CHAPTER 79 BASIC PRINCIPLES OF ANTIMICROBIAL THERAPY

Drugs used to treat infectious diseases constitute one of our most widely used families
of medicines.
- despite impressive advances, continued progress is needed = there are
organisms that respond poorly to
available drugs; there are effective drugs whose use is limited by toxicity;
there is the constant threat
that currently effective antibiotics will be rendered useless

Drug Clarification: chemotherapy – use of drugs to kill or suppress cancer cells; use of
chemicals against invading
organisms

antibiotic – chemical that is produced by one microorganism and has the

ability to harm other microbes
- only those compounds that are actually made by microorganisms
qualify as antibiotics

antimicrobial drug – any agent, natural or synthetic, with the ability to kill
or suppress microorganisms

What is selective toxicity?

I. SELECTIVE TOXICITY
selective toxicity – ability of a drug to injure a target cell or target
organism without injuring other cells
or organisms that are in intimate contact with the target
- as applied to antimicrobial drugs, indicates the ability of an
antibiotic to kill or suppress
infecting microbes without causing injury to the host
- property that make antibiotics valuable

II. CLASSIFICATION OF ANTIMICROBIAL DRUGS

A. CLASSIFICATION BY SUSCEPTIBLE ORGANISM

What is the difference between narrow and broad spectrum antibiotics?
Which is better?
narrow-spectrum antibiotics – active against only a few species of
microorganisms
- generally preferred

broad-spectrum antibiotics – active against a wide variety of microbes

- for successful therapy, one must choose an antibiotic that is active

against specific organism
responsible for the infection to be treated

What is the difference between bactericidal and bacteriostatic drugs?

 1. Groups:
a. antibacterial drugs
bactericidal drugs – directly lethal to bacteria at clinically
achievable concentrations
- ex. Penicillin

bacteriostatic drugs – slow microbial growth but do not

cause cell death
- elimination of bacteria must ultimately be
accomplished by host defenses
(immune system working in concert with
phagocytic cells)
- ex. Tetracycline

b. antifungal drugs
c. antiviral drugs
2. Classification of Mechanism of Action
• Inhibition of cell wall synthesis or activate enzymes that disrupt the
cell wall (penicillin, cephalosporin)
• Drugs that increase cell membrane permeability
• Drugs that cause lethal inhibition of bacterial protein synthesis
(aminoglycosides)
• drugs that cause non-lethal inhibition of protein synthesis
(tetracyclines)
• drugs that inhibit bacterial synthesis of nucleic acids
(fluroquinolones)
• Antimetabolites (sulpha)
• Inhibitors of viral enzymes (antivirals)

III. ACQUIRED RESISTANCE TO ANTIMICROBIAL DRUGS

- keep in mind, it is the microbe that becomes drug resistant, not the
patient

1. Mechanisms by which Resistance is Acquired

- alterations in structure and function are brought about by changes
in the microbial genome

a. Spontaneous Mutation – produce random changes in a microbe’s

DNA
- result is a gradual increase in resistance
- confer resistance to only one drug

b. Conjunction – process by which extra chromosomal DNA is

transferred from one bacterium to
another
- to transfer resistance, the donor organism must possess two
unique DNA segments,
one that codes for the mechanisms of drug resistance
and one that codes for
 the “sexual” apparatus required for DNA transfer
- constitute an R factor (resistance factor)
- because transfer of R factors is not species specific, it
is possible for
pathogenic bacteria to acquire R factors from the normal
flora of the body
- serious clinical concern
- frequently results in multiple drug resistance

2. Relationships between Antibiotic Use and Emergence of Drug-

Resistant Microbes
- use of antibiotics promotes the emergence of drug-resistant
microbes
- antibiotics are not mutagenic and do not directly cause the genetic
changes that underlie
reduced drug sensitivity
- drugs simply serve to make conditions favorable for
overgrowth of those microbes that
have already acquired mechanisms for drug resistance
- spontaneous mutation and conjugation incidence are independent
of drug use

a. How Antibiotics Promote Resistance

- if a drug-resistant organism is present, antibiotics will create
selection pressure
favoring the growth of that microbe
- by killing off the sensitive organisms, the drug will
eliminate toxins produced
by those microbes, facilitating survival of the microbe
that is drug resistant
- elimination of sensitive organisms will remove competition
for available nutrients,
making conditions even more favorable for the drug-
resistant microbe to
flourish

b. Which Antibiotics Promote Resistance?

