Unit 4 Study Guide: Chapter 15
List potential points in viral replication that antiviral drugs may target.
-Attachment -Penetration -Uncoating -Viral replication and assembly -Viral release
Describe the premise of antibiotic susceptibility testing and explain its general limitations in a clinical context.
2 million people suffer from antimicrobial-resistant infections yearly, 23,000 of these patients die due to an infection -agar diffusion tests are used to determine basic antimicrobial susceptibility profile for a specific bacterium; these are relatively inexpensive and can be used to determine pathogen susceptibility to a wide variety of antimicrobial drugs -clinical microbiology laboratories perform susceptibility testing on bacteria Limitations: some bacteria cannot be cultured; bacteria isolated in a lab does not reflect how bacteria performs in the body with the presence of competition and immune system; patient may be unable to wait for results
Discuss the main antihelminthic drugs, their mechanisms of action, and medical applications.
Albendazole and mebendazole: broad-spectrum; interfere with glucose uptake in worms by targeting microtubules; effective against a wide collection of roundworms (Ascaris, hookworms, pinworms, Trichinella, and certain tapeworms) Praziquantel (Bilticide) paralyzes the parasites which are then expelled in the feces; effective against flukes and tapeworms
Explain how Alexander Fleming discovered penicillin and name the genus of the fungus that makes this antibiotic.
Alexander Fleming studied Staphylococcus aureus. He noticed a plate was contaminated with mold and S. aureus were unable to grow near the mold. Fleming determined that the mold excreted a compound that could inhibit the bacteria, it was named penicillin after the Penicillium genus species of mold that contaminated the plate.
Define the terms broad spectrum and narrow spectrum as they relate to antimicrobials and state why an empiric therapy may be intentionally broad spectrum.
Broad-spectrum drugs are effective against both Gram-negative and Gram-positive bacteria. Narrow-spectrum drugs target a limited range of bacteria, these are usually preferred because they present less disruption to the normal microbiota. Empiric therapy is commonly started to protect the patient because the definitive pathogen identification can take several days. The clinician needs to have an idea of the pathogen to prescribe narrow-spectrum drugs.
Describe the challenges and opportunities that exist in developing new antimicrobial drugs.
Challenges: identifying new antimicrobials is difficult, time consuming, and costly -for every 1 antimicrobial that makes it to the clinic, 5,000-10,000 candidate compounds may be screened -development of a successful drug takes 10-15 years and has net cost near a billion dollars -additionally, profit from a new antimicrobial is less than medication for chronic conditions. -economically, there is little incentive to discover, test, and market antimicrobials -fewer large pharmaceutical companies are developing antimicrobials -discovery and development are left to smaller newer companies Opportunities: -many nations have committed money to subsidizing antimicrobial development -in 2012, the US passed legislation to extend patent rights on antimicrobial drugs to 20 years before generic drugs can be sold
Define the following and discuss how they relate to drug development: therapeutic index, selective toxicity, and drug half-life.
Drug development is difficult because new drugs must possess a number of key properties -therapeutic index: ratio of maximum tolerated or safe dose to the minimum effective or therapeutic dose -selective toxicity: shouldn't be dangerously toxic to patient/target patient cells -half-life: time it takes for half of a dose to be eliminated or deactivated by the body; half-life determines frequency of administration
Describe how the E-test works and what information it can provide.
E test: procedure involves spreading test bacterium on the surface of agar plates -strips infused with a variable gradient of drug are placed on the agar surface -plates are incubated -minimal inhibitory concentration (MIC) is determined; MIC is the lowest concentration that inhibits the microbes growth Provides clinician information on what dose is needed
Give examples of glycopeptide drugs, state how they work, and describe how they differ from beta-lactam drugs.
Examples: teicoplanin and vancomycin How they work: interfere with cell wall construction Differences from beta-lactam drugs: still target cell wall synthesis and are usually bactericidal BUT glycopeptide drugs lack a beta-lactam ring -also glycopeptides are narrow spectrum while beta-lactams activity spectrum ranges
Discuss hepatotoxicity and nephrotoxicity as they relate to antimicrobials and provide examples of drug classes associated with each effect.
