ANTIMICROBIAL DRUGS

Trivia Questions
What was the first
antimicrobial utilized to treat
an infection?
 • SALVARSAN (ARSPHENAMINE)
• The "magic bullet" among chemical derivatives of
the dangerously toxic drug atoxyl.
• A treatment for syphilis.
•What was the first
antibiotic agent?
 PENICILLIN
Upon examining some colonies of Staphylococcus
aureus, Dr. Fleming noted that a mold called
Penicillium notatum had contaminated his Petri
dishes. After carefully placing the dishes under his
microscope, he was amazed to find that the mold
prevented the normal growth of the staphylococci.
 THOUGHTS TO PONDER ON…
WHAT IS THEN AN ANTIMICROBIAL DRUG?

CAN THE TERM “ANTIBIOTICS” BE UTILIZED IN LIEU

OF ANTIMICROBIALS?

ARE ALL ANTIMICROBIALS BIOLOGIC IN SOURCE?

Antimicrobial Drugs (definition of terms)

• Chemotherapy: The use of drugs to treat a disease.

• Antimicrobial/ anti-infective drugs: Interfere with
the growth of microbes within a host.
• Antibiotic: Of biological origin. Produced by a
microbe, inhibits other microbes.
• Chemotherapeutic agent: synthetic chemicals
• Today distinction blurred  many newer
"antibiotics" are biological products that are
– chemically modified or
– chemically synthesized
The History of Chemotherapy

– Paul Ehrlich and Sahachiro Hata

developed Salvarsan
(Arsphenamine) against syphilis
in 1910:
– The concept of chemotherapy to
treat microbial diseases was born.
– Sulfa drugs (sulfanilamide)
discovered in 1932  against
Gram+ bacteria
• For centuries, people used various naturally occurring
chemicals to treat diseases. Often, this was a random
act that proved useful.
• Chinese found that applying moldy soybean curds to
boils and infected wound is a great cure.
• Their findings was, perhaps, a precursor to the
penicillins today.
 The History of Chemotherapy cont.
1928: Fleming
discovered penicillin
Fig 20.1

1940: Howard Florey

and Ernst Chain
performed first
clinical trials of
penicillin.
 Antimicrobial drugs-Introduction
• Anti-infective/antimicrobial drugs are designed
to act selectively on foreign organisms that have
invaded and infected the body of a human host.
• Ideally these drugs would be toxic to the
infecting organisms only and would have no
effect on the host cells
 Antimicrobial drugs-Introduction

• Although human cells are different from the cells

of invading organisms, they are somewhat
similar, and no anti-infective drug has yet been
developed that does not affect the host.
 Antimicrobial drugs-Introduction
• Antimicrobials are vast and varied and they are
classified or grouped as the following:
1. Antibiotics-___________
2. Antivirals- ___________
3. Antifungals-___________
4. Antiprotozoals-_________
5. Anthelmintics- __________
6. Antineoplastics-__________
 Features of Antimicrobial Drugs

• Selective toxicity: Drug kills pathogens without damaging

the host.
• Therapeutic index: ratio between toxic dose and
therapeutic dose – or ratio of LD50 to ED50
High therapeutic index  less toxic
• Antimicrobial action – Bacteriostatic vs. bactericidal
• Activity Spectrum – Broad-spectrum vs. narrow- spectrum
• Tissue distribution, metabolism, and excretion – BBB;
Unstable in acid; half-life duration
 Mechanisms of Action
• Anti-infective agents may act on the cells of the
invading organisms in several different ways.
• The goal is interference with the normal function
of the invading organism to prevent it from
reproducing and to cause cell death without
affecting host cells.
• The following are various mechanisms of actions:
 Mechanisms of Action
• Some antimicrobials interfere with the
biosynthesis of the bacterial cell wall.
(penicillins)
• Some antimicrobials prevent the cells of the
invading organism from using substances
essential to their growth and development,
leading to the inability to divide and eventually
to cell death. (sulfonamides, trimethoprim and
antimycobacterial)
 Mechanisms of Action
• Many antimicrobials interfere with the steps
involved in protein synthesis. (aminoglycosides,
macrolides and chloramphenicol)
• Some antimicrobials interfere with DNA synthesis
in the cell, leading to inability to divide and cell
death (fluoroquinolones)
 Mechanisms of Action
• Other antimicrobials alter the permeability of the
cell membrane to allow essential cellular
components to leak out, causing cell death.
(some antibiotics, antifungals, and antiprotozoal
drugs)
 Antimicrobial activity
• The antimicrobials that are used today vary in
their effectiveness against invading organisms,
that is, the spectrum of activity varies.

