Transcript Antimicrobial Drugs

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
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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 it’s toxins or Candida albicans.
Mechanisms of action of
Antibacterial Drugs
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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:
b-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
• b-lactam ring similar in structure to
normal substrate of enzyme
• Drug binds to enzyme, competitively inhibit
enzymatic activity
b-Lactam Drugs
• Some bacteria produce b-lactamaseenzyme that breaks the critical b-lactam
ring
• b-lactam drugs include: penicillins and
cephalosporins
Penicillins (Benzylpenicillin)
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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 grambacteria.
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 β-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-βlactamase-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 β-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 p’col 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 β-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
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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.
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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, Δ envellope to prevent drug
access, and Δ 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
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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.
Don’t cross the BBB – ineffective against meningitis.
Resistance- occurs bec of plasmid-controlled Δ 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 3’OH; 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., β-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