Chapter 10 Flashcards
Characteristics of ideal antimicrobial drugs
- toxic to microbe but not host
- microbicidal
- does not lead to resistance
- readily delivered to site of infection
- remains potent long enough/not broken down/excreted prematurely
- remains active in tissues and body fluids
- does not disrupt host’s health by causing allergies and superinfection
- relatively soluble
use of a drug to prevent infection of a person at risk
prophylaxis
the use of drugs to control infection
antimicrobial chemotherapy
all-inclusive term for any antimicrobial drug, regardless of its origin
antimicrobials
substances produced by the natural metabolic processes of some microorganisms that can inhibit or destroy other microorganisms; generally the term is used for drugs targeting bacteria and not other types of microbes
antibiotics
drugs that are chemically modified in the lab after being isolated from natural resources
semisynthetic drugs
drugs produced entirely by chemical reactions
synthetic drugs
narrow spectrum drugs
target specific microbes
broad spectrum
target variety of microbes (gram pos and gram neg)
but can cause resistance
antibiotics are originally metabolic products of _______ and _______
bacteria and fungi
produced by microbes in order to reduce competition for nutrients and space in their habitat
antibiotics
what bacteria genera and mold genera have the greatest number of antibiotics
Streptomyces and Bacillus
Penicillium and Cephalosporium
before antimicrobial therapy begins, what three factors need to be considered?
- identity of microbe causing infection
- degree of the microbes susceptibility (sensitivity) to various drugs
- overall medical condition of the patient
drug sensitivity testing
involve exposing a pure culture of the microbe to several different drugs and observing the effects of the drug on growth
Kirby-Bauer technique
an agar diffusion test that provides useful data on antimicrobial susceptibility
- The surface of a plate of special medium is spread with test bacterium
- Small discs containing premeasured amounts of antimicrobial are dispensed onto the bacterial lawn
- After incubation the zone of inhibition surrounding the discs is measured and compared
E-Test
provides additional information on drug effectiveness
Zone of inhibition
roughly speaking, the larger the size of the zone, the greater the bacterium’s sensitivity to the drug
Tube dilution tests
the antimicrobial is diluted serially in tubes of broth
each tube is then inoculated with a small uniform sample of pure culture, incubated, and then examined for growth (turbidity)
the smallest concentration (highest dilution) of a drug that visibly INHIBITS growth is called the
minimum inhibitory concentration (MIC)
defined as a ration of the dose of the drug that is toxic to humans compared to its minimum effective (therapeutic) dose.
therapeutic index
does a smaller therapeutic index indicate more of a risk or less?
MORE RISKY
what should the physician consider before prescribing antimicrobials?
- preexisting medical conditions
- allergies
- underlying liver/kidney disease (depends where the drug is metabolized/excreted)
- infants, elderly, (gastro /organ absorption) and pregnant women (placental barrier) require special precautions
- other drugs currently taking
alcohol and cephalosporins have drug _____
interactions
what are the goals of antimicrobial drugs
disrupt cell processes, disrupt structures of bacteria, fungi, and protozoa, or to inhibit virus replication
drugs should kill or inhibit microbial cells without simultaneously damaging host tissues
selectively toxic
example of drugs with excellent selective toxicity
those that block the synthesis of the cell wall in bacteria e.g. penicillins
-they have low toxicity and few direct effects on human cells b/c human cells lack the chemical peptidoglycan
What are the five categories based on what metabolic targets antimicrobial drugs affect?
