Download 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
•
•
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 it’s 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:
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)
•
•
•
•
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
•
•
•
•
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, 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
•
•
•
•
•
•
•
•
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