2.

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

Disease w/ absolute or functional

deficiency of Phagocytic Activity
- Phagocytic funtion impaired both by
disease and by use of potent cytotoxic
drugs; destroy healthy,malignant,WBC
- essential to select agents that are
bactericidal, as bacteriostatic drug
ex. Tetracyclines,Sulphonamides

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.

Malfunction of excretory glands:

CHAPTER 14: Clinical Uses of

Antimicrobial Drugs
INRODUCTION:

- 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.

- hydrolyse most cephalosporins and

penicillins,
-limiting therapeutic options to
carbapenems or aminoglycosides.
-can be chromosomally mediated (e.g.
Pseudomonas spp.,Citrobacter spp.) or
plasmid - mediated (e.g. Klebsiellaspp
Carbapenem Resistance, via metallo -
lactamase
- seen in outbreak strains of Pseudomonas
aeruginosa and Acinetobacter baumannii
- potentially toxic agents such as
colistin are often
the only effective choice.
o

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.

Risk toxicity from drug

accumulation
Reduce urinary concentration of
drug primarily by glomercular
filtration

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

MULTI DRUG RESITANCE :

o MRSA
- meticillin resistant Staph. Aureus
- have the ability tocolonize staff and patients
and to spread readily
-glycopeptides vancomycin or teicoplanin,
linezolid are the currently recommended
agents for treating patients infected with
these organisms.
o

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

Drug -resistant Enterococci.

- include Enterococcus faecalis, E. faecium
- Resistance to the glycopeptides has again
been a problem among patients in high
dependency units.
-Four different phenotypes are
VanA-resistant to both glycopeptides
Van B- sensitive to teicoplanin but
demonstrate high resistance
Van C- sensitive to teicoplanin but
demonstrate intermediate resistance
Van D- resistance to vancomycin;
Extended - spectrum - lactamase
(ESBL)
- produce Gram - negative organisms

-The choice of antimicrobial chemotherapy is

initially dependent on the clinical diagnosis.
- Laboratory isolation and susceptibility testing of
the causative agent establish the diagnosis with
certainty and make drug selection more rational.
-Knowledge of the usual microbiological cause of
a particular infection and its susceptibility to
antimicrobial agents is essential for effective drug
prescribing.
o Clinical Diagnosis
- implies a microbiological diagnosis which
may dictate specific therapy.
- In some, establishing a clinical diagnosis
implies a range of possible microbiological
causes and requires laboratory confirmation
from samples collected.

1. Respiratory Tract Infections

-among the commonest of infections
-Divided into infections :
A. UPPER RESPIRATORY TRACT
-ears, throat, nasal sinuses, and the
trachea
-Bacterial infections may complicate viral
illnesses, and are also primary causes of
ear and sinus infections
-Streptococcus pneumoniae and
Haemophilus infl uenzae are the
commonest bacterial pathogens.
o

Acute pharyngitis

- presents a diagnostic and therapeutic

dilemma
- potentially responsive to antibiotic therapy.
- causes otitis media and sinusitis, they are
generally self limiting
o Strep. Pyogenes
- is the most important bacterial pathogen
and this
responds to oral penicillin.
-causes otitis media and sinusitis, they are
generally self -limiting
o Amoxicillin
-widely prescribed
-microbiologically active
- penetrates the middle ear and sinuses

B. LOWER RESPIRATORY TRACT

-airways, lungs and pleura
-infections include pneumonia, lung
abscess,bronchitis, bronchiectasis and
infective complications ofcystic fibrosis.
-Each presents a specific diagnostic and
therapeutic challenge
-Alternative diagnostic samples:

- range in severity from fatal anaphylaxis to

minor and reversible hypersensitivity
- It is important to question patients
concerning hypersensitivity before
prescribing, as it precludes the use of all
compounds within a class.
o Drug toxicity
- often dose related
- may affect a variety of organs or tissues
- may be genetically determined
7. SUPERINFECTION
o Anti - infective drugs
-not only affect the invading organism
undergoing treatment but also have an
impact on the normal bacterial flora,
especially of the skin and mucous membranes
- may result in microbial overgrowth of
resistant organisms with subsequent
superinfection.

