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HOST FACTORS
-plays an important role in determining
outcome and applies particularly to
circulating and tissue pathogenic activity.
-In some organism the pathogenic
organisms are located intracellulary within
pathogenic cells ; protected from drugs
that is absorbes poorly
o
3. PHARMACOLOGICAL FACTORS
o
Clinical Efficacy
- dependent on achieving satisfactory drug
concentration at infection site.
-influenced by standard pharmacological
factors (absorption, distribution, excretion
metabolism)
-may be impaired by factors such as:
presence of food
drug interactions
impaired gastrointestinal function
Oral agent
-gastrointestinal absorption is satisfactory
-inappropriate if patient is vomiting, or
undergone surgery; Parental agent will be
required and has advantage of rapid
effectivity
Antibiotic selection
- varies accordingly to anatomical site
Lipid Solubility
-is importance in relation to drug distribution
Presence of Inflammation
-may affect drug penetration into the tissues
Biliary Excretion
-where therapeutic drug concentrations within
bile duct and gallbladder depends
-in presence of biliary disease the drug
concentration may fail to reach therapeutic
levels.
- reduced dosage w/ presence of renal and
hepatic function.
- continues to rise
-In UK antibiotic prescribing:
90% topical and oral agents and 10% injectibles
- Clinical use of these agents be based on clear
understanding of principles that have evolve to
ensure safety ,yet effective, prescribing
o Antimicrobial Chemotherapy
- advantages are self evident
-prescribers face a dilemma: initial antimicrobial
therapy must be effective against all likely
infective organisms for the indiv. presentation,
but excessive use of broad spectrum agents
contributes to development and selection of drug
resistant organisms.
o Anti-infectives
-only class where inappropriate use in one patient
can jeopardize the efficacy of treatment in other
individuals
-Use of Antibiotic/Anti-infectives:
veterinary practice as growth promoters.
In humans in management of bacterial
infection, parasitic, fungal disease,etc.
Prevention of infection in various high risk
circumstances
PRINCIPLES OF USE OF
ANTIMICROBIAL DRUGS :
1. SUSCEPTIBILITY OF INFECTING
ORGANISMS
o
o
Drug selection
-based on knowledge of activity against
infecting microorganisms
Selected Organism
-predictably susceptible to particular
agent
-laboratory testing rarely performed
Streptococcus pyogenes
- uniformly sensitive to penicillin
Gram-negative enteric bacteria
- less predictable, laboratory
guidance is essential
Common bacterial pathogens
- some that are susceptible in vitro
to particular agent but can be
inappropriate to use.
Tuberculosis
- drug resistant strains have emerged
largely among inadequately treated or non
- compliant patients.
-Resistance patterns vary but increasingly
include rifampicin and isoniazid.
5. DRUG COMBINATIONS
-Antibiotics are generally used alone, but may be
prescribed in combination
- prevent resistance emerging during treatment
-Combining two antibiotics may result in:
o Indifference or antagonism
o Synergism
- microbial inhibition is achieved at
concentrations below that for each agent
alone
- Advantages:
treating relatively insusceptible
infections such as enterococcal
endocarditis
is that it may enable the use of toxic
agents where dose reductions are
possible
-Common reason for using combined
therapy is for
treatment of confirmed/suspected
mixed infections
where a single agent alone will fail to
cover all
pathogenic organisms.
4. DRUG RESISTANCE
-may result to:
Impaired cell wall/cell envelope
penetration
Enzymatic inactivation
Altered binding sites or active extrusion
-It may be (types):
a) Neutral
b) Acquired characteristic of
microorganism
- result from mutation, adaptation, or
gene transfer
o
Spontaneous Mutation
-occurs at low frequency
Genetic Resistance
- may be chromosomal or transferable on
tansposons or plasmids
Plasmid-mediated-resistance
-increasingly recognize among
gram-negative enteric pathogens
-by process of conjugation
plasmids may be transferred
-code for multiple antibiotic
resistance
6 . ADVERSE REACTIONS
- all chemotherapeutic agents have the potential
to produce adverse reactions with varying
degrees of
frequency and severity, including hypersensitivity
reactions and toxic effects.
-many adverse events are idiosyncratic and
unpredictable
o
Hypersensitivity reactions
Acute pharyngitis
8. CHEMOPROPHYLAXIS
- increasingly important use of antimicrobial
agents is
that of infection prevention, especially in
relationship to surgery.
-The principles that underlie the
chemoprophylactic use of antibacterials relate to
the predictability of infection for a particular
surgical procedure, in terms of its occurrence,
microbial aetiology and susceptibility to
antibiotics.
- Extended to other surgical procedures where
the risk of infection may be low but its occurrence
has serious consequences
- It is important that chemoprophylaxis be limited
to the
perioperative period ; first dose being
administered
approximately 1 hour before surgery (injectable)
-single dose is now considered sufficient.
