ANTIMICROBIAL SELECTION

GUIDES

Pharmacokinetic - Pharmacodynami
wien - Faculty of Medicine UB
Antimicrobial selection

Host defenses are intact and active, a minimum

inhibitory effect (bacteriostatic agents) may be
sufficient

Host defenses are impaired, antibiotic-mediated

killing (bactericidal effect) may be required to
eradicate the infection.

Guidance
 Successful therapy also depends on achieving
a drug concentration that is sufficient to
inhibit or kill bacteria at the site of the
infection without harming the patient

 The inhibitory concentration of drug at the site of

infection also must remain below the level which is
toxic to human cells

the m.o. is susceptible

 Optimal and judicious selection of antimicrobial
agents for the therapy of infectious diseases
requires clinical judgement and detailed knowledge
of microbiological and pharmacological factors

Guidance
Microbiological aspects
 Is microorganism susceptible or resistant ?
achieved by in vitro susceptibility testing

Dilution test Disk diffusion test

(broth or agar dilution test)

MIC and MBC Sensitive, Intermediate,

or Resistant

In vivo ?
Microbiological aspect
 In vitro activity, although critical, is only a
guide as to whether an antibiotic is likely to
be effective for an infection.
 Successful therapy also depends on achieving
a drug concentration that is sufficient to
inhibit or kill bacteria at the site of the
infection without harming the patient.
 To accomplish this therapeutic goal, several
pharmacokinetic and host factors must be
evaluated.
 The most valuable and time-tested method for
immediate identification of bacteria is examination
of the infected secretion or body fluid with Gram's
stain
 help to narrow the list of potential pathogens
and permit more rational selection of initial
antibiotic therapy

Microbiological aspect
 Identification of the morphology of the infecting
organism is not adequate to arrive at a specific
bacteriological diagnosis, and the selection of a single
narrow-spectrum antibiotic may be inappropriate
 BROAD SPECTRUM ANTIMICROBIAL coverage is
then indicated, pending isolation and identifi-
cation of the microorganism

Microbiological aspect
 ANTIMICROBIAL TESTING

1. DIFFUSION METHOD
using solid medium

2. DILUTION METHOD
● Liquid Medium - Microdilution (Microplate)
- Macrodilution (Tube Dilution Test)
● Solid Medium (Agar Dilution)

Microbiological aspect
1. Diffusion Method
- parameter observed  zone of inhibition diameter
- drug mixed with agar medium  solidify , then make several
holes with a certain apparatus
- the tested bacteria is entered into the holes
- other reservoir : paper disk
(streaking the tested bacteria onto the medium)

Microbiological aspect
 Disk Diffusion Test

• The antimicrobe was saturated in the paper disk

• Observed : zone of inhibition diameter
• Criteria : sensitive, intermediate, resistant
• Advantage : easy, practical
Microbiological aspect
2. Dilution method
Tube dilution
- the antimicrobial mixed with liquid medium (in tubes)
- parameter  bacterial growth which is observed visually
(the turbidity) & colony count (on solid media)
- to determine MIC & MBC
MIC : the lowest concentration which inhibits the bacterial growth
MBC : the lowest concentration which kills bacteria
(kill the 99,9% bacterial inoculum )

Agar Dilution
- the antimicrobial mixed with solid medium (in petri disk)
- to determine MIC

Microbiological aspect
Tube Dilution Test
Microbiological aspect
The beginning inoculum

KBM

Microbiological aspect
Pharmacological aspects
 The concentration at the site of infection may be
considerably lower than achievable serum concentrations
(e.g., vitreous fluid of the eye or cerebrospinal fluid)
 Local factors (e.g., low pH, high protein concentration, and
anaerobic conditions) also may impair drug activity
Thus, the drug may be only marginally effective or
ineffective in such cases

 Conversely, concentrations of drug in urine may be much

higher than those in plasma  m.o.that might otherwise be
considered "resistant" may be eradicated when infection is limited to
the urinary tract.

