Antimicrobial Drugs

Antimicrobial Drugs
Chemicals used to treat microbial
infections
Before antimicrobials, large number of
people died from common illnesses
Now many illnesses easily treated with
antimicrobials
However, many antimicrobial drugs are
becoming less useful

Antimicrobial Drugs
Chemotherapeutic agent=
Antimicrobial drug=
Different types of antimicrobial drugs:
Antibacterial drugs
Antifungal drugs
Antiprotozoan drugs
Antihelminthic drugs

Features of Antimicrobial Drugs

1.
2.
3.
4.

Most modern antibiotics come from

species of microorganisms that live in the
soil
To commercially produce antibiotic:
Select strain and grow in broth
When maximum antibiotic concentration
reached, extract from medium
Purify
Chemical alter to make it more stable

Features of Antimicrobial Drugs:

Selective Toxicity
Cause greater harm to microorganisms
than to host
Chemotherapeutic index: lowest dose
toxic to patient divided by dose typically
used for therapy

Features of Antimicrobial Drugs:

Antimicrobial Action
Bacteriostatic: inhibit growth of
microorganisms
Bactericidal: Kill microorganisms

Features of Antimicrobial Drugs:

Spectrum of Activity
Antimicrobial medications vary with
respect to the range of microorganisms
they kill or inhibit
Some kill only limited range : Narrowspectrum antimicrobial
While others kill wide range of
microorganisms: Broad-spectrum
antimicrobial

Features of Antimicrobial Drugs:

Effects of Combining Drugs

Combinations are sometimes used to fight
infections
Synergistic: action of one drug enhances
the activity of another or vice versa.
Antagonistic: activity of one drug interferes
with the action of another.

Features of Antimicrobial Drugs:

Adverse Effects
1. Allergic Reactions: some people develop
hypersensitivities to antimicrobials
2. Toxic Effects: some antimicrobials toxic
at high concentrations or cause adverse
effects
3. Suppression of normal flora: when
normal flora killed, other pathogens may
be able to grow to high numbers

Features of Antimicrobial Drugs:

Resistance to Antimicrobials
Some microorganisms inherently resistant
to effects of a particular drug
Other previously sensitive microorganisms
can develop resistance through
spontaneous mutations or acquisition of
new genes (more later).

So, The Criteria of the Ideal Antibiotic:

Selectively toxic to microbe but nontoxic to host.
Soluble in body- tissue distribution BBB.
Remains in body long enough to be effective resists excretion and breakdown.
Shelf life.
Does not lead to resistance.
Cost not excessive.
Hypoallergenic.
Microbiocidal rather than microbiostatic.
Concerns suppression of normal flora antibiotic associated colitis with Clostridium
difficule and its toxins or Candida albicans.

Mechanisms of action of
Antibacterial Drugs
1.
2.
3.
4.
5.

Inhibit cell wall synthesis

Inhibit protein synthesis
Inhibit nucleic acid synthesis
Injury to plasma membrane
Inhibit synthesis of essential metabolites

Figure 20.2

Inhibition of Cell Wall

Synthesis:
Lactam Drugs

Irreversibly inhibit enzymes involved in the

final steps of cell wall synthesis
These enzymes mediate formation of
peptide bridges between adjacent stands
of peptidoglycan
lactam ring similar in structure to
normal substrate of enzyme
Drug binds to enzyme, competitively
inhibit enzymatic activity

Lactam Drugs
Some bacteria produce -lactamaseenzyme that breaks the critical lactam ring
-lactam drugs include: penicillins
and cephalosporins

Penicillins (Benzylpenicillin)

Acid-labile.
Gram+ bacteria.
So, take phenoxymethylpenicillin.
Large Vd, but penetration into brain: poor,
except when the meninges are inflammed.
Broad spectrum penicillins: amoxicillin and
ampicillin are more hydrophillic and
therefore, are active against gram- bacteria.