- Inhibition of cell wall synthesis
- Inhibition of nucleic acid (RNA and DNA) structure and fx
- Inhibition of the ribosome in protein synthesis
- Interference with cytoplasmic membrane structure or fx
- Inhibition of folic acid synthesis
Drugs that target the cell wall
Penicillins
-natural form used to treat gram-pos cocci, some gram-neg bacteria (meningococci, syphilis, spirochetes)
Cephalosporins
- Cefazolin
- Cefaclor
- Cephalexin
Carbapenems
- Aztreonam (narrow-spectrum)
- Doripenem
- Imipenem
Miscellaneous (Vancomycin, Bacitracin, Isoniazid(tuberculosis), Fosfomycin tromethamine)
Drugs that target PROTEIN SYNTHESIS
Aminoglycosides
-Streptomycin (broad spectrum-gram neg rods, gram pos, bubonic plague, tuberculosis)
Tetracyclines
- block the attachment of tRNA on the A acceptor site and stop further protein synthesis
- tetracycline
Glyclycyclines
- Tigecycline
- effective against bacteria that have become resistant to Tetracyclines
Macrolides
- inhibit translocation of the subunit during translation (erythromycin)
- azithromycin, clarithromycin
- relatively broad spectrum, semisynthetic, AIDS treatment
Miscellaneous
- Linezolid
- Quinupristin + dalfopristin
Drugs that target FOLIC ACID SYNTHESIS
Sulfonamides
- interfere with folate metabolism by blocking enzymes required for synthesis of tetrahydrofolate
- Sulfamethoxazole, Silver sulfadiazine (burns, eye infections), Trimethoprim
Drugs that target DNA OR RNA
Fluoroquinolones
- inhibit DNA unwinding enzymes or helicases-> stopping DNA transcription
- Levofloxacin, Ciprofloxacin
Miscellaneous
-Rifampin
Drugs that target CYTOPLASMIC OR CELL MEMBRANES
Polymyxins (colistins)
- interact with membrane phospholipids distort cell surface and cause leakage of protein and nitrogen bases
- Polymyxin B
- Daptomycin (most active against gram-pos bacteria)
examples of gram neg bacteria
salmonellosis, plague, gonorrhea
List narrow spectrum penicillins
G (best drug choice when bacteria are sensitive; low cost; low toxicity)
V
Methicillin, nafcillin (poor absorption; growing resistance)
List broad spectrum penicillins
Ampicillin - work on gram-neg bacilli
Amoxicillin - work on gram-neg infections; good absorption
VERY BROAD:
Azlocillin, Mezlocillin, Ticarcillin - effective against Pseudomonas species; low toxicity compared with aminoglycosides
TRUE OR FALSE
Biofilm inhabitants are often affected by the same antimicrobials that work against them when they are free living.
FALSE
they are often unaffected by the same ones when they are in biofilms that would usually work when they are free living
Why can some antibiotics now work as well on biofilms?
cannot easily penetrate the sticky extracellular material surrounding biofilm
*b/c of the different phenotype expressed by biofilm bacteria (different genes are expressed and therefore there are different antibiotic susceptibility profiles than if the microbes were free living)
A lipopeptide that is effective in deep tissue infections with resistant bacteria
- has shown success in biofilm infection treatment
Daptomycin (Cubicin)
what is a risk because of the similarity between fungal and human cells?
often means that drugs toxic to fungal cells are also capable of harming human tissues
Macrolide polyenes
Agents used to treat fungal infections
ex: Amphotericin B
- bind to fungal membranes, causing loss of selective permeability
- can be used to treat skin, mucous, membrane lesions caused by Candida albicans
- injectable form of drug can be used to treat histoplasmosis and Cryptococcus meningitis
Azoles
Agents used to treat fungal infections
Ex: Ketoconazole. Fluconazole, Clotrimazole, Miconazole
- interferes with sterol synthesis in fungi
- Ketoconazole -> cutaneous mycoses, vaginal and oral candidiasis, systemic mycoses
Echinocandins
Agents used to treat fungal infections
Ex: Micafungin, caspofungin
- inhibit fungal cell wall synthesis
- used against Candida strains and aspergiollosis
Allylamines
Agents used to treat fungal infections
Ex: Terbinafine, naftifine
- inhibit enzyme critical for ergosterol synthesis
- used to treat ringworm and other cutaneous mycoses
principal tx for malaria for hundreds of years; extracted from the bark of the cinchona tree
-has since been replaced by synthesized quinolones (less toxicity)
Quinine
malaria parasite
Plasmodium
why is no single drug universally effective for malaria?
because there are several species of plasmodium, and many stages in its life cycle
Artemisinin
a drug which originates from a plant called sweet wormwood; is a staple for malaria tx
Metronidazole (Flagyl)
anti-protozoal drug
;effective in treating severe intestinal infections and hepatic disease caused by Entamoeba histolytica
;orally it can treat Giardia lamblia and Trichomonas vaginalis
Other drugs besides Metronidazole that antiprotozoal activities
Quinacrine (a quinine-based drug)
Sulfonamides
Tetracyclines
what do the most effective drugs against helminths do?
immobilize, disintegrate, or inhibit the metabolism in all stages of the life cycle
broad spectrum antiparasitic drug used for several types of roundworm infestations; works in intestines to inhibit the fx of the microtubules or worms, eggs, and larvae = parasite can no longer utilize glucose = death
Albendazole
antihelminthic drug used to treat strongyloidiasis and onchocerciasis in humans
Ivermectin
antihelminthic drug used to treat various tapeworm and flukeworm infections
Praziquantel
What are the three major modes of action of agents that treat viral infection?