Hepatotoxic: antimicrobial drugs can induce liver damage (leading agents of drug-induced liver injury/DILI); liver is a fairly resilient organ that tends to recuperate after the drug regimen is stopped; DILI is the most commonly cited reason for discontinuing drug development or removing a drug from the market -drugs associated with hepatotoxicity: amoxicillin-clavulanate (which is known as Augmentin, Clavulin) is most prevalent cause; drugs like Tylenol, statins that lower cholesterol, and other dietary and herbal supplements also cause liver damage Nephrotoxic (or kidney-toxic): antimicrobials are a leading cause of drug-associated nephropathy; aminoglycosides and extended use of nonsteroidal anti-inflammatory drugs -examples of nephrotoxic drugs: intravenously administered aminoglycosides; polyenes (especially Nystatin and Amphotericin B), many can't be IV administered for this reason; long list of agents with aminoglycosides prevalent on the list (drugs that tend to end in "mycin" or "micin," such as gentamicin, vancomycin, streptomycin, etc.); many nonsteroidal anti-inflammatory drugs like aspirin, contrast dyes used in MRIs, several blood pressure medications, and even Chinese herbals containing aristocholic acid may be nephrotoxic
Describe the four main groups of beta-lactam drugs and state how they work.
In general, beta-lactam antimicrobial interfere with cell wall synthesis by blocked transpeptidation—the formation of peptide linkages between the sugar chains in peptiodoglycan. This weakens the cell wall and leads to bacterial cell lysis. Four main groups: penicillins, cephalosporins, carbapenems, monobactems
Describe the difficulties of developing drugs against viruses and eukaryotic pathogens.
It is difficult to develop drugs that specifically target viruses and eukaryotic pathogens without inflicting collateral damage on our own cells Effective antiprotozoan and antihelminthic drugs are difficult to develop because these eukaryotes have complex life cycles; drugs that target one stage may be ineffective against other stages.
Summarize what healthcare workers and patients can do to reduce the emergence of antimicrobial resistance.
It is essential healthcare workers follow proper hand hygiene practices and enforce contact precautions Healthcare workers can also: -Limit unnecessary antimicrobial prescriptions -Use narrow-spectrum drugs when possible -Educate patients about the importance of following their drug-dosing regimen Patients should: -Follow all drug-dosing instructions -Execute follow-up as recommended -Properly store medications -Not demand antibiotics from their physicians
Explain how the Kirby-Bauer test works and what information it provides.
Kirby-Bauer test (disk diffusion test) is an agar diffusion test Procedure: -involves spreading test bacterium (previously cultured and isolated) on the surface of Muller Hinton agar -disks infused with a set amount of a specific drug are placed on the agar surface -plates are inoculated -zone of inhibition appears if the bacteria are prevented from growing -diameter is measured -diameter of the zones of inhibition must be measured and compared to a standardized table to determine the bacterium's response to the tested drugs Provides information on whether a bacterium is resistant, sensitive, or intermediate to a drug
State how macrolides, lincosamides, phenicols, tetracyclines, and aminoglycosides each work and describe the potential adverse effects of each.
Macrolides, lincosamides, phenicols, tetracyclines, and aminoglycosides are drug families that target protein synthesis. Macrolides: Target 50S subunit of prokaryotic ribosomes to block protein synthesis; broad spectrum Lincosamides: Bind to 50S subunit of prokaryotic ribosomes to block protein synthesis; broad-spectrum; broad-spectrum; side effect of clindamycin (a lincosamide) is possible pseudomembranous colitis caused by Clostridium difficile Phenicols: Bind to 50S subunit; broad-spectrum; narrow therapeutic index; unfavorable side effects include bone marrow toxicity and aplastic anemia; reserved for treating severe infections caused by multidrug-resistant bacteria Tetracyclines: Bind to 30S subunit; broad-spectrum; bacteriostatic; side effects include increased risk of C. difficile infection, photosensitivity, and not for children under 8 due to detrimental effects on bones and teeth Aminoglycosides: Bind to 30S ribosomal subunit to block protein synthesis; narrow spectrum; side effects of intravenously administered aminoglycosides amikacin, tobramycin, streptomycin, and gentamicin include irreversible hearing loss, nephrotoxicity
Outline how sulfa drugs work and explain why they don't target human cells.
