Antimicrobials general considerations

Antimicrobials- general
considerations
Copyright ©2021 Periowiki.com

C
O
N
T
E
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T
S
 Introduction and related terms
 History
 Classification
 Characteristics of ideal antibiotics
 Choice of an antimicrobial agent
 Indications
 Contraindications
 Problems associated with the use of
AMAs

 Antimicrobial therapy: causes of failure
 Combined use of AMAs
 AMAs: prophylactic use
 Misuse
 Adverse effects
 Drug interactions
 Conclusion
 Bibliography
C
O
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E
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S

INTRODUCTION
 J.A. Vuillemin (1889) : coined the term antibiosis
 Waksman (1942) : 1st to use the term antibiotic
 Antimicrobial agent (WHO) :
is a substance of natural, synthetic or semi-synthetic origin
which at low concentrations kills or inhibits the growth
of microorganisms but causes little or no host damage.

Chemotherapy
• Which means treatment of systemic infections with specific
drugs that selectively suppress the infecting microorganism
without significantly affecting the host
Anti-infective
agent
• Is a chemotherapeutic agent that works by reducing the
number of bacteria present
Antibiotic
• substances produced by microorganisms, which suppress the
growth of or kill other microorganisms at very low
concentrations

Antiseptic :
Is a chemical antimicrobial agent
applied topically or sub-gingivally
to mucous membranes, wounds or
intact dermal surfaces to destroy
microorganisms and inhibit their
reproduction or metabolism
Disinfectant:
A subcategory of antiseptics,
are antimicrobial agents that
are generally applied to
inanimate surfaces to
destroy microorganisms

Minimum Inhibitory Concentration (MIC):
The lowest concentration of an antibiotic which prevents
visible growth of a bacterium
Minimum Bactericidal Concentration (MBC):
Is the concentration of the antibiotic which kills 99.9% of the bacteria
Chemotherapeutic index:
The ratio of toxic dosage level to the therapeutic dosage level

HISTORY
1st period :
 involved the use of alkaloids
 example: cinchona bark to cure malaria (1619)
mouldy curd to cure boils by Chinese
2nd period : (Ehrlich’s phase)
 involved use of synthetic compounds
 Domagk in 1935 demonstrated the
therapeutic effect of prontosil
which lead to development of sulfonilamide

3rd period : the era of antibiotics
Pasteur in the 1870s was one of the early pioneers in
the study of intermicrobic antagonism
Discovery of penicillin by sir Alexander fleming (1929)
The present era of antibiotics:
- Started with discovery of streptomycin (1944)

Classification:
A. On the basis of chemical structure:
Sulfonamides: dapsone, PAS Polypeptides: polymixin B, bacitracin
Diaminopyrimidines: trimethoprim,
pyrimethamine
Glycopeptide: vancomycin,
teicoplanin
Quinolones: nalidixic acid, norfloxacin,
ciprofloxacin
Oxazolidinone: linezolid
Beta lactam antibiotics: penicillins,
cephalosporins, monobactems
Nitrofuran derivatives: nitrofurantoin
Tetracyclines: oxytetracycline,
deoxycycline
Nicotinic acid derivatives: isoniazid,
ethionamide
Nitrobenzene derivatives:
chloramphenicol
Polyene antibiotics: nystatin,
amphotericin B
Aminoglycosides: streptomycin,
gentamicin, neomycin
Azole derivatives: clotrimazole,
ketoconazole, fluconazole
Macrolides: erythromycin, azithromycin Others: rifampicin, griseofulvin

B. Mechanism of action:

C. Type of microorganism against which primarily active
. PENICILLIN . ERYTHROMYCIN
. AMINOGLYCOSIDES
. IDOXURIDINE . AMANTIDINE
• . ACYCLOVIR . ZIDOVUDINE
•
. GRISEOFULVIN . KETOCONAZOLE
• . AMPHOTERICIN B
. CHLOROQUINE . METRONIDAZOLE
• . PYRIMETHAMINE . DILOXANIDE
•
. MEBENDAZOLE . NICLOSAMIDE
• . PYRANTEL . DIETHYL CARBAMAZINE
•
antibacterial
antifungal
antiprotozoal
antihelminthic
antiviral

D. Spectrum of activity
Broad Narrow
tetracycline
Chloramphenicol
Sulphonamides
trimethoprim
Penicillin G
Streptomycin
Erythromycin
Lincosamides
glycopeptides

E. Type of action

Characteristics of ideal antibiotics
1. Selectively toxic to the microbe
but nontoxic to eukaryotic cells
2. Bactericidal rather
than bacteriostatic
3. Active even when highly diluted
in body fluids
4. Effective for long periods of time
5. Does not easily induce
antimicrobial resistance
6. Assists host defence activities
7. Dose not induce allergic
reactions in host
8. Commensal microflora
not notable affected
9. Minimal drug interactions
or adverse effects