- Barring penetration of the virus into the host cell
- Blocking the transcription and translation of viral molecules
- Preventing the maturation of viral particles
Enfuvirtide (Fuzeon)
Inhibition of virus entry
-blocks HIV by preventing the binding of viral proteins to cell receptor, thereby preventing fusion of virus with cell
Amantadine (Symmetrel)
inhibition of virus entry
-blocks entry of influenza by interfering with fusion of virus with cell membrane
Acyclovir, Ribavirin, Remdesivir, Nevirapine, etc.
inhibition of nucleic acid synthesis
Indinavir, Saquinavir, Zanamivir, Oseltamivir
inhibition of viral assembly and release
- stop action of virus and result in inactive/noninfectious viruses
- block exit of influenza viruses from host cells
10.3
An adaptive response in which microorganisms begin to tolerate an amount of a drug that would normally be inhibitory
drug resistance
whether antibiotics are present or not, microbes become newly resistant to a drug after one of the following two events:
- Spontaneous mutation in critical chromosomal genes
or - Acquisition of entire new genes or sets of genes via horizontal transfer from another species
Potential third mechanism of acquiring drug resistance that is a phenotypic adaptation
recent studies suggest that bacteria can “go to sleep” when exposed to antibiotics, meaning they will slow or stop their metabolism so that they cannot be harmed by the antibiotic
-> and they can then rev back up after the antibiotic concentration decreases
sometimes these bacteria are called “persisters”
additional option by fungi for antibiotic resistance
a small regulatory RNA called interfering RNA (RNAi), has been found to temporarily bind to a genetic sequence which silences the gene and the target of the antibiotic resistance is not manufactured by the fungus, thus allowing it to temporarily resist the drug
-> the fungus can later express the gene when the antibiotic is no longer present
heritable change in gene expression that does not involve change in the gene itself but chemical additions to it
epimutation
refers to “above the gene”, specifically additions to the DNA that do not change the gene but can change its expression
ie. reversible mechanism that fungus undergo r/t drug resistance
Epigenetic
drug resistance that is found on chromosomes usually results from what
random mutations in bacterial populations
drug resistance occurring through horizontal transfer originates from
plasmids called resistance (R) factors that are transferred through conjugation, transformation, or transduction.
Mechanisms of drug resistance
How does new enzymes being synthesized and inactivating the drug occur?
occurs when new genes are acquired
Mechanisms of drug resistance
How does the permeability and uptake of a drug into the cell being decreased occur?
occurs via mutation
Mechanisms of drug resistance
How does the drug being immediately eliminated occur?
occurs through the acquisition of new genes
many bacteria possess multidrug-resistant pumps that actively transport drugs out of cells
Mechanisms of drug resistance
How does the number of binding sites for drugs being decreased in affinity and/or number occur?
occurs via mutation or through acquisition of new genes
Mechanisms of drug resistance
How does an affected metabolic pathway being shut down or an alternative pathway being used occur?
occurs via mutation of original enzymes
Examples of Urgent Threat (hazard level) resistant bacteria
C. diff
Carbapenem-resistant Eterobacteriaceae
Drug-resistant Neisseria gonorrhea
Examples of Serious Threats (hazard level) drug resistant bacteria
Multidrug-resistant Acinetobacter
Drug-resistant Campylobacter
Fluconazole-resistant Candida (a fungus)
Extended spectrum Beta-lactamase-producing Enterobacteriaceae
Vancomycin-resistant Enterococcus Multidrug-resistant Pseudomonas aeruginosa Drug-resistant non-typhoidal Salmonella Drug-resistant Salmonella typhi Drug-resistant Shigella Methicillin-resistant Staphylococcus aureus (MRSA) Drug-resistant Streptococcus pneumoniae Drug-resistant tuberculosis
Examples of Concerning Threats (hazard levels) of drug resistant bacteria
Vancomycin-resistant Staphylococcus aureus (VRSA)
Erythromycin-resistant Group A Streptococcus
Clindamycin-resistant Group B Streptococcus
In the US alone 23,000 deaths annually are attributed to
infection with resistant bacteria
mcr-1 gene
gene that makes bacteria resistant to colistin (polymyxin), which is considered a last-resort antibiotic treatment for bacteria that are multi-drug resistant
RNA interference
refers to small pieces of RNA that regulate the expression of genes
*being exploited in attempt to the shut down the metabolism of pathogenic microbes
Host defense peptides
peptides of 20-50 amino acids secreted as part of the mammalian innate immune system
Defensins, magainins, protegrins
Host defense peptides
Fuzeon
a drug used in HIV infections that is a peptide that inhibits fusion of the virus to human cells
some bacteria produce similar peptides called
Bacteriocins and lantibiotics
SNAPP
artificially engineered peptide polymer that has shown promise in killing multiple types of bacteria that have become resistant to other drugs
CRISPR system
provides hope that science may be capable of overcoming antibiotic resistance.