Penicillins (Benzylpenicillin)
Penicillinase-resistant penicillins Flucloxacillin
Indicated in infections caused by penicillinaseproducing pen-resistant staphlococci.
Has an isoxazolyl group at R1 sterically hinders
access of the enzyme to the -lactam ring.
Less effective than benzylpen.
So, should be used only for pen-resistant infections.
Well-absorbed orally, but in severe infections,
should be i.v. and not alone.
Staphlococci aureas-resistant strains to flucloxicillin
and MRSA (methicillin-resistant Staph aureas)
increasing problem.

Broad-Spectrum Penicillins
Ampicillin and amoxicillin very active against non-lactamase-producing gram+ bacteria.
Because they diffuse readily into Gram- bacteria, also
very active against many strains of E. coli, H. influenzae,
and Salmonella typhimurium.
Orally, amoxicillin is better because absorption is better.
Ineffective against penicillinase-producing bacteria (e.g.,
S. aureus, 50% of E. coli strains, and up to 15 % of H.
influenzae strains.
Many baterial -lactamases are inhibited by clavulaic
acid amoxicillin (co-amoxiclav) antibiotic is effective
against penicillinase-producing organisms.
Co-amoxiclav indicated in resp and UT infections, which
are confirmed to be resistant to amoxicillin.

Cephalosporins
Used for treatment of meningitis, pneumonia, and
septicemia.
Same mech and pcol as that of pens.
May allergic rxn and cross-reactivity to pen.
Similar to pens in broad-spectrum antibacterial activity.
Cedadroxil (for UTI) in case of antibact resist.
Cefuroxime (prophylactic in surgery) Resistant to
inactivation by -lactamases and used in severe
infections (others ineffective).
Ceftazidine wide range of activity against gram- including
Pseudomonas aeruginosa), but is less active than
cefurozime against gram+ bact (S aureus).
Used in meningitis (CNS-accessible) caused by grambacteria.

Vancomycin

Not well absorbed orally.

Inhibits peptidoglycan formation.
Active against most gram+ organisms.
I.v. treatment for septicemia or
endocarditis caused by MRSA.
Used for pseudomembranous colitis
(superinfection of the bowel by Clostridium
difficile produces a toxin that damages
the colon mucosa)

Antibacterial Drugs
that Inhibit
Cell Wall Synthesis

Antibacterial Medications that

Inhibit Protein Synthesis
Target ribosomes of bacteria
Aminoglycosides: bind to 30S subunit
causing it to distort and malfunction; blocks
initiation of translation
Tetracyclines: bind to 30S subunit blocking
attachment of tRNA.
Macrolides: bind 50S subunit and prevents
protein synthesis from continuing.

Aminoglycosides
Against many gram- and some gram+.
Narrow TI very potentially toxic.
Most important adverse side-effect: VIIIth
cranial n. (ototoxicity) and kidney damage.
Resistance several mechs: inactivation
of the drug by acetylation, phos, or
adenylation, envellope to prevent drug
access, and the binding site of the 30S
subunit (streptomycin only).

Aminoglycosides
Gentamicin used for acute, life-thretening graminfections. Has synergism with pen and van and combo.
Amikacin used for bact that are gent-resistant.
Netilmicin less toxic than gentamicin.
Neomycin too toxic for parenteral use. Used for
topically for skin infections and orally for sterilizing bowel
before surgery.
Streptomycin active against Mycobacterium
tuberculosis. But bec of its ototoxicity, rifampicin
replaces.
Rifampicin resistance develops quickly alone; so, with
TB, combine with isoniazid, ethambutol, and
pyrazinamide for the 1st 2 mos of treatment, followed by
another 4 mos with rifampicin and isoniazid.

Macrolides

Very safe drugs.

Ususally given orally.
Erythromycin and clarithomycin
Effective against gram- bact and can be used as an alt to
pen-sensitive patients, esp in infections caused by
streptococci, staphylococci, pneumococci, and clostridia.
Dont cross the BBB ineffective against meningitis.
Resistance- occurs bec of plasmid-controlled of their
receptor on the 50S subunit.
Erythromycin in high doses, may cause nausea and
vomiting (less so with clarithromycin and azithromycin).
Azithromycin very long t1/2 (~40-60 hr) and a single
dose is as effective in treating chlamydial non-specific
urethritis as tretracycline admin over 7 days,

Tetracyclines
Broad-spectrum.
Penetrate microorganisms well.
Sensitive organisms accumulate it through partly passive
diffusion and partly through active transport.
Resistant organisms develop an efflux pump and do not
accumulate the drug.
Genes for tet-resistance transmitted by plasmids.
Closely assoc with those for other drugs to which the
organisms will also be resistant (e.g., sulphonamides,
aminoglycosides, chloramphenicol).
Tets bind to Ca in growing bones and teeth can
discolor teeth. So, should be avoided in children < 8 yrs
old.