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:

-aspiration of oropharyngeal secretion can

lead to chronic low grade sepsis with abscess
formation and the expectoration of foul
smelling sputum that characterizes anaerobic
sepsis.
- responds to high dose penicillin; against
most of the
normal oropharyngeal flora
- metronidazole may be appropriate for
strictly
anaerobic infections.
- For aerobic gram negative bacillary sepsis
the agent of
choice is aminoglycosides

Acute staphylococcal pneumonia

-extremely serious infection
- requires treatment with high
dose flucloxacillin alone or in
combination with
fusidic acid.

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

needle aspiration of sputum

directly from the trachea
fluid within the pleural cavity
Blood cultured and serum
examined
o Pneumonia
- pathogens causing acute pneumonia
includes viruses, bacteria and, in the
immunocompromised host, parasites and
fungi
- Clinical assessment includes
details of the evolution of the infection
evidence of a recent viral infection
age of the patient
risk factors
- typical infections may cause pneumonia:
Mycoplasma pneumoniae
Legionella pneumophila
Psittacosis
- history of contact with parrots or
budgerigars;
while legionnaires
Q fever
- atypical pneumonias, unlike
pneumococcal
pneumonia, do not respond to penicillin.

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

2. URINARY TRACT INFECTIONS

- common problem in both community and
hospital practice
-more common in preschool girls , women, and
elderly
-predisposed by factors that impair urine flow
which include
congenital abnormalities
reflux of urine from the bladder into
the ureters,
kidney stones
in males, enlargement of the prostate
gland.
-Bladder catheterization is an important cause of
urinary
tract infection in hospitalized patients.

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

- ensures a sterile urine

Nitrofurantoin
- alternative agent
Bacteraemia
-a condition in which there are
bacteria circulating in the blood
-may complicate infection of the
kidney

-Infections of the prostate tend to be:

Persistent
Recurrent
Difficult to treat
- Acid environment of the prostate gland, inhibits
drug penetration by many of the antibiotics used
to treat
urinary tract infection.
Basic agents
-achieve therapeutic concentrations
within the gland
-not active against the pathogens
- active against many of the causative
pathogens
Drug Resistance
-has increased substantially
-reduced the value of formerly widely prescribed
agents such as the sulphonamides and ampicillin.

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

as Panton Valentine Leukocidin (PVL)

Strep. pyogenes - responsible for a
range of skin infections; usually treated w/
penicillin
Impetigo- superficial infection of the
epidermis
which is common in childhood and is
highly contagious
Cellulitis - deep seated infection,
spreads rapidly through the tissues to
involve the lymphatics and
bloodstream
Erysipelas- rapidly spreading
cellulitis commonly involving the face
Necrotizing fasciitis- more serious,
rapidly progressive infection of the
skin and subcutaneous structure
Ps. aeruginosa
Anaerobic bacteria- associated w/ foul
smelling wounds found in association with
surgical incisions following intra abdominal
procedures and pressure sores - infected
with faecal flora
- frequently mixed and include Gram
negative enteric bacilli
Principle of treating
Anaerobic Soft Tissue Infection
- emphasize the need for removal of all
foreign and devitalized material
- metronidazole or clindamycin should be
considered
Infected Burn
- initially sterile, esp. when all layers
are involved
- rapidly become colonized w/ bacteria
supported by
the protein rich exudate jeopardize
survival of skin
grafts or bloodstream invasion
Staphylococci
Strep. pyogenes
Ps. Aeruginosa- requires
combined therapy with an
aminoglycoside
- produces high therapeutic
concentrations ; act in a
synergistic manner
o

5. Central Nervous System Infections

- meninges and the spinal cord are subject to
infection (usually blood borne) penetrating
injuries or direct spread from infection in middle
ear or nasal sinuses
o Viral meningitis
-most common infection
-self limiting
- is caused by a variety of bacteria
neonate- E. coli and group B streptococci

- acquired by ingestion of salmonellae, Sal.