• The two types are presented with such actions:

1. ________________________
• Some are so selective in their action that they
are effective against only a few organisms with a
very specific metabolic pathway or enzyme.

2. ________________________
• Some interfere with biochemical reactions in
many different kinds of microorganisms, making
them useful in treatment of a wide variety of
infection.
 Human immune response
• The goal of an antimicrobial therapy is reduction
of the population of the invading organism to a
point at which the human immune response can
take care of the infection.
• If the drug is aggressive enough to eliminate all
traces of any invading pathogen, it might be toxic
to the host as well.
 Human immune response
• The immune response involves a complex
interaction among chemical mediators, cells,
antibodies and enzymes.
• When this response is completely functional, it
can isolate and eliminate foreign proteins,
including bacteria, fungi and viruses
 Human immune response
• However, if a person is immunocompromised for
any reason, the immune system may be
incapable of dealing effectively with the invading
organisms.
• It is difficult to treat any infections in such
patients for two reasons:
 Human immune response
1.The antimicrobial drug cannot totally eliminate
the pathogen without causing severe toxicity to the
host.

2.These patients do not have the immune response

in place to deal with even few invading organisms
• Immunocompromised patients present a real
challenge to health care providers.
• To address this case, prevention of infection and
proper nutrition is a must.
 Resistance
• Because antimicrobials act on specific enzyme systems
or biological processes, many microorganisms that do
not use that system or process are not affected by a
particular antimicrobial drug.
• This organisms are said to have natural or intrinsic
resistance to that drug.
 Resistance
• When prescribing a drug for treatment of an
infection, this innate resistance should be
anticipated.

• The selected drug should be one that is known to

affect the specific microorganism that is causing
infection.
 Resistance
• But one of the most common problems today
about antimicrobials is resistance.
• The emergence of resistant strains of bacteria
and other organisms poses a threat:
• Antimicrobials may no longer control potentially
life-threatening diseases, and uncontrollable
epidemics may occur
 Ways of acquiring resistance
Microorganisms develop resistance in a number of
ways, including the following:
• Producing an enzyme that deactivates the
antimicrobial drug.
• Changing cellular permeability to prevent the
drug from entering the cell or altering the
transport systems to exclude the drug from
active transport into the cell.
 Ways of acquiring resistance
• Altering binding sites on the membranes of
ribosomes, which then no longer accept the
drug.

• Producing a chemical that acts as an antagonist

to the drug
 Treatment of infections
• Several factors should be considered before
beginning one of these chemotherapeutic
regimens to ensure that the patient obtains
the greatest benefit possible with the
fewest adverse effects
 Treatment of infections
• These factors include identification of the correct
pathogen and selection of a drug that is most likely to:

1. Cause the least complications for that particular

patient.
2. Be most effective against the pathogen involved.
 Combination Therapy
• In some situations, a combination of two or more
types of drugs effectively treats the infection.
When the offending pathogen is known,
combination drugs may be effective in interfering
with its cellular structure in different areas or
developmental phases.
 Combination therapy
• Combination therapy may be used for several reasons:
1. Smaller dose of each drug to be used, leading to fewer
adverse effects but still having a therapeutic impact on
the pathogen

2. Synergism effect
 Combination therapy
3. To address multiple infections.
(many infections are caused by more than one organism)
Therefore: Each pathogen may react to a different
antimicrobial.