Chloramphenicol
Broad-spectrum.
Serious side-effects: bone marrow aplasia,
suppression of RBCs, WBCs, encephalopathy,
optic neuritis.
So, periodic blood counts required, esp in high
doses.
Large Vd, including CNS.
Inhibits the actions of other drugs and may incr
the actions of phenytoin, sulphonlureas, and
warfarin.
Neonates cannot met the drug rapidly accum
grey baby syndrome (pallor, abdominal
distension, vomiting, and collapse).

Antibacterial
Drugs that Inhibit
Protein Synthesis

Antibacterial Medications that

Inhibit Nucleic Acid Synthesis
Target enzymes required for nucleic acid
synthesis
Fluoroquinolones: inhibit enzymes that
maintain the supercoiling of closed circular
DNA
Rifamycins: block prokaryotic DNAdependent RNA polymerase from initiating
transcription

Sulphonamides
Sulfadiazine well-absorbed orally. Used to treat
UTIs.
But many strains of E. coli are resistant.
So, use less toxic drugs instead.
Adverse effects: allergic rxns, skin rashes, fever.
Trimethoprin used for UTIs and Resp TIs
Co-trimoxazole (trimethoprin +
sulfamethoxazole) used mostly for pneumonia,
neocarditis, and toxoplasmosis.

Antibacterials Competitive Inhibitors

Sulfonamides (Sulfa drugs)
Inhibit folic acid synthesis
Broad spectrum

Figure 5.7

Figure 20.13

Quinolones (GABA antagonists)

Inhibit DNA gyrase.
Nalidixic acid used only for UTIs.
Ciprofloxin (6-fluoro substituent) that greatly
enhances its effectiveness against both gramand gram+ bacteria.
Well-absorbed both orally and i.v.
Eliminated largely unchanged by the kidneys.
Side-effects (headache, vomiting, nausea) are
rare; but convulsions may occur.

5-Nitroimidazoles
Wide-spectrum
Metronidazole against anaerobic
bacteria and protozoan infections.
Tinidazole longer duration of action.
Diffuses into the organism where the nitro
group is reduced chemically reactive
intermediates are formed that inhibit DNA
synthesis and/or damage DNA.

Antibacterial Drugs that Inhibit Nucleic Acids

Antibacterial medications that Injure

Plasma Membrane
Polymyxin B: binds to membrane of Gbacteria and alters permeability
This leads to leakage of cellular contents
and cell death
These drugs also bind to eukaryotic cells
to some extent, which limits their use to
topical applications

Antibacterial Drugs that Inhibit

Synthesis of Essential Metabolites
Competitive inhibition by substance that
resembles normal substrate of enzyme
Sulfa drugs

Antiviral Drugs
Very few antiviral drugs approved for use
in US
Effective against a very limited group of
diseases
Targets for antiviral drugs are various
points of viral reproduction

Drugs that Prevent the Virus from Entering

or Leaving the Host Cells
Amantadine interferes with replication of influenza A by
inhibiting the transmembrane M2 protein that is essential
for uncoating the virus.
- Has a narrow spectrum; so, flu vaccine is usually
preferable.
Zanamivir inhibits both influenza A and B
neuraminadase. Decr duration of symptoms if given
within 48 hr of the onset of symptoms. Prophylactic in
healthy adults.
Immunoglobulins Human Ig contains specific Abs
against superficial Ags of viruses can interfere with
their entry into host cells. Protection against hepA,
measles, and rubellla (German measles).