enterica serovar Typhi and Sal. enterica
serovar Paratyphi
- largely systemic infections
- antibiotic therapy is mandatory;
ciprofloxacin is the drug of choice;
trimethoprim or chloramphenicol are
alternatives
o Gut excretion of Sal. enterica serovar
Typhi
- well known complication of typhoid fever
- major public health hazard in developing
countries
- Treatment: ciprofloxacin or high - dose
ampicillin
- presence of gallstones reduces the chance of
cure
o Cholera
- serious infection causing epidemics in Asia
- controlled with replacement of fluid and
electrolyte
losses
- Mdication: Tetracycline
o Traveller s diarrhoea
-may be caused by one of many
gastrointestinal pathogens
- short lived
o Escherichia coli
- most common pathogen
- enterotoxigenic severe disease

4. Skin and Soft tissue Infections

-commonly follow traumatic injury to the
epithelium
- may be blood borne
- Interruption of the integrity of the skin allows
ingress of microorganisms to produce superficial,
localized infections which may become more
deep seated and spread rapidly through tissues.
- Skin trauma complicates surgical incisions and
accidents
- prolonged immobilization = pressure damage to
skin from impaired blood flow; most commonly
seen in
unconscious patients
- normal skin flora where microbes responsible for
skin infection often arise:
Staph. Aureus -is responsible for a
variety of skin infections require
therapeutic approaches different from
those of streptococcal infections
- postoperative
wound infections
- important cause of
superficial
localized skin sepsis
- may express a toxin
complex known

- common but can be avoided by careful

dosaging or the use of liposomal
formulations.

7. Medical Device Associated Infections

- wide variety of medical devices are increasingly
used
in clinical practice
- infection is the most frequent complication of
their use and may result in the need to replace or
remove the device, sometimes with potentially
life - threatening and fatal consequences.
- caused by organisms arising from the normal
skin flora, which gain access at the time of
insertion of the device.
o Microorganisms within biofilm
- less vulnerable to attack by host defences
(phagocytes, complement and antibodies) and
are relatively insusceptible to antibiotic therapy
o Management approaches
- need for prevention through the addition of
good
sterile technique at the time of insertion

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

2. Types of antibiotic policies

preschool child H. infl uenzae was the

commonest pathogen
o Bacterial Infections
- include meningitis and brain abscesses
- high risk of mortality
- residual neurological damage or impairment
of intellectual function may follow
o Fungal infections of the brain
-rare
-particularly found among
immunocompromised patients who either
have underlying malignant conditions or are
on potent cytotoxic drugs
o Neisseria meningitidis
- peak incidence between 5 and 15 years old
o Ceftriaxone
-drug of choice for the treatment of group B
streptococcal, meningococcal and
pneumococcal infections
-CSF concentrations of penicillin are
significantly
influenced by the intensity of inflammatory
response.
- SF, high dosages are required

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

-not stocked but can be obtained in

short notice
D. ANTIMICROBIAL STEWARDSHIP TEAM
- ensure antimicrobials are prescribed appropriate
- emerged to advise and educate staff while
monitoring compliance with prescribing policies
as well
as ensuring good standards of patient
management
-typically these teams comprise :
Consultant in infectious diseases
and/or clinical microbiology, and a
senior pharmacist specializing in
infectious diseases
infection control practitioners
- lead in reviewing the therapy of individual
patients and setting treatment plans, and, often
as part of
a wider team, will coordinate the writing and
review of
antibiotic treatment policies
- Other responsibilities :
education and training of clinical staff
audit of how well prescribers are adhering
to the carefully written policies
provision of feedback to prescribers
-multidisciplinary approach, aligned with targeted
and timely feedback, can improve adherence to
prescribing policy, reduce drug expenditure, and
improve patient outcomes.

- antibiotics tested will vary according to the site

of infection
C. Restricted Dispensing
-most draconian of all antibiotic policies is the
absolute restriction of drug dispensing pending
expert approval
- expert opinion = microbiologist or infectious
disease specialist
- effective in large institutions where staff are
available 24
-desirable new agents are added as they become
available and
is most appropriate
- arrangement between senior pharmacists and
microbiologists
-effective and provides a powerful educational
tool
- widely used approach is to divide agents:
Approved for unrestricted use
- majority of common clinical
situations
-not stocked but can be obtained in
short notice
Restricted
- may include agents where
microbiological sensitivity information
is essential