- all antimicrobial drugs promote the emergence of drug-
resistant organisms
c. Does the Amount of Antibiotic Use Influence the Emergence of
Resistance?
- YES, the more that antibiotics are used, the faster drug-
resistant organisms emerge
- every effort should be made to avoid use of antibiotics by
individuals who don’t
actually need them
Why does drug resistance occur?

What is a nosocomial infection? Give an example of one.

nosocomial infections – infections acquired in hospitals, typically
caused by invasive devices
 (foley catheters, subclavian catheters, endotracheal tubes,
etc.)
- most difficult to treat
- ex. UTI from catheters is the most common
ventilator associated pneumonia

Can you provide an example of a suprainfection?

A. SUPRAINFECTION – special example of the emergence of drug resistance
- new infection that appears during the course of treatment for a primary
infection
- more likely in patients receiving broad-spectrum agents
- caused by drug-resistant microbes and are often difficult to treat
- referred to as superinfections
- ex. when a patient is being treated with antibiotics for several weeks and
develops oral thrush

Please list the 12 steps to prevent antimicrobial resistance among

hospitalized adults
1. 12 Steps to Prevent Antimicrobial Resistance
Prevent Infection
a. Vaccinate – reduces the use of antimicrobial drugs, helping to
prevent emergence of resistance
- recommendation that predischarge vaccination of all at-risk
patients, especially
against two repiratory infections; influenza and
pneumococcal pneumonia; all
health care personnel who have patient care duties
should receive a flu shot
annually

b. Get the Catheters Out – catheters and other invasive devises are the
leading exogenous cause
of nosocomial infections
- can occur in association with IV catheters, arterial catheters,
urinary tract catheters,
endotracheal tubes, and other devices
- catheters should be used only when essential for patient
care, and should be removed
as soon as they are no longer needed

What does Culture and Sensitivity mean?

Diagnose and Treat Infection Effectively

c. Target the Pathogen – choose drugs that are active against the
causative organism
- determine both the identity and drug sensitivity of the
pathogen
- culture and sensitivity
 d. Access the Experts – input from infectious disease expert can
improve patient outcomes,
decrease treatment costs, and shorten the time to discharge
- especially helpful in: patients with serious infections
patients receiving complex antimicrobial
regimens
patients who fail to respond as expected
patients with complicated underlying
illnesses

Use Antimicrobials Wisely

e. Practice Antimicrobial Control – most effective option is to implement
a computerized support
system designed to help clinicians select antimicrobial
regimens
- measures include use of standardized antimicrobial order
forms, providing interactive
education for prescribers, giving individual prescribers
critical feedback on their
choices, and establishing a multidisciplinary system to
evaluate drug utilization

f. Use Local Data – drug susceptibility of microbes varies over time and
according to locale,
patient population, and hospital unit
- compile data on drug susceptibility into an “antibiogram”,
providing an overview of
common local pathogens and their current pattern of
drug sensitivity

g. Treat Infection, Not Contamination – contamination of culture

samples can lead to false-positive
results on bacteriologic tests, leading to unneeded treatment
with antimicrobial drugs
- major cause of unnecessary antimicrobial use

h. Treat Infection, Not Colonization – a small, localized colony of

bacteria does not constitute an
infection
- colonization is a concern because:
in patients who do not have an active infection,
treatment because of
colonization would be an unnecessary use of
antibiotics
in patients who do have an active infection, wrongly
attributing the infection to
colonizing bacteria could lead to treatment with
drugs that are inactive
against the real cause
 i. Know when to say “No” to Vanco – vanco is a drug of last resort
against several important
pathogens, including methicillin-resistant Staphylococcus
Aureus (MRSA) and
multidrug-resistant Streptococcus pneumoniae
- use the drug only when clearly necessary

