be recorded
• Most medicines in bottles must be disposed of or used within 28 days of breaching the bottle
(may be sooner)
Mode of action of abs
bactericidal abs
beta lactams
- penicillin, cephalosporins, semisynthetic penicillins - amoxicillin cloxacillin
aminoglycosides
streptomycin
fluoroquinolones
TMPS
some groups are bacteriostatic at low concentrations
Preferred uses
infections that cannot be controlled or eradicated by host mechanisms alone because of the nature or site of infection e.g. bacterial endocarditis
or due to reduced immunocompetence of the host e.g. acute septicaemic infection, in which there is frequently a significant leukopenia and a quick maximal bactericidal effect is required and there is also the need to prevent subsequent localisation
bacteriostatic abs
tetracyclines
macrolides
chloramphenicol - florfenicol
drugs temporarily inhibit the growth of organisms, but effect is reversible once drug removed
to be effective clinically, the drug concentration should be maintained
above the MIC
throughout the dosing interval
many can be bactericidal if drug exposure is sufficiently high or prolonged
Highest Priority Critically Important Antimicrobials (HP-CIAs)
Quinolones
known to select for quinolone-resistant salmonella and E coli in animals
one of few available therapies for serious salmonella and E coli infections
notably licensed in food producing animals
Cephalosporins (3rd + higher generation)
known to select for cephalosporin-resistant salmonella and E coli in animals
one of few available therapies for serious Salmonella and E. coli infections in humans, particularly in children.
notably licensed in food producing animals
Macrolides and ketolides
known to select for macrolide-resistant campylobacter spp. in animals, esp campylobacter jejuni in poultry
one of few available therapies for serious Campylobacter infections, particularly in children, for whom quinolones are not recommended for treatmen
notably licensed in food producing animals
Glycopeptides
known to select for glycopeptide-resistant Enterococcus spp. in food animals (e.g. when avoparcin was used as a growth promoter, vancomycin-resistant enterococci (VRE) developed in food animals and were transmitted to people)
glycopeptides are one of the few available therapies for serious enterococcal infections
Polymyxins
known to select for
plasmid mediated polymyxin-resistant E. coli
in food animals. At the same time, intravenous polymyxins are one of few available therapies for serious
Enterobactericeae
and
Pseudomonas aeruginosa multi-resistant infections
in people in healthcare settings in many countries, especially in seriously ill patients in critical care.
https://www.noah.co.uk/focus-areas/antibiotics-for-animals/critically-important-antibiotics-veterinary-medicine-european-medicines-agency-recommendations/
European Medicines Agency (EMA)
category 1: low or limited risk to public health
includes macrocodes, certain penicillins and tetracyclines
general principles of responsible use to be applied
category 2: higher risk to public health
fluoroquinolones
3rd and 4th generation cephalosporins
colistin
(aminoglycosides, broad-spectrum penicillins)
restricted to use where there are no alternatives or response to alternatives expected to be poor
Antimicrobial resistance
natural or intrinsic resistance (predictable resistance)
Mutational resistance (unpredictable resistance)
extrachromosomal or acquired resistance
1) Use antibiotics whenever bacterial infection is confirmed.
2) Start treatment early
3) Dose correctly: (Too low a dose and there is concern over creating antimicrobial resistance -
AMR, and too high a dose and there can be concerns over toxicity and also cost.)
4) Avoid prolonged use of antibiotics.
5) When possible, select narrow-spectrum agents, based on definitive identification of the
infectious agent, rather than broad-spectrum agents.
6) Maintain the dosage – What is an appropriate length of course? Most therapeutics are licensed
in large animals for 3-5 days. Chronic infections may require 4 to 6 weeks of treatment. In human medicine there has been a trend within the last 5 years to reduce course length. Often course length can be determined by the cessation of clinical signs.
7) Susceptibility tests: Not practical for each case, periodic testing will help establish a trend for a particular disease or on a particular premise.
8) Evaluate clinical effectiveness: Improvement by 4 days after initiation of treatment
9) Prevention and good management: As simple as controlling ventilation, humidity, sanitary
environment, and avoiding stress, but in practice often hard to achieve.
Avoiding AMR – The “D”s
•
De-escalate
: No antibiotic usage when alternate therapy is available, limit duration of treatment (shortest course of therapy clinically acceptable), rotate the usage of antibiotics on a regular schedule
•
Design
: Effective dosing regimen, selection of most appropriate antibiotic for the organism while narrowing spectrum of activity
•
Decontaminate
: Reduce bacterial exposure (wearing gloves, hand washing, proper bandaging, strict asepsis during surgery, etc.).
