Principles of Antimicrobial

Therapy

NAFRIALDI

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 Principles of Antimicrobial Therapy
• Antimicrobial agents are the most commonly
used and misused of all drugs
• The inevitable consequence  emergence of
antibiotic-resistant pathogens
• Reducing inappropriate AM use is thought to be
the best way to control resistance.
• Over prescribing remains widespread.
– patients demand,
– time pressure on clinician,
– diagnostic uncertainty

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Susceptibility of Microorganism to AMA

• Successful AM therapy depends on

concentration of AMA at the site of infection
– must be sufficient to inhibit the growth of
microorganism
– must remain below toxic level
 in this condition, microorganism is considered
susceptible to AMA
• If host defenses are intact and active,
bacteriostatic agent may be sufficient.
• If host defenses are impaired, a bactericidal
effect is required
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 Bacterial Resistance to AMA
• The emergence of bacterial resistance to AMA is
a very serious development that threatens the
end of antibiotic era
• Some steps to diminish AM resistance:
– Choosing AM based on local pattern of susceptibility
– Judicious use and proper attention to indwelling
catheter
– Proper antiseptic technique
– Appropriate use of prophylactic AB in surgery
– Strict compliance to hand hygiene
– Vaccination
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 Selection of AMA (1)
• Four options of AM therapy:
– Empirical, experimental, definitive,
prophylaxis
• Empirical th/ is widely utilized, and is
potential for abuse

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CONSIDERATIONS IN SELECTING AMA

– Whether it is even indicated.

– In cases of symptoms are present but are not life-
threatening, it is better to postpone the AM until the D/
is obvious. Example: FUO
– The Diagnosis may be masked if therapy is started
and appropriate culture are not obtained.
– AM often may be used if disease is severe or if
withholding of therapy will result in failure to manage
a potentially serious life-threatening infection.

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 Selection of AMA (2)
• Optimal and judicious selection of AM requires
– clinical judgment
– detailed knowledge of pharmacological and
microbiological factors
– knowledge of the most likely infecting microorganisms
and their susceptibility to AMA.
• The most practical method for immediate
identification of bacteria is examination of the
infected secretion or body fluids with gram stain.

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 Selection of AMA (3)
• In many situations, identification of morphology
of the infecting organism is not adequate to
arrive at specific bacteriological diagnosis
 Broad spectrum AM is then indicated,
 Culture of the presumed site of infection and
blood, should be taken prior to the institution of
drug therapy.
• For definitive therapy, once an organism has
been isolated and results of susceptibility tests
are known, the regimen should be changed to
specific and narrow spectrum AMA
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 Pharmacokinetic Factor of AM Th/ (1)
• In vitro activity is only a guide as to whether an
AM is likely to be effective for an infection.
• Successful th/ depends on achieving a drug
concentration that is sufficient to inhibit or kill
bacteria at the site of infection without harming
the patient.
• The drug concentration at the infected site
should be at least equal to the MIC for the
infecting microorganism (it is advisable to
achieve multiples of this concentration).

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 Pharmacokinetic Factor of AM Th/ (2)

• Three most important pharmacokinetic

parameters for evaluating antibiotic
efficacy:
– Peak serum level (Cmax),
– Trough level (Cmin),
– Area Under the serum concentration time
Curve (AUC).
• While the PK parameters quantify the
serum level time course, they do not
describe the killing activity of an antibiotic.
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 PK/PD
• Integrating the PK parameters with the MIC
gives three PK/PD parameters which quantify
the activity of an antibiotic:
– Peak / MIC ratio,
– T > MIC,
– 24h-AUC / MIC ratio.
 For “concentration-dependent killing” the high Peak/MIC
ratio is important
 For “time-dependent killing” AM, the T above MIC and
AUC24/MIC ratio is important

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PK/PD Parameters

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 Pharmacokinetic factor of AM Th/ (2)
• Penetration of drugs into sites of infection almost
always depends on passive diffusion. The rate of
penetration is proportional to the concentration
of free drug in the plasma or extracellular fluid.
• Drugs with high protein bound have limited
penetration, and thus may have reduced activity
because only the unbound fraction is free to
interact with the target.
• Fluoroquinolones, isoniazid, cotrimoxazole, and
rifampicin penetrate cell well and achieve
concentration that inhibit or kill pathogens
residing within cells.
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 Pharmacokinetic Factor of AM Th/ (3)
• Pharmacokinetic properties of AM
determine their ability to eradicate bacteria
at concentration attained during therapy.
• These properties are:
– 1) Time above MIC  (time-dependent AB)
– 2) Peak / MIC ratio
– 3) AUC24 / MIC ratio (AUIC).
 2) and 3) for concentration-
dependent killing
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 Concentration-dependent killing AM
• Aminoglycosides, metronidazole and
fluoroquinolone exibits concentration-dependent
activity.
• Their efficacy is correlated with Cmax /MIC and
AUC24 /MIC ratios.
• For example, an AUC24 /MIC ratio of 30 to 50 (at
least 10) is thought to predict optimal bacterial
activity
• For this class of drug, administration of
maximum dose for a shorter time would be
optimal.