j. Stop Treatment when Infection is Cured or Unlikely – administer

antibiotics only when they are
actually needed

Prevent Transmission
k. Isolate the Pathogen – proper containment and disposal of
contagious body fluids
- reduces the risk of transferring resistant organisms from one
patient to another

l. Break the Chain of Contagion – WASH YOUR HANDS!!! before and

after touching any patient

Your patient is being prescribed Bactrim for an urinary tract infection –

What education would you provide regarding this antibiotic prescription?
2. Bactrim – Patient Education
Are you allergic to Sulfa?
Please take all medication as prescribed
Drink plenty of fluids with the medication
Report sore throat, fever, jaundice (early sign of serious reactions)

IV. SELECTION OF ANTIBIOTICS

- therapeutic objective = produce maximal antimicrobial effects while
causing minimal harm to the host

Principal Factors: identity of the infecting organism, drug sensitivity of the

infecting organism
host factors, such as the site of infection and the status of host
defenses

- usually one drug of first choice may be preferred for several reasons, such as
greater efficacy, lower toxicity, or
more narrow spectrum
- conditions might rule out a first-choice agent, such as allergy to the drug of
choice, inability of the drug of
choice to penetrate to the site of infection, and unusual susceptibility of
the patient to toxicity of the first-
choice drug

A. EMPIRIC THERAPY PRIOR TO COMPLETION OF LABORATORY TESTS

 - drug selection must be based on clinical evaluation and knowledge of
which microbes are most likely
to cause infection at a particular site
- broad-spectrum agent can be used for initial treatment; however, once
the identity and drug sensitivity
of the infecting organism have been determined, switch to a more
selective antibiotic
- essential that samples of exudates and body fluids be obtained for
culture prior to initiation of
treatment
- if antibiotics are present, these agents can suppress microbial
growth in culture and confound
identification

B. IDENTIFYING THE INFECTING ORGANISM

- match the drug with the bug
- infecting organism should be identified prior to initiation of therapy
- quickest, simplest and most versatile technique for identification is
microscopic exam of a gram-
stained preparation
- samples can be obtained from pus, sputum, urine, blood, and other
body fluids
- most useful are direct aspirates from the site of infection
- should be taken in a fashion that minimizes contamination with
normal body flora
- should not be exposed to low temperature, antiseptics, or oxygen

C. DETERMINING DRUG SUSCEPTIBILITY

- testing is common, indicated only when the infecting organism is one in
which resistance is likely

1. Disk-Diffusion Test – most widely used method

- also known as the Kirby-Bauer test
- performed by inoculating an agar plate with the infecting organism
and then placing on that
plate several small disks, each of which is impregnated with a
different antibiotic
- growth will be inhibited around the disks that contain an
antibiotic to which the
bacteria are sensitive

What is the Broth Dilution Procedure?

2. Broth Dilution Procedure – bacteria are grown in a series of tubes

containing different concentrations
of an antibiotic
- provides a more precise measure of drug sensitivity
- useful for guiding therapy of infections that are unusually difficult
to treat
- can establish close estimates of:
 minimum inhibitory concentration (MIC) – lowest
concentration of drug that
produces a complete inhibition of bacterial growth (but
does not kill bacteria)
minimum bacterial concentration (MBC) – lowest
concentration of a drug that
produces a 99.9% decline in the number of bacterial
colonies (indicating
bacterial kill)

V. HOST FACTORS THAT MODIFY DRUG CHOICE, ROUTE OF ADMINISTRATION, OR

DOSAGE
- host defenses and site of infection are unique to the selection of
antibiotics
- other factors such as age, pregnancy and previous drug reactions are the
same factors that must be
considered when choosing any other drug