-system found in bacteria that can cause very specific cuts in genes
Teixobactin
antibiotic that inhibits cell wall synthesis using a unique mechanism, and MOST STRIKINGLY: bacteria seem unable to or at least are very slow to develop resistant to the drug
name a clear advantage of bacteriophage tx
its extreme specificity of the phages, only one species of bacterium in affected, leaving the normal inhabitants of the body alone.
nutrients used to stimulate the growth of favorable biota in the intestine
Prebiotics
Preparations of live microbes used as preventative or therapeutic measure to displace or compete with potential pathogens
;fed to animals and humans to improve intestinal biota
Probiotics
is postbiotic diarrhea considered a drug toxicity, an allergic reaction, or neither?
Neither, it is a side effect caused by disruption of the gut microbiome and not a result of the drug harming human cells
fecal transplants
involves transfer of feces from a healthy patient via colonoscopy, establishing a rich microbiota in the intestines
Which medication could be used again gram-neg, gram-pos, and chlamydias, and rickettsias?
a. tobramycin
b. penicillin
c. tetracyclines
d. cephalosporins and sulfonamides
c. tetracyclines
10.4
Three categories of major side effects of drugs
- Direct damage to tissues through toxicity
- Allergic reactions
- Disruption in the balance of normal microbial biota
It is estimated that at least _% of all persons taking an antimicrobial drug experience some type of adverse effect.
5%
Drugs most adversely affect what organs?
Liver (hepatoxic) Kidneys (nephrotoxic) Gastrointestinal tract Cardiovascular system and blood-forming tissue (hemotoxic) Nervous system (neurotoxic) Respiratory tract Skin Bones Teeth
adverse reactions
Penicillin G
Rash, hives, watery eyes
adverse reactions
Carbenicillin
Abnormal bleeding
adverse reactions
Ampicillin
diarrhea and enterocolitis
Adverse reactions
Cephalosporins
inhibition of platelet fx
decreased circulation of WBC
nephritis
Adverse reactions
Sulfonamides
formation of crystals in kidney; blockage of urine flow
hemolysis
reduction in number of red blood cells
Adverse reactions
Polymyxin (Colistin)
kidney damage
weakened muscular responses
Adverse reactions
Quinolones (norfloxacin, ciprofloxacin)
headache, dizziness, tremors, GI distress
Adverse reactions
Rifampin
damage to hepatic cells
dermatitis
Adverse reactions (antifungals)
Amphotericin B
altered kidney function
Adverse reactions (antifungals)
Flucytosine
decreased number of white blood cells
Adverse reactions (antiprotozoal drugs)
Metronidazole
nausea, vomiting
Adverse reactions (antihelminthics)
Pyrantel
intestinal irritation
headache, dizziness
Adverse reactions (antivirals)
Acyclovir
seizures, confusion
rash
Adverse reactions (antivirals)
Amantadine
nervousness, light-headedness
nausea
Adverse reactions (antivirals)
AZT
immunosuppression, anemia
the altered, usually exaggerated, immune response to an allergen. Also called hypersensitivity
allergy
this reaction occurs b/c the drug acts as an antigen (a foreign material capable of stimulating the immune system) and stimulates an allergic response
allergy
what drug accounts for the greatest number of allergic reactions
penicillins
provoked by an intact drug molecule, or by substances that develop from the body’s metabolic alteration of the drug.
ex: in the case of penicillin, it is not the penicillin molecule itself that causes the reaction, but a product called benzylpenicilloyl
allergy
beneficial or harmless resident bacteria found on and/or in the human body
biota/microbiota
an infection occurring during antimicrobial therapy that is caused by an overgrowth of drug-resistant bacteria
superinfection
oral therapy with some antimicrobials is associated with a serious and potentially fatal condition known as antibiotic-associated colitis, this is caused by an overgrowth of the endospore-forming bacterium
Clostridius difficile
drugs that prevent the formation of bacterial cell walls are
a. quinolones
b. penicillins
c. tetracyclines
d. aminoglycosides
b. penicillins
a compound synthesized by bacteria or fungi that destroys or inhibits the growth of other microbes is
a. synthetic drug
b. antibiotic
c. interferon
d. competitive inhibitor
b. antibiotic
R factors are ______ that contain a code for ________
plasmids
drug resistance
treating malarial infections is theoretically difficult b/c
a. the protozoal parasite is eukaryotic and therefore similar to human cells.
b. there are several species of Plasmodium
c. no single drug can target all life stages of Plasmodium
d. all the above are true
d. all the above are true
an antimicrobial drug with a _______ therapeutic index is better than one with a _______ therapeutic index.
high / low