Pharmacological aspect
 Antibiotics have three general uses:
1. Empirical therapy
2. Definitive therapy
3. Prophylactic or preventive therapy

Empirical, or initial therapy:

 AM should cover all the likely pathogens because the infecting
organism(s) has not yet been defined.
Preferably, treatment with a single broad-spectrum agent
Definitive therapy:
 when the infecting microorganism is identified
 a narrow-spectrum, low toxicity agent
Pharmacological aspect
Consideration:
 The diagnosis may be masked if therapy is started and
appropriate cultures are not obtained.
 Antibiotics are potentially toxic, and antimicrobial
agents promote selection of resistant microorganisms.
 In the absence of a clear indication, antibiotics often
may be used if disease is severe and if it seems likely
that withholding therapy will result in life-threatening
infection

Pharmacological aspect
When a drug enters the body, the body begins immediately
to work on the drug: absorption, distribution, metabolism
(biotransformation), and elimination.
Pharmacokinetics

The drug also acts on the body, an interaction to which

the concept of a drug receptor is key, since the receptor is
responsible for the selectivity of drug action and for
the quantitative relationship between drug and effect
Pharmacodynamics
 The location of the infection  may dictate the choice
of drug and the route of administration
 The minimal drug concentration achieved at the
infected site should be approximately equal to the MIC
for the infecting organism
 There is an evidence to suggest that even
subinhibitory concentrations of antibiotics may
enhance phagocytosis

Pharmakokinetic aspect
 Pharmacodynamic properties can be used to divide
antibiotics into two major classes based on their mechanism
of bactericidal action:

(1) Concentration-dependent drugs

such as aminoglycosides and fluoroquinolones
- the higher the drug concentration, the faster the
eradication of pathogens

(2) Concentration-independent drugs

e.g. the β-lactams
- peak concentrations are relatively unimportant
- time-dependent drugs

Pharmacodynamic aspect
 Antibiotics also differ in the post antibiotic effect (PAE) that
they exert
The postantibiotic effect (PAE):
is the phenomenon of continued suppression of
bacterial growth after a short exposure of bacteria to
antimicrobial agents
This effect is probably as the result of:
- non lethal damage caused by the antibiotic
- continued persistence of the drug at the bacteria’s drug-
binding site for a time after drug is removed
Pharmacodynamic aspect
• β-lactam agents
 the PAE against Gram-positive pathogens lasts approximately
1 to 2 hours
• Aminoglycosides and fluoroquinolones
 Gram-negative PAE is about ≤ 2 h

The PAE is influenced by several factors:

- the microorganism,
- the inoculum size,
- the antibiotic,
- the concentration of antibiotic,
- the duration of exposure

Pharmacodynamic aspect
Therapeutic goal factors
Factors to accomplish therapeutic goal

1. Sites of infection
2. Route of administration
3. Host Factors
4. Host Defense Mechanisms
5. Local Factors
6. Age
7. Genetic Factors
8. Pregnancy
9. Drug Allergy
10. Comorbid Conditions

therapeutic goal factor

1. Sites of infection

Cerebrospinal fluid (CSF), the drug must pass the blood-

brain barrier

Antimicrobial agents that are polar at physiological pH

generally penetrate poorly; some, such as penicillin G, are
actively transported out of the CSF by an anion transport
mechanism in the choroid plexus
The integrity of the blood-brain barrier is diminished during
active bacterial infection; tight junctions in cerebral capillaries open,
leading to a marked increase in the penetration of even polar drugs

therapeutic goal factor

 Penetration of drugs into sites of infection almost
always depends on passive diffusion
 The rate of penetration is thus proportional to the
concentration of free drug in the plasma or
extracellular fluid.
 Drugs that are extensively bound to protein thus may
not penetrate to the same extent as those bound to a
lesser extent. Drugs that are highly protein bound also
may have reduced activity because only the unbound
fraction of drug is free to interact with its target.