Sulfa drugs (sulfonamids) are antifolates (target folic acid production) -bacteriostatic -broad spectrum of action Sulfonamides act as competitive inhibitors of folic acid production -do not affect mammalian cells because they do not make their own folic acid
Discuss how the use of antimicrobials selects for resistant microbes and summarize how resistance may spread by agricultural and clinical misuse.
Antibiotic resistance is fueled by natural selection. When antibiotics are used, selective pressure is applied and there is the potential for resistance to develop. Noncompliance with prescribed dosing parameters along antimicrobial misuse are key factors that accelerated the evolution of drug-resistant pathogens Agricultural practices that promote resistance: -antimicrobials in animal feed select for resistant bacteria in animal GI tract; resistant microbes spread in manure -animals fed antimicrobials are slaughtered; meat may become contaminated with resistant microbes -manure-contaminated water and manure-based fertilizers introduce resistant bacteria into food chain Clinical practices that promote resistance: -unregulated antibiotic use in developing countries -noncompliance with prescription dosing and inappropriate prescriptions -healthcare settings are the perfect place for resistant microbes to thrive (many pathogens, many transmission opportunities, many drugs) - Healthcare workers and staff often pick up resistant strains on their hands, scrubs, and personal electronic devices = allow for transfer to themselves, others in their community, or to patients On patient misuse and noncompliance: -many patients miss doses, don't finish drug regimen, and/or self-medicate with leftover prescriptions -low-dose exposures serve as a selective pressure -some patients can't afford a full regiment On inappropriate prescriptions: -inappropriately prescribing antimicrobial drugs for self-limiting infections, noninfectious conditions, and viral infections
Define the terms antibiotic and antimicrobial drug.
Antibiotic: naturally occurring antimicrobial compounds; substances produced by the natural metabolic processes of some microorganisms (or created by scientists) that can inhibit or destroy microorganisms; generally, the term is used for drugs targeting bacteria and not other types of microbes Antimicrobials: therapeutic drugs that kill microbes or inhibit their growth; all-inclusive term for any antimicrobial drug, regardless of what type of organism it targets; categorized by pathogen targeted (antibacterial, antiviral, antifungal, and antiparasitic)
Explain what is meant by antimicrobial resistance and compare intrinsic to acquired resistance.
Antimicrobial resistance occurs when a microbe is not affected by a drug therapy that is intended to inhibit or eliminate the pathogen; resistant microbes are called superbugs. Intrinsic (natural) resistance: natural resistance to antimicrobial drugs; makes certain pathogens harder to eliminate -Examples: Mycoplasma pneumoniae lacks a cell wall and is intrinsically resistant to drugs that target cell wall synthesis; Clostridium difficile forms endospores that resist most antibiotics due to their dormant nature and tough spore coat; Mycobacterium tuberculosis has a waxy cell wall enriched with mycolic acid that prevents diffuse of many drugs; Gram-negative bacteria are naturally resistant to drugs that are unable to cross their lipid outermembrane; drugs do not often permeate deep into biofilms Acquired resistance: resistance comes from genetic mutations and/or acquisition of resistance genes through horizontal gene transfer (conjugation, transformation, and transduction). -examples: target alterations, drug inactivation (breakdown or chemical modification), and reducing drug concentration within a cell (through efflux pumps and/or reduced permeability) are main acquired resistance mechanisms.
Describe antiprotozoal drugs—including examples, mechanisms of action, and therapeutic applications.
Antiprotozoal drugs are split into antimalarial drugs and nonmalarial antiprotozoan drugs. Antimalarial drugs target Plasmodium species (e.g., P. falciparum or P. vivax) that cause malaria. The six main classes are aminoquinolines, arylaminoalcohols, artemisinins, respiratory chain inhibitors, anti-folates, and cross-over antibacterial drugs (e.g., doxycycline and clindamycin). Examples: Chloroquine (an aminoquinoline), quinine (an arylaminoalcohol), artesunate (artemisinin) -artemisinin-based combination therapies (ACT) combine an artemisinin class drug with one or more nonartemisinin drugs Nonmalarial antiprotozoan drugs: -metronidazole (Flagyl): member of the nitroimidazoles; targets nucleic acids; effective against toxoplasma gondii, trichmonas vaginalis, giardia lamblia, and entamoeba hystolytica -trimethoprim-sulfamethoxazole (TMP/SMX): antifolate drug combination that blocks folate production in certain bacteria and protozoans; effective against toxoplasma gondii, giardia, cryptosporidium, and entamoeba -nitrazoxanide: blocks anaerobic energy metabolism in protozoa; effective against giardia, cryptosporidium, and certain parasitic worms
Compare bacteriostatic to bactericidal drugs, discuss scenarios where each may be useful, and explain why these terms are less concrete in clinical scenarios.