A. HOST DEFENSES
- consist primarily of the immune system and phagocytic cells
- drugs used to treat infections do not produce cure on their own
- they work in concert with host defense system to subdue infection
- objective of antibiotic treatment is not outright kill of infecting
organisms, rather to suppress
microbial growth to the point at which the balance is tipped in
favor of the host
- people whose defenses are impaired, such as those with AIDS and those
undergoing cancer
chemotherapy, frequently die from infections that drugs alone are
unable to control

B. SITE INFECTION
OF
- an antibiotic must be present at the site of infection in a concentration
greater than the MIC
- drug penetration may be hampered, making it difficult to achieve the MIC
- when pus and other fluids hinder drug access, surgical drainage is
indicated
- foreign materials (cardiac pacemakers, prosthetic joints) present a
special local problem
- when attempts are made to treat these infections, relapse and
failure are common

C. OTHER HOST FACTORS

1. Age – multiple factors contribute to infants being highly vulnerable to drug
toxicity
- poorly developed kidney and liver function
- drug sensitivity is heightened in the elderly due in large to reduced
rates of drug metabolism
and drug secretion, which can result in accumulation of
antibiotics to toxic levels
 2. Pregnancy and Lactation – antimicrobial drugs can cross the placenta
and enter breast milk
- antibiotic use may pose a risk to the expectant mother also

3. Previous Allergic Reaction – severe allergic reactions are more common

with the penicillins than any
other family of drugs
- patients with a history of allergy to penicillins should not receive
them again, except with a life-
threatening infection for which no suitable alternative is
available

4. Genetic Factors – genetic factors can influence responses to antibiotics

and also affect the rate of
metabolism

VI. DOSAGE SIZE AND DURATION OF TREATMENT

- successful therapy requires that the antibiotic be present at the site of
infection in an effective
concentration for a sufficient time
- dosages should be adjusted to produce drug concentrations that are
equal to or greater than MIC for
the infection being treated
- drug levels 4 – 8 times the MIC are often desirable

- duration of therapy depends on a number of variables, including the

status of host defenses, the site of
the infection and the identity of the infecting organism
- it is imperative that antibiotics not be discontinued prematurely
- patients should be instructed to take their medication for the entire
prescribed course, even
though symptoms may subside before the full course has been
completed
- early withdrawal is a common cause of recurrent infection, and the
organisms responsible for
relapse are likely to be more drug resistant

VII. THERAPY WITH ANTIBIOTIC COMBINATIONS

- combination of antimicrobial agents is indicated only in specific situations
- although antibiotic combinations do have a valuable therapeutic role,
routine use of two or more
antibiotics should be discouraged

A. ANTIMICROBIAL EFFECTS OF ANTIBIOTIC COMBINATIONS

additive response - one in which the antimicrobial effect of the
combination is equal to the sum of the
effects of the two drugs alone
 potentiative interaction – one in which the effect of the combination is
greater than the sum of the
effects of the individual agents
- also called a synergistic interaction

- in certain cases, combination of two antibiotics may be less effective

than one of the agents by itself
- indicate antagonism between the drugs
- most likely when bacteriostatic agent (tetracycline) is combined
with a bactericidal drug
(penicillin)
- occurs because bactericidal drugs are usually effective only against
organisms that are
actively growing
- if host defenses are compromised, consequences of antagonism
can be dire

B. INDICATIONS FOR ANTIBIOTIC COMBINATIONS

1. Initial Therapy of Severe Infection – until the infecting organism has
been identified, wide
antimicrobial coverage is indicated
- just how broad depends on the clinician’s skill in narrowing the field
of potential causative
organisms
- once the infecting microbe is identified, drug selection can be
adjusted accordingly

2. Mixed Infections – multiple infecting organisms are common in brain

abscesses, pelvic infections, and
infections resulting from perforation of abdominal organs
- when the infecting microbes differ from one another in drug
susceptibility, treatment with more
than one antibiotic is required