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 Pharmacokinetic/Pharmacodynamic
(PK/PD) Parameters
• Time-dependent killing
Time above MIC required: > 40%
CON Cmax • Concentration-dependent
C. killing
Cmax/MIC required > 10 x

Area Under the

Curve

MIC

Time
Time above-MIC 17
 Relationship between time above MIC
and bacterial eradication for β -lactams

10
0
Bacterial eradication

8
0
60

40
(%)

20

2 4 60 8 10
0
Time 0
above MIC (%) 0 0
(Craig,200
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2)
 Time-dependent killing AM

• Type II antibiotics (beta-lactams, clindamycin,

erythromcyin, and linezolid) demonstrate the
complete opposite properties. The ideal dosing
regimen for these antibiotics maximizes the
duration of exposure. The T>MIC is the
parameter that best correlates with efficacy. For
beta-lactams and erythromycin, maximum killing
is seen when the time above MIC is at least
70% of the dosing interval.

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 Penetration of AMs into CSF
• The integrity of BBB is diminished during active
bacterial infection; tight junctions in cerebral
capillaries open, leading to a marked increase in
the penetration of even polar drugs.
• As the infection is eradicated, and the
inflammatory reaction subsides, penetration
return to normal. Since this may occur while
viable microorganisms persist in the CSF, drug
dosage should not be reduced as the patient
improves.
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 Penetration of AMs into CSF
• Meninges normal; good penetration:
– 3rd cephalosporins (exclude ceftriaxone),
chloramphenicol, ethambutol, isoniazid,
metronidazole, rifampicin, sulphonamide,
trimetoprim.
• Meninges inflamed; good penetration:
– penicillins, ceftriaxone, cefuroxime,
cefotaxime, tetracycline, fluconazole.
• Meninges inflamed; poor penetration:
– 1st and 2nd cephalopsporins, aminoglycosides,
macrolides, vancomycin.
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 Role of Host Factors in AMT (1)
• The functional state of host defense mechanisms
is a critical determinant of therapeutic
effectiveness of AMAs. Both humoral and celular
immunity are important
• In the immunocompetent host, halting the
multiplication of microorganisms with a
bacteriostatic agent is sufficient to cure the
infection
• In immunocompromized host, a bactericidal agent
is required (bacterial endocarditis, bacterial
meningitis, infections in neutropenic patients,
HIV/AIDS, uncontrolled DM, malnutrition, …)
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 Role of Host Factors in AMT (2)
• Local factors affect the AM activity.
– Pus, can bind drugs or inhibit drug action. Low
pH in infected sites and anaerobic condition can
reduce AM activity, particularly aminoglycosides.
– Foreign body markedly reduces the likelihood of
successful AM therapy.
– Prosthetic materials promotes a bacterial biofilm
that impairs phagocytosis. Within the biofilm ,
bacterial density is high and bacterial growth is
slow.
 favor bacterial persistence  frequent relapses

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 Combined AMAs
INDICATIONS:
• Severe infection in which the cause is unknown.
Prolong use should be avoided, because
toxicity, superinfection, and selection of multiple
drug resistant may result.
• Polymicrobial infection
• To have synergistic effect in specific infection
(endocarditis, Ps aeruginosa infection, H
influenza infection).
• To prevent the emergence of resistant
microorganism (in TBC, H pylori infection)
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 Disadvantage of Combinations of AMAs

• Increase risk of toxicity

• Selection of multiple-drug resistant
microorganisms
• Eradication of normal host flora with
subsequent superinfection.
• Increase cost to patients
• Possibility of antagonistic effect.

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Prophylaxis of Infection with AM
• Chemoprophylaxis is used to protect patients
from invasion by specific microorganisms to
which they are exposed. But it remains
controversial in numerous situations.
• If a single, effective, and non toxic drug is used
to prevent infection by a specific microorganism
or to eradicate an early infection, the prophylaxis
is successful.
• 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 fail.
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Successful Examples of Chemoprophylaxis

• Rifampicin used to prevent meningococcal

meningitis
• Prevention of gonorrhoea or syphilis after
contact with with an infected person
• Intermittent use of cotrimoxazole to prevent
recurrent UTI caused by E coli.
• AM prophylaxis to prevent infections in
transplantation or chemotherapy
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Successful Examples of Chemoprophylaxis

• Primary or secondary infection in AIDS

patients whose CD4 counts are less than
200
• Patients with valvular or other structural
lesion of heart who are undergoing dental
surgery
• Prophylactic antibiotic in surgical
procedure.
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 Effective and Judicious Use of Surgical
Antibiotic Prophylaxis
• AMA must be present at wound site at the
time of its closure. The drug must be given
iv within 1 hour before incision and
another one dose intra operatively for
prolong procedure.
• The AMA must be active against the most
likely contaminating microorganisms

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 Effective and Judicious Use of Surgical
Antibiotic Prophylaxis

• The continued use of AMA after surgical

procedure is unwarranted and potentially
harmful.
• Use beyond 24 hour is unnecessary
• Prophylaxis is justified in dirty and contaminated
procedure
• In clean surgery, AMA should not be used routinely

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 Superinfection
• Definition: appearance of bacteriological and clinical
evidence of new infection during the AM therapy
• Therapeutic doses of AMA alter the normal microbial
population of intestinal, respiratory, and urinary tracts;
as a result, some develop superinfection,
• Microorganism responsible for the new infection can
be drug-resistant strain of enterobacteriaceae,
Pseudomonas, and Candida.
• The broader the AM spectrum, and the longer the
period of AM treatment, the greater is the possibility of
superinfection produced by a typical drug-resistant
microorganism.