Bacteriostatic: prevent bacteria from growing, tend to target bacterial protein synthesis and metabolic pathways Bactericidal: kill bacteria, tend to target cell walls or cell membranes and nucleic acids -kills normal microbiota and can lead to a spike in bacterial toxin release that can be deadly (LPS) These terms are less concrete in clinical scenarios because a drug's bactericidal or bacteriostatic properties can change based on pathogen type, dose, length of drug regimen, pathogen load, and route of administration. -an antimicrobial drug that is bactericidal for one pathogen may be bacteriostatic for anther Scenarios: Bacteriostatic drugs, such as erythromycin, are typically effective for patients who havea healthy immune system that can destroy the bacteria during the drug course; kill normal microbiota, drawback large if broad-spectrum -can also lead to spike in bacterial toxin release that can be deadly, for example, lipopolysaccharide (LPS or endotoxin) made by a Gram-negative bacteria is mainly released as cells die. Administering a bactericidal drug in a patient with a Gram-negative infection could trigger a dangerous surge in LPS levels in the patient -better for bacterial endocarditis and bacterial meningitis (if bacterial meningitis is caused by Gram-negative bacteria the bactericidal antibiotic is usually administered along with a steroid anti-inflammatory drug because as the Gram-negative bacteria die, the release of LPS can cause damaging inflammation)
Provide examples of antifungal agents, describe the fungal infections they may treat, and discuss how they target fungi.
Most antifungals target fungal cell walls, plasma membranes, and nucleic acid synthesis. Azoles, allyamines, and polyenes are classes of antifungals that target fungal cell membranes (which contain a sterol called ergosterol that is not found in human cells). DESCRIPTION: -Azoles like fluconazole and ketoconazole and allyamines like terbinafine and naftifine, inhibit enzymes that build ergosterol. Azoles and allyamines are both used to treat athlete's foot, ringworm, and yeast infections. -Polyenes directly interact with ergosterols, causing targeted plasma membranes to become leaky and leads to cell lysis. They have a narrow therapeutic index. Nystatin is too toxic to administer systemically, it is used in topical preparations, and is used to treat cutaneous candidiasis caused by Candida albicans. Amphotericin B is reserved for treating life-threatening systemic fungal infections. Echinocandin drugs target the enzyme that makes beta-glucan, inhibiting fungal cell wall synthesis; these are mainly used against systemic fungal infections in immune-compromised patients (for example, caspofungin acetate). Flucytosine targets fungal DNA replication and blocks transcription when converted to a nucleic acid analog that blocks DNA and RNA (nucleic acid) synthesis. It may be used in combination with amphotericin B for severe fungal infections, like Cryptococcus meningitis and systemic Candidiasis infections.
Describe the terms natural, semisynthetic, and synthetic antimicrobials and state the potential value of drug modifications.
Natural antimicrobials are antibiotics Synthetic antimicrobials are manufactured by chemical processes Semisynthetic antimicrobials are a chemical modification of naturally occurring antibiotics Value of drug modifications: drugs in later generations have expanded capabilities over their predecessors; extended spectrum, increased stability, ability to circumvent resistance mechanisms
Give examples of polypeptide drugs, describe how they work, and state when they may be used.
Polypeptide drugs are narrow-spectrum, narrow-therapeutic index, usually bactericidal drugs that target cell membranes. -work by interacting with lipopolysaccharide: they destabilize outer membrane of Gram-negative cell walls and further destabilize the plasma membrane to cause cytoplasmic leakage and cell lysis -the polypeptide drugs polymyxin B and colistin (polymyxin E) are mainly used topically, but they are administered intravenously in life-threatening, multidrug-resistant infections by Pseudomonas aeruginosa, Acinetobacter baummanii, and Klebsiella pneumoniae (mainly mycobacteria)
Discuss how broth dilution tests work and state what information they provide.