Indications of antibiotics:
Each antibiotic is characterized by
specific properties, so there are
individual indications for each antibiotic
Antibiotics indications:
•pneumonia
•sepsis
•meningitis
•osteomyelitis
•urinogenital infections
•gall infections
•quinsy,
•skin infections
•mucous membrane infections
•scarlet fever
•diphtheria
•Siberian ulcer
•gynecologic infections
•syphilis
•respiratory infections
•ENT infections
•fungous infections

Contraindications of AMAs:
Contraindications for antibiotics refer to those
circumstances under which these medications shouldn’t
be used because they might be ineffective or dangerous
Decided
on the
basis of
Nature of
infection
Patient’s
age
Existing
medical
condition
History

Bacteriostatic Vs bacteriocidal …!!!
Mechanism of
action
4 reasons why bactericidal drugs are preferred
1. Mechanism of action
2. less time of resolution of infection
3. to avoid cases of recurrence
4. concentrations of the drug need not have to be maintained

Disadvantages of bactericidal agents:
- potentially adverse clinical consequences may
result from the rapid lytic action of bactericidal
antibacterial agents
Advantages of bacteriostatic
agents:
Inhibit protein synthesis in resting slow
growing bacteria not affected by
bactericidal agents

Choice of an antimicrobial agent
Patient factors
Microbe related
factors
Drug factors

Age
Impaired host
defence
Comorbid
conditions
Pregnancy
Hepatic &
renal function
Drug allergy
Genetic
factors
Local factors
Patient factors

Age: example : kernicterus in neonates due to sulfonamides
VIII nerve toxicity in elderly due to aminoglycosides
Renal and hepatic function: is important when concerned with the
drug disposal by the organ if it is
defective
Local factors: like presence of pus, secretions, haematomas, abscess,
SABE
Drug allergy: history of previous drug allergy should be obtained
example: beta lactams, sulfonamides, fluoroquinolones
Impaired host defence: integrity of host defence plays a crucial role
in overcoming an infection and is
important in deciding the type AMA to be
used Ex: SABE,AIDS.

Pregnancy: AMAs used can impose increased risk of reaction
for both mother and fetus
however, penicillin, many cephalosporins & erythromycin
are safe
Genetic factors: example: hemolysis in G-6PD deficient patient due to
primaquine, nitrofurantoin, sulfonamides,
chloramphenicol
Comorbid conditions: examples:
HIV – infected patients :- bone marrow
depression, make them susceptible to
hematologic side effects of antibiotics

Microbe related factors

Drug factors
Spectrum
of activity
Type of
activity

Spectrum of activity: of AMA is decided whether the therapy is
definitive or empirical
Type of activity: depends upon factors like impaired host defence,
carrier state is possible, life- threatening infections
Sensitivity of the organism: determined by MIC values ,
post antibiotic effect
Relative toxicity: preference to less toxic drug
Pharmacokinetic profile: - concentration dependent inhibition:
ex: aminoglycosides, fluoroquonolones
- time dependent inhibition:
ex: beta lactams

Route of administration: severity of infection can be considered
as a deciding factor
eg: meningitis, septicemias, parenteral
route is chosen
Evidence of clinical efficacy: decided on the basis of:
comparative clinical trials
Cost : less expensive drugs are to be preferred

problems asso. with the use of AMAs
1. toxicity
Direct
mild: eg – local
discomfort
Severe: eg –
ototoxicity,
nephrotoxicity
Indirect
allergic reaction
Cross-reactivity

2. Disturbances of host microflora
 symptoms : superinfections, diarrhoea, flatulence, angular stomatitis,
black furred tongue, glossodynia, vitamin deficiencies
 superinfections:
- broader the spectrum of antibacterial action,
the greater the incidence of superinfection
- a serious form of antibiotic- induced superinfection is
pseudomembranous colitis
 nutritional deficiency:
- prolonged use of antimicrobials alter the intestinal flora resulting
vitamin deficiency ( eg: vit B complex and vit K )

3. Hypersensitivity reactions
4. Masking of infection
Example:
(i) penicillin tt for
gonorrhoea masks syphilis
(ii) Streptomycin tt for
respiratory infection masks
tuberculosis

5. Drug resistance
 Unresponsiveness of a microorganism to an AMA
 Selection pressure
 Types:
Natural acquired
 Reasons:
- mutations: is a stable and heritable genetic change that occurs spontaneously and
randomly among microorganisms
types of which are – single step or multistep