therapeutic goal factor

2. Route of Administration

- oral administration is preferred whenever possible

- parenteral administration of antibiotics usually is
recommended in seriously ill patients in whom
predictable concentrations of drug must be achieved

therapeutic goal factor

3. Host Factors

Innate host factors can be the prime determinants not

only of the type of drug selected but also of its dosage,
route of administration, risk and nature of untoward
effects, and therapeutic effectiveness
- Knowledge of the status of the individual patient's renal and
hepatic function also is essential, especially when excessive
plasma or tissue concentrations of the drugs may cause serious
toxicity

therapeutic goal factor

4. Host Defense Mechanisms

• A critical determinant of the therapeutic effectiveness of

antimicrobial agents is the functional state of host
defense mechanisms
• Both humoral and cellular immunity are important.
- Inadequacy of type, quality, and quantity of the Ig
- Alteration of the cellular immune system
- A qualitative or quantitative defect in phagocytic cells
may result in therapeutic failure even though the use of
otherwise appropriate and effective drugs
(e.g.meningitis, endocarditis, AIDS)

therapeutic goal factor

5. Local Factors

- Antimicrobial activity may be reduced significantly in pus,

which contains phagocytes, cellular debris, and proteins that
can bind drugs or create conditions unfavorable to drug action
- Anaerobic conditions can reduce the antimicrobial activity of
some agents markedly, particularly the aminoglycosides
- Foreign body as prosthetic material (e.g., prosthetic cardiac
valves, prosthetic joints, pacemakers, vascular grafts, and
various vascular and CNS shunts) promotes formation of a
bacterial biofilm that impairs phagocytosis

therapeutic goal factor

6. Age

- Mechanisms of elimination, especially renal excretion and

hepatic biotransformation, are poorly developed in the
newborn, especially the premature infant

- Elderly patients clear drugs eliminated by the kidneys less

well because of reduced creatinine clearance
Elderly patients therefore are more likely to suffer toxicity
at otherwise safe concentrations of drugs, as is the case
for aminoglycoside ototoxicity

therapeutic goal factor

7. Genetic Factors

Certain genetic or metabolic abnormalities must be

considered when prescribing antibiotics
a number of drugs (e.g., sulfonamides, nitrofurantoin,
chloramphenicol, and nalidixic acid) may produce acute
hemolysis in patients with glucose-6-phosphate
dehydrogenase deficiency (G6PD)

therapeutic goal factor

8. Pregnancy

- Pregnancy may impose an increased risk of reaction

to antimicrobial agents for both mother and fetus
 hearing loss in the child has been associated with
administration of streptomycin to the mother during
pregnancy

- The lactating female can pass antimicrobial agents to

her nursing child

therapeutic goal factor

9. Drug Allergy

Antibiotics, especially β-lactams, are notorious for

provoking allergic reactions. Patients with a history of
atopy seem particularly susceptible to the
development of these reactions

therapeutic goal factor

10. Comorbid conditions

Patients predisposed to seizures are at risk for

localized or major motor seizures while taking high
doses of penicillin G. This neurotoxicity of penicillin
and other β-lactam antibiotics correlates with high
concentrations of drug in the CSF and typically
occurs in patients with impaired renal function who
are given large doses of the drugs

therapeutic goal factor

COMBINED ANTIMICROBIAL AGENTS
 Combined Antimicrobial Agents

- The simultaneous use of two or more antimicrobial

agents is recommended in specifically defined
situations based on pharmacological rationale
- So that, selection of an appropriate combination
requires an understanding of the potential for
interaction between the antimicrobial agents.
Interactions may affect either the microorganism or
the patient
Disadvantages

- increased risk of toxicity from two or more agents,

- selection of multiple-drug-resistant microorganisms,
- eradication of normal host flora with subsequent
superinfection,
- increased cost to the patient

The addition of a bacteriostatic drug to a bactericidal drug

frequently results in a bacteriostatic effect, but antagonism
between antibiotics probably is relatively unimportant when
host defenses are adequate e.g. Penicillin - Chlortetracycline
 Chemoprophylaxis is highly effective in some clinical settings
 In others, it accounts for some of the most misuses of
antimicrobials, is totally without value, and may be deleterious
 Use of antimicrobial compounds to prevent infections remains
controversial in numerous situations

may be used to protect healthy persons from acquisition of or

invasion by specific microorganisms to which they are exposed
e.g. rifampin administration to prevent meningococcal
meningitis in people who are in close contact with a case
 In general, if a single, effective, nontoxic drug is used
to prevent infection by a specific microorganism or to
eradicate an early infection, then chemoprophylaxis
frequently is successful
 On the other hand, if the aim of prophylaxis is to
prevent colonization or infection by any or all
microorganisms present in the environment of a
patient, then prophylaxis often fails
 TQ

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