Antibiotics, Antiviral, and Antifungal Flashcards
How do bacteria harm the host?
Divert nutrition away from host, depriving cells of O2 and food
Elaborate toxic chemicals
Activate a harmful immune response
Not all bacteria are harmful…
Source of vitamins (K) & essential fatty acids
Prevent over-growth of harmful bacteria
How the body defends against bugs
Infections are typically “partially controlled” by the
body’s own immune system
The invading organism gets a “foot hold”, but
can’t flourish, except in overt infections
How do antibiotics works with the body’s immune system
Most antibiotics “tip the scales” in favor of the
immune system
“slow” bacterial spread and reproduction so immune system can kill it of
Bactericidal
kills bacterial D E A D
* Penicillins and Vancomycin
Bacteriostatic
Blocks replication of bacteria
* Tetracycline
* Chloramphenicol
In an “immunocompramized patient”, which is the preferred type of antibiotic, a bacteriosidal or a bacteriostatic agent?
Bactericidal
Bacteria - Prokaryotes
- Cell wall
- Cell membrane (unique phospholipids)
- 60s (larger) ribosome
- No nuclear membrane
- Unique mechanism of RNA/DNA synthesis
Human Hosts (Eukaryotes)
- No cell wall
- Cell membrane (but different phospholipids compared to bacteria)
- 50s (larger) ribosome
- Nuclear membrane
- standard eukaryotic RNA/DNA synthesis
What is selective toxicity
Degree to which the drug impairs/kills invading
organism’s cells compared to the host’s cells –> similar to therapeutic window
When to use Broad spectrum antibiotics:
Useful when infection is caused by “unknown”
organism
Broad spectrum antibiotics side effects
Kill off “good” bacteria”
Predispose to resistance
Typically strong medications with toxic side effects (except penicillins)
Narrow Spectrum Antibiotics
Specifically target one type of bacteria
May have better side effect profile
Less resistance
Less effect on normal bacteria in and on body
Mechanisms of antibiotic drugs
Cell wall synthesis inhibitors
Cell membrane inhibitors
Protein synthesis inhibitors
Metabolic and nucleic acid (RNA and/or DNA) synthesis inhibitors
Inhibition of Cell wall synthesis and function
- bacteria have a rigid cell wall
- Drugs targeting the synthesis of bacterial cell wall typically have good selective toxicity
Bacteria have a rigid cell wall -
Key constituent is peptidoglycans
Peptidoglycans are cross-linked in a way that
provides strength
Any compromise of bacterial cell architecture
activates a suicide/autolysis pathway
One new antibiotic targets…..
bacterial lipid II and III, important precursor molecules for forming the cell wall
Bacterial Cell Wall Inhibitors
Beta-Lactam antibiotics
Cephalosporins & Penicillins
What is the first known antibiotic
Penicillins
How do penicillins work
Binds to a special bacterial cell wall enzyme (penicillin binding protein) used in peptidoglycan synthesis
Bacteria develop a special enzyme that degrades penicillins (penicillinase)
Naturally occurring penicillins
Penicillin G & V
Narrow
Synthetic penicillins
Ampicillin & Amoxicillin
Broader
What penicillins have been developed that are resistant to breakdown or are combined with penicillinase-blocker
Augmenten (Amoxicillin plus Clavulate, inhibits breakdown)
Imipenem
Relatively narrow spectrum penicillin
Cilastatin
a compound that prevents the excretion of impenem from the kidney, thus trapping it
Primaxin
- a combination of Imipenem and Cilastatin that has very broad spectrum antibiotic activity
Active against > 90% of all clinically important
bacterial infectious agents
Overcomes resistance in many infectious agents Acts synergistically with aminoglycside antibiotics
Uses of Penicillins
Still one of the most useful classes of antibiotics
Mainstay of therapy for skin, respiratory, GI
infections
Generally well tolerated
Very high therapeutic window
Limitations of Penicillins
Methicillin-resistant S. aureus (MRSA) –> Other beta-lactam resistant strains have also developed
Allergic reactions –> Type II hypersensitivity reactions; Potential for anaphylactic shock and bronchospasm
Prolonged use: CNS & hematological side effects
Cephalosporins
Different class, but similar mechanism as
penicillins
3 generations of drugs within cephalosporins
1st- narrow, mainly gram +
2nd-broader,gram + & -
3rd-broad against gram -, but no effect on gram + 4th generation, but mainly used in Europe
Uses of Cephalosporins
Drug of choice for UTIs, prophylaxis post-surgery Alternative or “second line” of defense if penicillin
fails
1st Generation Cephalosporin
Cefazolin
Limitations of Cephalosporins
Most cephalosporins are well tolerated
Produce type-II hypersensitivity reaction, similar to penicillins
Often there is “Cross-reaction” with penicillins
(i.e. if patients is allergic to one, greater chance
they are allergic to the other)
Susceptible to resistance if infection is resistant to penicillin (Methicillin)
Polymixins
- Bacterial Cell Membrane Inhibitors
- Cationic compounds attracted to the bacterial cell
phospholipid membrane (more than the host’s cell membrane) - Directly “Punch holes” in the cell membrane layer
- Results in connection between inside and outside:
creates a “leak” that is fatal - Rapidly lethal to bacteria
- Not very selectively toxic (i.e. many adverse/side
effects)
Vancomycin
- Bacterial Cell Membrane Inhibitors
- Reserved for serious life-threatening infections (C-diff, staph, endocarditis)
- Ototoxic and nephrotoxic
Bacitracin
- Bacterial Cell membranes inhibitors
- Useful for STDs and a wife variety of infections, but limited by side effects when given systemically
- Used topically for burns and skin infections
How to bacterial protein synthesis inhibitors work
Most bind to bacterial ribosomes
Inhibit polypeptide synthesis or leads to misreading of mRNA
May be bacteriostatic or bactericidal
Largest subclass of bacterial protein synthesis inhibitors
Aminoglycosides
- very broad spectrum
- toxicity problems, monitors liver enzymes
Macrolides/Erythromycins
- Bacterial Protein Synthesis Inhibitors
- good for gram +’s, but side effects include hepatitis
- Bacteriostatic at low dose, bactericidal at high dose
Azithromycin
- Macrolides/Erythromycin
- ear & respiratory tract infections
- Has added benefit of being packaged as a “Z-pack” allowing short duration of Rx
Tetracyclines
- Bacterial Protein Synthesis Inhibitors
- broad spectrum, in general can’t be taken with Ca
foods - Doxycycline (Vibramycin)- broad spectrum bacteriostatic agent
Chloramphenicol
- Bacterial Protein Synthesis Inhibitors
- Broad spectrum, severe infections
Uses and Limitations of Tetracycline
Useful for hard to Rx infections like Chlamydial and Rickettsia and spirochetes
Limited by development of tetracycline- resistant bacteria strains
Ethionamide
- inhibits bacteria protein synthesis
- used as a second line of defense to treat tuberculosis or Hansen’s disease
How do Bacterial RNA/DNA Synthesis Inhibitors work?