3. Prevention of Resistance – one disease – tuberculosis – drug

combinations are employed for specific
purpose of suppressing the emergence of resistant bacteria

4. Decreased Toxicity

5. Enhanced Antibacterial Action

6. Disadvantages of Antibiotic Combinations

• increased risk of toxic and allergic reactions
• possible antagonism of antimicrobial effects
• increased risk of suprainfeciton
• selection of drug-resistant bacteria
 • increased cost

VIII. PROPHYLACTIC USE OF ANTIMICROBIAL DRUGS

- agents are given to prevent infection rather than to treat an established
infection
- much of the prophylactic use of antibiotics is uncalled for
- when prophylaxis is attempted, benefits must be weighed against the
risks of toxicity, allergic
reactions, suprainfection, and selection of drug-resistant organisms

A. SURGERY
- antibiotics can decrease the incident of infection in certain kinds of
surgery, such as cardiac surgery,
peripheral vascular surgery, orthopedic surgery, and surgery on the
GI tract
- beneficial for women undergoing a hysterectomy or an emergency
cesarean section
- in “dirty” surgery (operations performed on perforated abdominal organs,
compound fractures, or
lacerations from animal bites), use of antibiotics is considered
treatment
- when given for prophylaxis, antibiotics should be administered before
surgery has begun and may
need to be readministered if the procedure is unusually long

B. BACTERIAL ENDOCARDITIS
- individuals with congenital or valvular heart disease and those with
prosthetic heart valves are
unusually susceptible to bacterial endocarditis
- endocarditis can develop following surgery, dental procedures, and other
procedures that may
dislodge bacteria into the bloodstream

C. OTHER INDICATIONS FOR ANTIMICROBIAL PROPHYLAXIS

- young women with recurrent urinary tract infection
- against type A influenza
- severe rheumatic endocarditis
- following exposure to organisms responsible for sexually transmitted
diseases

IX. MISUSES OF ANTIMICROBIAL DRUGS

A. ATTEMPTED TREATMENT OF UNTREATABLE INFECTION

- majority of viral infections – including mumps, chickenpox, and the
common cold do not respond to
currently available drugs

B. TREATMENT OF FEVER OF UNKNOWN ORIGIN

 - although fever can be a sign of infection, it can also signify other
diseases, including hepatitis, arthritis,
and cancer
- unless the cause of a fever is a proven infection, antibiotics should
not be employed because:
• if the fever is not due to an infection, antibiotics would not
only be inappropriate, they would expose the patient to
unnecessary toxicity and delay correct diagnosis of the fever’s
cause
• if the fever is caused by infection, antibiotics could hamper
later attempts to identify the infecting organism
- the only situation in which fever, by itself, constitutes a legitimate
indication for antibiotic use is when
fever occurs in the severely immunocompromised host

C. IMPROPER DOSAGE
- if dosage is too low, the patient will be exposed to a risk of adverse
effects without benefit of
antibacterial effects
- if dosage is too high, the risks of suprainfection and adverse effects
become unnecessarily high
- lack of identification of the organism is the most common reason for
misdosing

D. OMISSION OF SURGICAL DRAINAGE

- antibiotics may have limited efficacy in the presence of foreign material,
necrotic tissue or pus
- when appropriate, surgical drainage and cleansing should be
performed to promote
antimicrobial effects

X. MONITORING ANTIMICROBIAL THERAPY

- therapy is assessed by monitoring clinical responses and laboratory
results
- frequency of monitoring is directly proportional to the severity of
infection
- indicators of success are reduction of fever and resolution of signs and
symptoms related to the
affected organ system
- serum levels may be monitored:
• to ensure that levels are sufficient for antimicrobial effects
• to avoid toxicity from excessive levels
- success of therapy is indicated by the disappearance of infectious
organisms from post-treatment
cultures

XI. ADVERSE EFFECTS OF THERAPY

• GI symptoms (nausea, vomiting, diarrhea)
• Suprainfection
• Organ toxicities
o liver
o kidney
• Other
o photosensitivity
o skin rash