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 Misuses of AMAs (1)
• Treatment of viral infections
• Therapy of FUO which can mask an underlying
infection, delay the diagnosis, prevent
identification of the infectious pathogen by
rendering culture negative.
• Improper dosage, wrong frequency, excessive or
subtherapeutic dose.
• Inappropriate reliance on chemotherapy alone.
Drainage, debridement, and removal of foreign
body are important.

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 Misuses of AMAs (2)
• AM for hospitalized patients is too often given in
the absence of supporting microbiological data.
• Selection and application of drug therapy
unmatched with bacterial culture and Gram
stains
• Frequent use of drug combinations or drugs with
broader spectra as a cover for diagnostic
imprecision.
• Routine dosage rather than individualized on the
basis of clinical situation, microbiological
information, and the pharmacological
consideration.
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New Strategies for Antimicrobial Use:

Mutant Prevention Concentration

• When 1010 microorganisms are applied to agar
plates containing drug, two point of reduction in
viable bacterial cell are seen.
• The first reduction occurred with the MIC drug
concentration where the fraction of cfu
recovered substantially declined.
• This is followed by a plateau whereby cells
containing first-step resistant mutation are
present and readily isolated from drug
containing plate.

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 Mutant Prevention Concentration

Method :
1 Agar dilution as
MIC for MIC but
apply 1010 cells
rather than 105
Fraction of colony -
forming units
recovered

First-step mutants

MPC
10-8
0
Log Concentration
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(Fluoroquinolone)
 Mutant Prevention Concentration

• If drug concentration is increased, this

plateau is decreased whereby the fgrowth
of the firs-step resistant mutation is
inhibited.
• The drug concentration required to inhibit
the growth of this first-step resistant
mutant is termed as: “mutant prevention
concentration”.

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 Time

MIC
20 000 in 1
2 in 1 billion
billion
200 in 1 Immunocompromised
billion state
Prior Infection

Prior antibotic exposure

Acute infections/failed therapy

Healty
immunne Potential Immune Threshold
system Breached
Clearance

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 New Strategies for Antimicrobial Use
• MIC90: minimum concentration that inhibit 90% of 105
cfu/ml (NCCLS standardized susceptibility testing)
• MPC90: the drug concentration that would require an
organism to possess two concurrent mutation for
growth in the presence of drug.
• It may also be defined as the MIC of the most first-
step resistant cell present in a bacterial population
• Measurement of MPC only apply to those organism
deemed to be susceptible to the antimicrobial
compound by NCCLS standardized susceptibility
testing
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 New Strategies for Antimicrobial Use:
Mutant Selection Window
• Another concept related to MPC is the mutant
selection window (MSW).
• MSW is defined as the antimicrobial drug
concentration lies between the MIC and MPC
drug concentration.
• The MSW is, in essence, the “danger zone” for
the drug accelerated selection of resistant
subpopulation.
• When AM concentration < MIC, neither
susceptible nor those that contain first-step
resistant mutant will be inhibited, therefore, no
selective amplification.
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 New Strategies for Antimicrobial Use
• When the drug concentration is > MPC value,
both susceptible and first-step resistant cells are
inhibited and selective amplification of resistant
cells does not occur.
• When drug concentration fall within the MSW,
susceptible cells are inhibited as drug
concentration exceed the MIC, but first step
mutant are not inhibited as the drug
concentration is below the MPC.
• The net result of drug concentration falling within
the MSW is the selective amplification of
resistant population if present in the bacterial
population.
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 New Strategies for Antimicrobial Use

• Recent thought seems to suggest that the

best way to treat an infectious disease
requiring therapy is to kill the pathogens
and kill them quickly.
• To do this, one may need to consider the
use of more potent agents, higher
dosages, with proper dosing frequencies
to keep the drug level higher and where
possible for shorter duration of therapy.

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 Past vs New Strategies
• Past strategies
– That narrow-spectrum agents be used.
– That agents be used at the minimum doses
possible based on clinical trial data.
– That antibiotic be used for unnecessarily long
period of treatment
• Net Results
– Emergence of antimicrobial resistance

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 Past vs New Strategies
• Future strategies
– Using more potent (not necessarily broader spectrum)
antimicrobial agent
– Using more appropriate (perhaps higher) doses and
more appropriate (more frequent) dosing interval
– Using antimicrobial for appropriate (possibly shorter)
duration.
• Net Results
– Delaying, reducing or reversing the trends toward
higher antimicrobial resistance rates

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