May bind bacterial DNA directly preventing replication or bind to and inhibit enzymes
used in replication or transcription
Mainly as “back up” antibiotics (when there
is resistance or reaction) or for severe infections
Are Bacterial RNA/DNA Synthesis Inhibitors bacteriostatic or bactericidal?
Most are bacteriostatic
Characteristics of Bacterial RNA/DNA Synthesis Inhibitors
- low selective toxicity/many side effects
- very diverse family
- Mainly as “back up” antibiotics (when there is resistance or reaction) or for severe infections
RNA/DNA Synthesis Inhibitor Drug
Ciprofloxacin (Cipro): useful for a variety of infections including UTI
Class: Floroquinolene: inhibits DNA gyrase, blocking DNA coiling
Antibiotic Resistance
- Antimicrobial Resistance is accelerating: MRSA, VRE, MDRSA, MDRTB
- New drug development is not keeping pace
Solutions to antibiotic resistance
Eliminating antibiotics from livestock feed
Decreasing use of antibiotics for self-limiting
infections
Eliminating use of antibiotics for viral infections
Do the matching the antibiotic with the correct cellular mechanism thing
Virus mechanisms
Work by being incorporated into host’s cell
DNA and directing their self replication and dispersal
Can be either DNA or RNA based
Usually have a protein coat, but can also
have a lipid/glycoprotein envelope
How to anti-viral drugs work
by inhibiting the DNA polymerase enzyme
Acyclovir (Zovirax)
- Anti-viral
- Treats Herpes infection
- In infected cell converted to acyclovir triphosphate
(ATP) by viral thymidine kinase enzyme - ATP inhibits the DNA polymerase enzyme
- ATP is also incorporated into viral DNA strands, further inhibiting function
- Only effective in preventing or “limiting” infection… does not kill off dormant virally infected cells
Side effects of Acyclovir
impaired renal function
hematological
GI and CNS disturbances
Antivirals to treat AIDS
- Zidovudine
- Inhibits the reverse transcriptase enzyme used to convert viral RNA to DNA
Saquinavir Mesylate
Anti-retroviral, protease inhibitor used to Rx AIDS Prevents cleavage of viral polypeptide such
that mature viruses cannot be formed
Used exclusively in advanced HIV infection with
low CD4 count
Many side effects including CNS disturbances
N&V and GI problems common
Pancytopenia- may be lethal
Terminology for AIDS therapies
cART = combination antiretroviral therapy
HART = highly active antiretroviral therapy These are synonymous and the specific combination of antiviral drugs differs
** These are synonymous and the specific combination of antiviral drugs differs
How many Hepatitis-B medications are out there
7 approved anti-viral drugs for chronic hepatitis B infection
Standard therapy for hepatitis B
Interferon - 2b (interferon A)
Side effects of hepatitis medications
Flu-like symptoms: pyrexia, myalgia and headache
Adverse effects Rx with NSAIDS
Other AE: dizziness, fatigue, arthralgia, diarrhea,
anorexia, neutropenia and leukemia, irritability & depression
What does hepatitis b medication result in
clearance of serum HBV DNA in 25% and
63% of patients with HBeAg+ and HBeAg- hepatitis B, respectively
Remdesivir
In October 2020, FDA approved remdesivir to Rx
COVID-19 in adults and children > 12 y/o.
Clinical trials suggest remdesivir may modestly
speed recovery
Mechanism: nucleoside analog and inhibits the
RNA-dependent RNA polymerase of SARS-CoV-2
Adverse Effects of Remdesivir
pain, bleeding, bruising of the skin, soreness, or swelling near the place where the medication was injected
Fungi
- ubiquitous throughout the soil, water and air… about 100,000 species
- normally harmless, but when immune fx is impaired, they may cause pathology
Primary fungi infections in humans
Aspergillosis, Blastomycosis, Cryptococcosis and
Histoplasmosis
What is Mycosis
infections caused by fungi
minor fungal infections are typically controlled by…
immune system
Amphotericin B
Most common antifungal agent prescribed
(Amphocin)
Useful for Candida and Cryptococcus
Administered by slow IV infusion or by local or topical
administration
Binds to fungal cell membrane lipid leading to increased permeability and death
Many side effects including HA, fever, muscle & joint pain, weakness, N&V, nephrotoxicity