-Gene transfer: is nothing but infectious resistance
can occur by:
Conjugation
Transduction
Transformation
Example : 1. chloramphenicol resistant to typhoid bacilli
2. streptomycin resistant to E.coli
3. penicillin resistant to haemophilus, gonococci
Example: penicillin
chloramphenicol
erythromycin
Example: isolated instances of pneumococcal
resistance to Penicillin G

-enzymes: eg: penicillinase, cephalosporinase, dihydrop-
teroate synthetase
2 mechanisms: inactivates the antibiotic or
alters the permeability of bacterial cell to
antimicrobial drugs
Adaptive resistance:
-No genetic change involved
- phenomenon seen against fluoroquinolones
- clinical significance uncertain

Antimicrobial susceptibility testing
 rationale:
1. to confirm susceptibility to chosen empirical
antimicrobial agents
2. to detect resistance in individual bacterial
isolates
3. Susceptibility testing of individual isolates is
important with species that may possess
acquired resistance mechanisms

methods used:
Broth dilution test:
Gradient method:
Disk diffusion test:
Advantages Disadvantages
- Simplicity
- no special equipment
all fastidious
or slow growing
bacteria cannot be
accurately tested
intrinsic flexibility by
being able to test the
drugs the laboratory
chooses
some systematic
biases toward higher or lower MICs
determined by the
Etest when testing certain organism-
antimicrobial agent combinations
-reproducibility
-preprepared panels,
-economy of reagents
-computerized reports
some inflexibility of drug
selections available in standard
commercial panels

antimicrobial therapy : causes of failure
1. Incorrect dose
2. Wrong diagnosis
3. Resistant pathogens
4. Superinfection
5. Drug withdrawal

6. Wrong
antibiotic
7. Mixed
infections
8. Inadequate
surgical
procedure
9. Inadequate
host defense
system

Combined use of AMAs:
Selection of an appropriate combination depends upon the understanding of
the potential for interaction between the antimicrobial agents
These interactions can either affect the microorganism or the patient
The drug combination results can have following effects:
1. Synergism 3. Indifference
2. Additive action 4. antagonism

 rationale for AMA combination:
- to achieve synergism
- to reduce severity or incidence of adverse effects
- minimize emergence of antibiotic – resistant microorganisms
- to broaden the spectrum of antimicrobial action : required in cases of
mixed infections, initial treatment of severe infections
- Increase certainty of a successful clinical outcome

Synergistic combination: (i) sulfonamide + trimethoprim
(ii) clavulanic acid/sulbactam + amoxicillin/ ampicillin
Additive combination: (i) penicillin /ampicillin + streptomycin/gentamicin
(ii) carbenicillin/ticarcillinn + gentamicin
Antagonism combination : (i) nalidixic acid + nitrofurantoin
(ii) penicillin + erythromycin

Bacteriostatic +
bacteriostatic
Bacteriocidal
+
bacteriostatic
Bacteriocidal
+
bacteriocidal
possible combinations:
2 possibilities:
-Microorganism highly sensitive to
cidal drug
-Microorganism has low sensitivity to
cidal drug

- Examples of various positive result of AMA combinations :
Condition AMA combination prescribed
Initial, uncomplicated tuberculosis Isoniazid and rifampin/ethambutol
Septicemia or pneumonia Carbenicillin and gentamicin
Sepsis caused by intestinal perforation Clindamycin/metronidazole & aminoglycoside
Enterococcal endocarditis Penicillin G & streptomycin/ gentamicin
brucellosis Tetracycline and streptomycin
pneumonia Cephalosporin and aminoglycoside

Foster a casual
outlook in the
diagnosis
Emergence of
resistance
Increased cost
of therapy
Increased
chances of
superinfections
Increased
prevelance of
adverse effects
Disadvantages of AMA combinations

Prophylaxis
against specific
organism
Prevention of
infection in
general
prevention of
infection in high
risk situations
AMAs:prophylactic use

Prophylaxis against specific organism Prevention of infection in general
-In general highly satisfactory
- choice of drug is clearcut
- for example:
• penicillin G for tt of rheumatic fever
• tetracycline for tt of rickettsial infections
• chloroquine for tt of malaria
-Highly unsatisfactory in most of the
cases
-disadvantages:
. Infection by resistant organisms
. Fungal & other superinfections
-for example:
. in neonates
. after normal delivery
. after clean elective surgery

Dental extractions,
tonsillectomy,
endoscopies
Catheterization or
instrumentation of
urinary tract
Chronic obstructive
lung disease,
chronic bronchitis
Immunocom-
promised patients
Contaminated wounds
Recurrances of UTI
infection in pts
with abnormalities
of the tract
Surgical
prophylaxis
Prevention of infection in high risk situation

tt of
nonresponsive
infections
inappropriate
reliance on
chemotherapy
lack of adequate
bacteriological
information
improper dosage
therapy of fever
of unknown
origin
Misuses of antibiotics