Procedure: -each antibiotic is diluted in a series -added to a set amount of growth medium -standardized amount of bacteria is added -incubation -level of growth is measured by assessing turbidity or colorimetric indicators -MIC is the lowest drug concentration at which turbidity or color intensity levels off To get minimum bactericidal concentration (MBC) -collect the dilution where MIC was observed along with at least 2 adjacent samples -plate on media that does not contain antibiotics -only live cells will be able to grow -plate with 99.9% colony reduction compared to MIC plate is deemed the MBC Broth dilution tests provide a differentiation between bactericidal versus bacteriostatic actions
Describe how quinolones and rifamycins work and state when each may be recommended.
Quinolones and rifamycins target nucleic acids. Fluoroquinolones (quinolones with a fluorine atom) are broad-spectrum, orally-administered synthetic antimicrobials that target DNA replication enzymes (e.g, DNA gyrase and topoisomerases). They have a long half life. Inability to relieve torsion stress results in halted DNA replication. -recommended (and reserved) for treating infections that show antimicrobial resistance. Examples include ciprofloxacin, a quinolone effective against Mycobacterium and Pseudomonas species, and Levofloxacin, used to treat "walking pneumonia" caused by Mycoplasma pneumoniae. Rifamycins were originally isolated from bacteria and mainly are produced as synthetic and semisynthetic compounds. One example called rifampin (rifampicin) binds to RNA polymerase and inhibits transcription; it is broad spectrum and effective against mycobacterial species, but it cannot be taken with certain drugs (inhibits digoxin, oral contraceptives, certain blood pressure medications, and anticoagulants).
Discuss how route of administration, drug interactions, and contraindications play into drug development.
Route of administration -Oral: preferred because it is easiest but [the drug] must be stable in the acidic environment of the stomach and sufficiently absorbed in the intestines -parenteral (injection or infusion): may be intravenously, intramuscularly, or subcutaneously injected; downsides include that needles and/or intravenous lines must be used and patient may have "needle phobia" and injection discomfort (also breaking skin barrier) Nearly every drug has some sort of contraindication or warning listed -Rifampin for TB inactivates oral contraceptives -Digoxin shows higher toxicity when a macrolide is also prescribed -tetracyclines are not recommended during pregnancy or for nursing mothers
Name and describe the three categories of acquired antimicrobial resistance tools that microbes may use to thwart drug action.
Three categories of acquired antimicrobial resistance tools: 1. Altering the drug's target -in many cases, a mutation in the targeted protein prevents drug binding. -examples: rifampin resistance has evolved as bacteria alter their RNA polymerases; RNA polymerase works perfectly well, but the drug cannot bind 2. Inactivating the drug -bacteria may produce enzymes that inactivate the drug by breaking down the drug (example: beta-lactamases, carbapenemases) or adding a chemical group (e.g., phosphate; example: chloramphenicol can be inactivated by adding an acetyl group). -plasmids commonly carry genes that encode drug-inactivation tools; allows for easy spreading by horizontal gene transfer 3. Reducing drug concentrations inside the cell Lowering concentration of a drug in a cell's cytoplasm to levels below MIC is an important resistance mechanism; can be accomplished two ways: -reduced permeability (preventing a drug's entry)—many drugs require transporters or porin channels to enter targeted cells (example: fluoroquinolones and carbapenems require porins); some become resistant by altering porins in a way that limit drug entry -efflux pumps (pumping drugs out of their cytoplasm)—tend to remove diverse classes of drugs; contribute to multidrug resistance; mutations that cause pumps to be overexpressed and/or expand their drug-binding potential lead to antimicrobial resistance; some efflux pump genes are found on plasmids and are easily shared through horizontal gene transfer. Example: Pseudomonas aeruginosa has extensive used of efflux pumps, protecting it from antibiotics and disinfectants, making it challenging to eliminate from healthcare settings; Candida species have azole drug resistance to increased efflux pump activity
List the top three urgent drug-resistant bacterial threats to health in the United States.
Urgent threats (2017): -Clostridium difficile -Carbapenem-resistant Enterobacteriaceae (CRE) -Drug-resistant Neisseria gonorrhoeae