4. To delay emergence of resistant strains

 Adverse reactions to antimicrobials
• Because antimicrobial agents affect cells, it is
always possible that the host cells will also be
affected.
• No antimicrobial has been developed that is
completely free of adverse effects.
 Adverse reactions to antimicrobials
• The most commonly encountered adverse effects
associated with the use of antimicrobials are:
1. Direct toxic effects
2. Hypersensitivity
3. Superfinfections
 Direct toxic effects
Nephrotoxicity
• Kidney damage occurs most frequently with the
use of antimicrobials that are metabolized by the
kidneys and eliminated in the urine.
• Such drugs, which have a direct toxic effect on
the fragile cells in the kidney can cause
conditions ranging from renal dysfunction to full-
blown renal failure.
• A- - - - - - - - - - - - - -
 Direct toxic effects
Gastrointestinal toxicity
• It is very common with many antimicrobials.
• Many of these agents have direct toxic effects on the
cells lining of the GI tract causing different symptoms.
• Death of microorganisms also releases chemicals and
toxins in the body which can stimulate the CTZ in the
medulla and induce nausea and vomiting.
 Direct toxic effects
• In addition, some antimicrobials are toxic to the liver.
• These drugs can cause hepatitis and even liver failure.
• Example is C __________________
• These patients should be monitored closely and the
drug should be stopped at any sign of liver dysfunction.
 Direct toxic effects
Neurotoxicity
• Some antimicrobials can damage or interfere with the
function of the nerve tissue, usually in areas where
drugs tend to accumulate in high concentrations.
• For example, the drugs Aminoglycosides and
Chloroquine.
 Hypersensitivity
• Allergic or hypersensitivity reactions reportedly occur
with many antimicrobials.
• Most of these agents, which are protein bound for
transfer in the cardiovascular system, are able to induce
antibody formation in susceptible people.
• With the next exposure to the drug, immediate or
delayed allergic responses may occur.
 Superinfections
• One offshoot of the use of antimicrobials, especially
broad-spectrum antimicrobials, is destruction of the
normal flora.
• When the normal flora is destroyed, opportunistic
pathogens that were kept in check by the “normal flora”
have the opportunity to invade tissues and cause
infections
 Antimicrobials as prophylaxis
• Sometime, it is also clinically useful to use
antimicrobials as a means of prophylaxis, to
prevent infections before they occur.
• For example, an antimalarial when patients
anticipate travel in a malaria endemic area.
• It can also be done in patients who are to
undergo surgical procedures.
ANTIBIOTICS
 Introduction
• Antibiotics are chemicals that inhibit specific
bacteria.
• Such inhibition is classified in 2 ways:
***Bactericidal
_________________________________________
***Bacteriostatic
_________________________________________
There are some antibiotics that act both as
bacteriostatic and bactericidal.
• The following are antibiotics classified as
bacteriostatic or bactericidal in action.
 Introduction
• Antibiotics are used to treat a variety of systemic
and topical infections.
• Many new infections appear each year, and
researchers are challenged to to develop new
antibiotics to deal with each new threat.
 Introduction
• Another major concern about antibiotics right now
is the
the growing number of antibiotic resistant strains
which are due to improper antibiotic usage or
stewardship
• Antibiotics are made in three ways:
a. _______________
b. _______________
c. _______________
 Major classes of Antibiotics
* Aminoglycosides *Penicillins
* Cephalosporins *Penicillinase-
resistant
* Fluoroquinolones antiniotics
* Macrolides *Sulfonamides
* Lincosamides *Tetracyclines
* Monobactams *Antimycobacterial
drugs
 The aminoglycosides
• A group of powerful antibiotics used to treat serious
infections caused gram-negative aerobic bacilli.

• Because most of these drugs have potentially serious

adverse effects, newer, less toxic drugs have replaced
aminoglycosides in the treatment of less serious
infections.
 The aminoglycosides
Aminoglycoside antibiotics
Drug name Forms Usual indication Comment
Amikacin (Amikin) IM/IV For serious gram Potential for
neg infections nephrotoxicity
and ototoxicity
Gentamicin Ophthalmic, For pseudomonal Reduce dosage in
(Gramycin) topical, IV, diseases and renal patients
intrathecal infections seen in
AIDS patients
Kanamycin Oral and For hepatic coma Should not be
(Kantrex) parenteral due to ammonia- used for more
producing than 7 to 10 days
bacteria of GI due to possibility
tract of renal dame
and BM
depression
 Aminoglycoside antibiotics
Drug name Forms Usual indication Comment
The aminoglycosides
Neomycin Oral/ Topical Suppresses GI In topical form, it
(Mycifradin) form bacteria is used to treat
preoperatively skin wounds and
and to treat infections
hepatic come
Streptomycin Oral/IM 4th drug in Very toxic to the
(generic) combination 8th cranial nerve
therapy for MTB and kidney.