Treatment of nonresponsive infections: example : most of the viruses
Type of fever: - (i) short duration or
(ii) of unknown nature
Improper dosage: (i ) too low a dose result is treatment failure
(ii) too high a dose: seizures with penicillin,
renal failure with aminoglycosides
Inappropriate reliance on chemotherapy alone:
example in cases like : abscess
necrotic tissue
foreign body

Adverse effects of antibiotics
1. T
O
X
I
C
I
T
y
hepatitis
liver cell damage
anemia
Leukopenia
Blood clotting disorders
discolouration
Seizures
Dizzines
Vertigo
deafness
- nonoliguric or
even polyuric renal
excretion dysfunction
- Tubular effects
-Diarrhoea
- vomiting

2. Allergic responses
- allergy is an immunological reaction towards a foreign molecule
- antimicrobial drugs or its metabolites act as antigens against which
antibodies are present
- 2 forms: immediate or delayed hypersensitivity reactions
- Penicillin accounts for the greatest number of antibiotic- induced
allergies

3. Suppression and alteration of the commensal microflora:
- resident bacteria are normally harmless harmless
- however, broad- spectrum antibiotics may cause
disturbance in their numbers
-Outcome is superinfection

Drug interactions
 “The pharmacologic or clinical response to the
administration of a drug combination different from
that anticipated from the known effects of the two
agents when given alone”
Tatro DS (Ed.) Drug Interaction Facts. J.B. Lippincott
Co. St. Louis 1992
 types:
1. pharmacokinetic : One drug alters the concentration of another by altering
its absorption, distribution, metabolism, or excretion
2. pharmacodynamic: One drug modulates the pharmacologic effect of
another: additive, synergistic, or antagonistic

before absorption
of the drugs
after absorption
of the drugs
 interactions between 2 drugs can occur :
 An important mechanism of interaction is the induction or
inhibition of hepatic enzymes resonsible for drug inactivation

AMA interacting drug Effect of interaction
Aminoglycoside Furosemide
Cepahalosporin
Vancomycin
Oto- & nephrotoxicity
Tetracycline Antacids and iron
Carbamazapine
Oral anticoagulants
Diminished tetracyline absorption
Decreased tetracyline half life
Potentiating effect of anticoagulant
Ciprofloxacin theophylline Theophylline toxicity
Metronidazole Alcohol
coumarin
Disulfiram effect inhibition
Sulfonamides Phenytoin
chlorpropamide
Potentiating effect
Increased hypoglycemic effect
Quinolones Antacids
NSAIDs
Morphine
Reduced oral bioavailability of
quinolone
Seizures
Decreased serum concentration of
quinolone

Conclusion:
Antimicrobial agents are some of the most widely, and often
injudiciously, used therapeutic drugs worldwide
Important considerations when prescribing antimicrobial therapy include obtaining
an accurate diagnosis of infection understanding the difference between empiric and
definitive therapy; identifying opportunities to switch to narrow-spectrum, cost-
effective oral agents for the shortest duration necessary; understanding drug
characteristics that are peculiar to antimicrobial agents (such as pharmacodynamics
and efficacy at the site of infection); accounting for host characteristics that
influence antimicrobial activity; and in turn, recognizing the adverse effects of
antimicrobial agents on the host
This in turn will help in serving the purpose of providing
a satisfactory treatment regimen

Bibliography:
 Essentials of medical pharmacology
KD Tripathi 5th edition
 Goodman & Gilman’s
The Pharmacological Basis of Therapeutics
Laurence L. Brunton, John S. Lazo, Keith L. Parker
11th edition
 Antibiotic and Antimicrobial use in dental practise
Michael G. Newman, Arie J. van Winkelhoff
2nd edition

 Pharmacology and therapeutics for dentistry
Enid A. Neidle, John A. Yagiela
3rd edition
 Bulletin of the New York academy of medicine
vol. 51, no. 9, October 1975,
A brief survey of the history of the antimicrobial agents
Antimicrobial Susceptibility Testing: A Review of General
Principles and Contemporary Practices
James H. Jorgensen and Mary Jane Ferraro
Clinical Infectious Diseases 2009; 49:1749–55
Clinical Relevance of Bacteriostatic versus Bactericidal Mechanisms
of Action in the Treatment of Gram-Positive Bacterial Infections
G. A. Pankey and L. D. Sabath
Clinical Infectious Diseases 2004; 38:864–70

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Antimicrobials general considerations

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