Penicillins
Beta lactams
bactericidal and time dependent
susceptible to beta lactamase producing bacteria
excreted in the urinary tract
course or time dependent
allergies/sensitivities to penicillin are most commonly reported drug allergy
Original penicillins e.g. penicillin G
good g +ve spectrum, relatively poor G -ve
not v efficacious in pus
Synthetic/amino penicillins e.g. amoxicillin
broad spectrum (G-ve and +ve)
work in pus
potentiated amoxicillin e.g. amoxicillin clavulanic acid
same spectrum as amoxicillins with added benefit of remaining effective in presence of beta lactamase producing bacteria
Synergistic with aminoglycosides
penicillin on its own is inactivated in acidic environments (abscesses/tissue necrosis
clinical applications
Pen Strep licensed for mixed infections - navel ill/ joint ill, pneumonia, listeriosis, meningitis, septicaemia, mastitis, urogenital infections, Salmonella enteritis (up to 3 days)
Betamox (Amoxicillin) licensed for mixed infections – lumpy jaw, wooden tongue, IBK,
pneumonia, mastitis, staph, strep and salmonellas, (up to 5 days)
Combiclav (Amoxicillin&Clavulanic Acid) licensed for
Wide range of diseases; respiratory, soft tissue (joints/navels/abscesses), metritis and mastitis (3-5 days)
Cephalosporins
beta lactams (bacteriocidal and time dependent)
widely distributed and renal excretion
As move down generations G +ve action declines and G –ve action
increases.
highly protein bound so not passed into the milk
acid stable so works in pus
only 3rd and 4th generation cephalosporins are HP-CIAs (need c+s)
Aminoglycosides
bactericidal and concentration dependent
G-ves and some have G+ve
Inhibit protein synthesis but penetrate cell membrane via an oxygen dependant mechanism
• Therefore minimal anaerobic activity
• High initial concentration key as adaptive resistance important.
• Doesn’t work in pus
• Narrow Spectrum Ags – Streptomycin
• Broad Spectrum Ags – Framomycin G –ve and some G +ve
• Incorporated in Ubro Red/Ubro Yellow for broad spectrum of activity
Nephrotoxic
Tetracyclines
broad spectrum bacteriostatic, cidal at high doses
aerobic and anaerobic
inhibit protein synthesis
distribute rapidly and extensively, but absorption decreased in presence of milk, require high doses to penetrate uterine lumen
resistance common
globally used (not UK) as in feed growth promoters and mass prophylaxis
Engemycin (Oxytetracycline) – licensed for Staph, Strep, Listeria, Campylobacter and Pneumonia bacteria but also spirochaetes eg. lepto, and mycoplasma, rickettsia and some protozoa
TMPS broad spectrum bactericidal
• Bacteriocidal (due to synergisitic action of sulphonamide and trimethoprim; on their own are bacteriostatic)
• G +ve, G –ve, aerobes with some anerobic activity
• Sulphonamides are a analogue of PABA; used in folic acid production
in bacteria, crucial to DNA/RNA production
• Negated by pus (bacteria able to bypass their need for folic acid)
• Trimethoprim works on the next stage of folate production
• Resistance common and plasmid mediated.
• Readily absorbed in the GIT, and distributed through out all tissues, but concentrates in soft tissue
• TMPS (Norodine 24) Licensed for Respiratory, including secondary to viral/mycoplasma, urogenital including metritis, and alimentary tract infection.
• Wary of inaction in pus and action on metritis
• For a maximum of 5 days, single dose may be sufficient
Macrolides
• Bacteriostatic and Time dependant (again in circumstance can be cidal
• G +ve, Mycoplasma with v minimal G –ve spectrum (struggle to penetrate
cell wall)
• Aerobic with some anaerobic activity
• Inhibit protein synthesis
• Accumulates within phagocytes; transported to site of infection and enhance phagocyte bacterial killing – Explains mycoplasmal activity
Tylosin (Tylan) – Licensed for Respiratory, Genito-urinary tract infections, cellulitis, post op infections, foul, mastitis and calf pneumonia.
• Staphs, Streps, Corynebacterium, Campylobacter, Spirochaetes, Mycoplasma, Pasteurella
Chloramphenicol
• Bacteriostatic and Time dependent
• G +ve and G –ve, aerobic and anaerobic, plus rickettsia
• Inhibit protein synthesis
• Plasmid borne resistance in both G +ve and G –ve organisms, 5xhigher in G +ve’s
• Benefit from florfenicol being veterinary only
• CSF conc may reach 60% that of blood
• Florfenicol (Nuflor/Shotaflor) licensed for Respiratory infections (mannheimia, pasteurella, and histophilus), however not licensed for lactating animals producing milk for human consumption
• Either 2 doses (1ml/15kg) 48hrs apart or single dose 2ml/15kg)
Fluoroquinolone
• Bacteriocidal and Concentration Dependant
• Only with a culture and sensitivity previous done would use of a
Fluroquinolone ever be justified
• G –ve aerobic activity with variable G +ve action (predominately vs staphs)
• Limited anaerobic activity
• Inhibits bacterial DNA
• Also concentrated in phagocytes so well transported to site of infection, well distributed in blood. (Explains mycoplasmal activity)
• Marbofloxacin (Marbocyl) Licensed for Respiratory infections and E.coli mastitis
• (Staphs), Enterobacteriacae, Salmonella, Pasteurella, Pseudomonads, Haemophilus)
• 3-5 days
• Forcyl – Licensed for Respiratory Infections, and acute mastitis