Tobramycin IM/IV For very serious Available in

(Nebcin and infections. ophthalmic
Tobrex) forms for ocular
infections caused
by susceptible
bacteria
 The aminoglycosides
Therapeutic actions and indications
1. The aminoglycosides are bactericidal.
2. They inhibit protein synthesis of susceptible bacteria.
3. These drugs are used to treat serious infections caused by
:
P. aueruginosa, E. coli, Proteus species, Klebsiella-
Enterobacter-Serratia group and citrobacter
 The aminoglycosides
4. These drugs are indicated for treatment of serious
infections that are susceptible to penicillin when penicillin
is contraindicated, and they can be used in severe
infections before culture and sensitivity tests have been
completed.
 Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis: Penicillin
Natural and semisynthetic penicilins contain β-lactam ring
Natural penicillins produced by Penicillium are effective
against Gram + cocci and spirochetes
Semisynthetic penicillins: made in laboratory by adding
different side chains onto β-lactam ring  penicillinase
resistant and broader spectrum of activity
Retention of Penicillin G

Figure 20.7
 Penicillin cont.
Penicillinase (β-lactamase): bacterial enzyme that
destroys natural penicillins
Penicillinase resistant penicillins: methicilin replaced by
oxacilin and nafcilin due to MRSA
Extended-spectrum penicilins: Ampicilin, amoxicilin; new:
carboxypenicilins and ureidopenicillins (also good against
P. aeruginosa)

Fig 20.8
 Cephalosporins

Fungi of genus
Cephalosporium 4
Generations of
cephalosporins

1. First-generation: Narrow spectrum, gram-positive

2. Second-generation: Extended spectrum includes
gram-negative
3. Third-generation: Includes pseudomonads; mostly
injected, some oral.
4. Fourth-generation: Most extended spectrum
 Cephalosporins cont.
Structure and mode of action resembles penicilins

1. More stable to
bacterial -
lactamases than
penicilins

2. Broader
spectrum  used
against penicillin-
resistant strains
 Vancomycin

– Glycopeptide from Streptomyces

– Inhibition of cell wall synthesis
– Used to kill MRSA
– Emerging Vancomycin
resistance: VRE and VRSA
 Antifungal Drugs
• Polyenes, such as nystatin and amphotericin B, for
systemic fungal infections. Inhibition of ergosterol
synthesis  fungicidal. Nephrotoxic
• Griseofulvin from Penicillium. Systemic/oral. Binds to
tubulin 
For Tineae
 Antiviral Drugs
Nucleoside analogs inhibit DNA synthesis
Acyclovir and newer derivatives: Selective inhibition of
herpes virus replication. Acyclovir conversion to
nucleotide analog only in virus infected cells  very
little harm to uninfected cells!

Fig 20.16
Mechanism of Action of Acyclovir

Fig 20.16
Antiviral Drugs for Treating HIV/AIDS:
HAART
1. NRTIs and NNRTIs
2. Protease Inhibitors
3. Fusion Inhibitors
4. Integrase Inhibitors

HIV protease cleaves viral polypeptide into

functional proteins
Protease inhibition  HIV cannot mature and
noninfectious viruses are produced.
 Antiprotozoan and Antihelminthic
Drugs
Examples of Antiprotozoan:
• Chloroquine: Malaria
• Quinacrine: Giardia
• Metronidazole (Flagyl): Vaginitis, anaerobic bacteria

Examples of Antihelminthic:
• Niclosamide and praziquantel: Tapeworm
• Mebendazole: broadspectrum antihelmintic
• Ivermectin: nematodes, mites, lice . . .
 Antibiotic Assays to Guide
Chemotherapy
Agar Disk Diffusion Method determines susceptibility
of an organism to a series of antibiotics: Kirby-Bauer
test
More sophisticated methods available for clinical labs
 Drug Resistance

Penicillin G resistance of S. aureus from 3% to > 90%

Multidrug-resistant S. aureus = MRSA or “super-bug”
Vancomycin-resistance 
Multi drug resistant TB = MDR-TB

Evolution of drug resistance:

• Vertical evolution due to spontaneous mutation
• Horizontal evolution due to gene transfer ??
 Antibiotic Resistance
• A variety of mutations can lead to antibiotic resistance
• Mechanisms of antibiotic resistance
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug
• Resistance genes are often on plasmids or transposons
that can be transferred between bacteria.
Resistance to Antibiotics

Fig 20.20
 Read Clinical Focus:
Antibiotic Resistance
Antibiotics in Animal Feed
Linked to Human Disease (p. 577)

• Misuse of antibiotics selects for resistance

mutants. Misuse includes
– Using outdated or weakened antibiotics
– Using antibiotics for the common cold and other
inappropriate conditions
– Using antibiotics in animal feed
– Failing complete the prescribed regimen
– Using someone else's leftover prescription
ANIMATION Antibiotic Resistance: Origins of Resistance
and Forms of Resistance