Drugs that Inhibit Nucleic Acid Synthesis

Nucleoside and Nucleotide Analogs
Acyclovir- used to treat genital herpes
Cidofovir- used for treatment of
cytomegaloviral infections of the eye
Lamivudine- used to treat Hepatitis B

Acyclovir
HSV and VZV contain a thymidine kinase (TK)
that acyclovir to a monophosphate
phosphorylated by host cell enzymes to
acycloguanosine triphosphate, which inhibits
viral DNA pol and viral DNA synthesis.
Selectively toxic (TK of uninfected host cells
activates only a little of the drug).
Viral enzymes have a much higher affinity than
the host enzymes for the drug.
Effective against HSV, but does not eradicate
them.
Need high doses to treat shingles.

Ganciclovir
Quite toxic (neutropenia) so, given only
for severe CMV infections in
immunosuppressed patients.
CMV is resistant to acyclovir because it
does not code for TK.

Antiretrovirals

Currently implies a drug used to treat HIV

Tenofovir- nucleotide reverse transcriptase inhibitor
Zidovudine- nucleoside analog inhibits RT of HIV and
is only used orally for AIDS.
- Activated by triple phosphorylation and then binds RT
(with100X affinity than for cellular DNA pols).
- Incorporated into the DNA chain, but lacks a 3OH; so
another nucleoside cannot form a 3-5-phosphodiester
bond DNA chain elongation is terminated.
-Severe adverse effects: anemia, neutropenia, myalgia,
nausea, and headaches.
Stavudine, didanosine, zalcitabine among other NRTIs.
Nevirapine, efavirenz Non nucleoside RTIs - denature
RT.

Life Cycle of
HIV

HIV gp41-mediated fusion and enfuvirtide (T-20) action Prohibits HIV entry

Other enzyme inhibitors

Zanamivir (Relenza) and Oseltamivir
phosphate (Tamiflu)- inhibitors of the
enzyme neuominidase
Used to treat influenza

Indinavir- protease inhibitors. Inhibit the

synthesis of essential viral proteins (e.g.,
RT) by viral-specific proteases.

Interferons
Cells infected by a virus often produce
interferon, which inhibits further spread of
the infection
Alpha-interferon - drug for treatment of
viral hepatitis infections

Kirby-Bauer Method for

Determining Drug Susceptibility
1. Bacteria spread on surface of agar plate
2. 12 disks, each with different antimicrobial
drug, placed on agar plate
3. Incubated- drugs diffuse outward and kill
susceptible bacteria
4. Zone of inhibition around each disk
5. Compare size of zone to chart

Figure 21.10

Resistance to Antimicrobial Drugs

Drug resistance limits use of ALL known
antimicrobials
Penicillin G: first introduced, only 3% of
bacteria resistant
Now, over 90% are resistant

Mechanisms Responsible for Resistance to

Antimicrobial Drugs Include the Following:
1. Inactivating enzymes that destroy the drug
(e.g., -lactamases).
2. Decreased drug accumulation (e.g., tet).
3. Altering the binding sites (e.g.,
aminoglycosides and erythromycin).
4. Development of alternative metabolic
pathways (sulphonamides ( dihydropteroate
synthease) and trimethoprim (dihydrofolate
reductase).

How do Bacteria Become Resistant?

1. Spontaneous Mutation: happen as cells
replicate Within a pop, there will be
some bact with acquired resistance. The
drug then elim the sensitive organisms,
while the resistant ones proliferate.
2. Gene Transfer or Transferred resistance:
Usually spread through conjugative
transfer of R plasmid ( may be virally
mediated).

Slowing the Emergence and

Spread of Antimicrobial Resistance
1. Responsibilities of Physicians: must work
to identify microbe and prescribe suitable
antimicrobials, must educate patients
2. Responsibilities of Patients: need to
carefully follow instructions

Slowing the emergence and spread

of antimicrobial resistance
3. Educate Public: must understand
appropriateness and limitations of
antibiotics; antibiotics not effective against
viruses
4. Global Impacts: organism that is resistant
can quickly travel to another country
- in some countries antibiotics available on
non-prescription basis
- antibiotics fed to animals can select for
drug- resistant organisms

New Approaches to Antibiotic

Therapy Are Needed
Scientists work to find new antibiotic
targets in pathogens
Discovery of new and unique antibiotics is
necessary