-If prolonged beyond period is becomes less cost
-effective and increases the risk of adverse drug
reactions and superinfection
Therapeutic drug concentrations
- reduce the number of potentially
infectious organisms
and prevent wound sepsis if present in
operative site
o Prophylaxis
- if delayed to the postoperative period,
then efficacy is
markedly impaired
o
CLINICAL USE:
o Cystic fibrosis
- multisystem congenital abnormality that
often affects the lungs and results in recurrent
infections
Staph. aureus >H. infl uenzae >
Pseudomonas aeruginosa
Pseudomonas aeruginosa
- associated with copious
quantities of purulent sputum
that are extremely difficult to
expectorate
-cofactor in the progressive lung
damage that is eventually fatal in
these patients.
-require repeated hospitalization
and administration of parenteral
antibiotics such as an
aminoglycoside, either alone or in
combination
Legionnaires disease
- treated with erythromycin and,
in the presence of severe
pneumonia rifampicin is added to
the regimen.
Mycoplasma infections
- best treated with either
erythromycin or tetracycline
Streptococcus pneumoniae
-commonest cause of
pneumonia
-responds well to penicillin
Respiratory Quinolones
- levofloxacin and moxifloxacin
- exhibit increased activity
against Gram
positive organisms compared to
ciprofloxacin
Tetracycline
- indicated for both psittacosis
and Q fever.
o Lung abscess
- Destruction of lung tissue may lead to
abscess formation
-feature of aerobic Gram - negative bacillary
and Staph. aureus infections
3. Gastrointestinal Infections
- gut is vulnerable to infection by
Viruses
Bacteria- cause disease of the gut as a
result of either
mucosal invasion or toxin production or
a combination
of the two mechanisms
Parasites
Fungi.
-Treatment: largely directed at replacing and
maintaining
an adequate intake of fluid and electrolytes.
- Self limiting
- Antibiotics are used to treat severe
Campylobacter and Shigella infections;
erythromycin and ciprofloxacin are the preferred
agents.
Virus infections
- most prevalent but are not susceptible to
chemotherapeutic intervention
o Bacterial infections
- more readily recognized and raise
questions concerning the role of antibiotic
management
o Typhoid and paratyphoid fevers
- known as enteric fevers
o
o Pathogenesis
-in structural or drainage problems the risk exists
of ascending infection to involve the kidney and
occasionally the bloodstream. - may be absent in
women of childbearing years
-infection can become:
Recurrent
symptomatic
extremely distressing
- normal maturation of the kidney may be
impaired and result to progressive damage in
later life (renal failure)
-it is essential to confirm the presence of
bacteriuria (a condition in which there are
bacteria in the urine) ; symptoms alone are not
reliable
- Indications for treating asymptomatic
bacteriuria:
presence of underlying renal abnormalities
(stones)
repeated infections caused by Proteus
spp.
o Drug therapy
- antimicrobial treatment of urinary tract infection
presents a number of interesting challenges
- Drugs is must have:
ability to achieve high urinary
concentrations
adequate tissue concentrations (kindney
involved)
Safety especially children and pregnant
women
-The choice of agent will be dictated by:
microbial aetiology
susceptibility findings
- vary widely among Gram negative
enteric bacilli
- important to demonstrate the cure of bacteriuria
with a repeat urine sample collected 4 6 weeks
after treatment,
or sooner
-important to maintain the urine in a sterile state
and it can be achieved with:
repeated courses of antibiotics
guided by laboratory sensitivity data
- long term chemoprophylaxis is used for 6
months to control infection by either prevention
or suppression.
Trimethoprim
-most common prescribed
chemoprophylactic
agent
-achieves high urinary
concentrations
throughout the night
ANTIBIOTIC POLICIES
1 . Rationale
- plethora of available antimicrobial agents
presents
both an increasing problem of selection to the
prescriber
and difficulties for the diagnostic laboratory as to
which
agents should be tested for susceptibility
o Generic Substitution
-also desirable provided that there is bio equivalence
6. Fungal Infections
- divided into
a) Superficial - affect the skin, nails or
mucosal surfaces of the mouth or genital
tract
b) Deep seated infections - may target the
lung or disseminate via the bloodstream
- griseofulvin and terbinafine ineffective
against yeast
- variety of topical and systemic antifungal agents
are available:
Imidazole
- clotrimazole and miconazole
- highly effective topically
A. Free Prescribing
- free prescribing policy argue that strict
antibiotic policies are both impractical and limit
clinical freedom
- greater the number of agents in use
- less likely it is that drug resistance will emerge
B. Restricted Reporting
- is widely practised in the UK
- tests only a limited range of agents against
bacterial isolates
- agents selected primarily by microbiological
staff or
clinical colleagues
Polyenes
-include amphotericin B
- remains the agent of choice for the
treatment
Triazoles
- second major class of systemic
antifungals
- well tolerated but may interact with
a number of drugs and drug classes
such as the sulphonylureas,
antihistamines and lipid - lowering
agents
o
Nephrotoxicity