Antimicrobials Outline PDF

Antimicrobials: pt.1 **Describe the basic MOA of penicillin and cephalosporins** - Penicillin interferes with the final stage of cell wall synthesis known as transpeptidation - Causes a weak cell wall and cell death - Bactericidal; susceptible to gram + - Gram -- has an outer membra...

Antimicrobials: pt.1 **Describe the basic MOA of penicillin and cephalosporins** - Penicillin interferes with the final stage of cell wall synthesis known as transpeptidation - Causes a weak cell wall and cell death - Bactericidal; susceptible to gram + - Gram -- has an outer membrane that acts as a barrier to PCN **Cephalosporins:** - Same as PCN; tend to be more resistant than PCN to certain b-lactams **Gram -- and gram + bacteria; what penicillin's/cephalosporins can penetrate the outer membrane of gram -?** - Gram -- have an outer lipopolysaccharide membrane surrounding their cell wall that acts as a barrier to PCN's - Gram + have a cell wall that's easily transversed by PCN - PCN G, ampicillin, and amoxicillin - 2^nd^ generation cephalosporins cover gram - ; 3^rd^ gen covers + and -- **Four main classes of penicillin's:** 1. **Narrow-spectrum penicillin's that are penicillinase sensitive** - Penicillin G and V - Covers streptococcus species, syphilis, gas gangrene, tetanus 2. **Narrow-spectrum penicillins that are penicillinase-resistant** - Methicillin, Nafcillin, oxacillin, dicloxacillin - Treat infections caused by penicillinase-producing staphylococci (MRSA); no activity against gram -- infections 3. **Broad-spectrum penicillin's** - Ampicillin and amoxicillin - Gram -- coverage of haemophilus influenza, E. coli, and Proteus mirabilis; Ampicillin is the DOC for Listeria; Amp is also used by dentist for prevention of bacterial endocarditis 4. Extended-spectrum **penicillin's** - Piperacillin - Active against Pseudomonas Aeruginosa; when combined with Zosyn, it extends the antimicrobial spectrum to cover penicillinase-producing organisms **Identify a prototype or representative example for each of the four generations of cephalosporins and differentiate the groups in terms of MOA, Spectrum of action, susceptibility to inactivation by b-lactamase, and access to CSF.** **1^st^ Generation: Cephalexin (Keflex)** - Moa: MOA, spectrum of action, susceptibility to inactivation by beta-lactamases, and access to cerebrospinal fluid. - Spectrum of action: NARROW GRAM + only - Susceptibility to b-lactamases: susceptible to inactivation by some bacterial beta-lactamases. - Cerebrospinal fluid: cannot readily cross the BBB and has low concentration in CSF **2^nd^ generation: Cefuroxime Sodium** - MOA: It inhibits bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins (PBPs) located on the inner surface of the bacterial cell wall. - Spectrum of action: Gram + and -- - Susceptibility to b-lactamases: more resistant to inactivation by beta-lactamases compared to first-generation cephalosporins. However, it can still be hydrolyzed by some extended-spectrum beta-lactamases (ESBLs) produced by certain bacteria. - CSF: achieves good concentrations in the CSF, especially when the meninges are inflamed. It is used to treat bacterial meningitis caused by susceptible organisms, such as *Streptococcus pneumoniae* and *Haemophilus influenzae*. **3^rd^ Generation: Ceftriaxone (Rocephin)** - MOA: It works by **i**nhibiting bacterial cell wall synthesis. Like other beta-lactams, it binds to and inactivates penicillin-binding proteins (PBPs) located on the inner surface of the bacterial cell wall. - Spectrum: Gram + and -- - Susceptibility: Ceftriaxone is relatively resistant to inactivation by many beta-lactamases, including some produced by gram-negative bacteria. This contributes to its broader spectrum compared to earlier cephalosporins. - CSF: Ceftriaxone penetrates the blood-brain barrier well, especially when the meninges are inflamed. It achieves therapeutic concentrations in the CSF and is a preferred agent for treating bacterial meningitis **4^th^ Generation: Cefepime** - MOA: cell wall synthesis - Spectrum: gram + and -- - Susceptibility: Cefepime is highly resistant to inactivation by most beta-lactamases - CSF: penetrates the blood-brain barrier well and achieves good concentrations in the CSF**.** **Advanced generation: Ceftaroline** - Gram + and -- (COVERS MRSA) - resistant to inactivation by many beta-lactamases - penetrates the CSF**,** but its use for meningitis is not well-established compared to ceftriaxone or cefepime. **Explain the beta-lactam ring and why penicillins/cephalosporins are part of the antibiotics called beta-lactam antibiotics, and how that relates to vulnerability of these antibiotic classes to inactivation by certain bacteria:** - The beta-lactam ring is essential for the antibacterial activity of these antibiotics. These drugs work by interfering with bacterial cell wall synthesis. This inhibition happens because the beta-lactam ring mimics the structure of a natural substrate that bacteria use in cell wall synthesis. Bacterial enzymes called penicillin-binding proteins (PBPs) normally use this substrate to build the cell wall. However, when a beta-lactam antibiotic is present, the PBPs mistakenly bind to the beta-lactam ring instead, blocking the cell wall synthesis process. Why Penicillins and Cephalosporins are Beta-Lactam Antibiotics - Shared Structure: Penicillins and cephalosporins both possess the beta-lactam ring as their core functional group. Vulnerability to Inactivation by Bacteria - Beta-Lactamases: Bacteria have evolved a defense mechanism against beta-lactam antibiotics. They produce enzymes called beta-lactamases that can break open the beta-lactam ring. This renders the antibiotic inactive, as it can no longer bind effectively to PBPs. Think of it like snipping a key in half -- it no longer fits the lock. - Resistance: The production of beta-lactamases is a major cause of bacterial resistance to penicillins and cephalosporins. Bacteria that produce high levels of these enzymes are able to survive in the presence of the antibiotic. - Different Beta-Lactamases: There are many different types of beta-lactamases, some are specific to certain types of beta-lactam antibiotics while others have a broader range. For example, some can inactivate only penicillins (penicillinases) while others can inactivate both penicillins and cephalosporins. Combating Resistance - Structural Modifications: Scientists have developed modified beta-lactam antibiotics that are less susceptible to inactivation by some beta-lactamases. - Beta-Lactamase Inhibitors: Another strategy is to combine beta-lactam antibiotics with beta-lactamase inhibitors, such as clavulanic acid, sulbactam, or tazobactam. These inhibitors bind to beta-lactamases, preventing them from breaking down the antibiotic. For example, amoxicillin is often combined with clavulanic acid (Augmentin) to protect the amoxicillin from inactivation by some bacterial enzymes. **Identify drug-induced allergic reactions caused by penicillin's and cephalosporins. Immediate, accelerated, and delayed hypersensitivity reactions in terms of time of onset and main s/s.** - Penicillins can cause urticaria, anaphylactic shock, diarrhea, nephritis, neurotoxicity, hematologic effect - Red man syndrome -- rapid infusion of vancomycin - The HX of Steven-Johnson syndrome or Toxic epidermal necrosis from antibiotics should **NEVER** be rechallenged - **Immediate**: minutes to an hour, hives, anaphylaxis - **Accelerated:** 1-72 hours, less severe, hives, fever, joint pain - **Delayed hypersensitivity:** days to weeks after drug exposure; skin rash, blisters, Steven Johnson or toxic epidermal necrosis **What is the importance of clavulanic acid as penicillinase inhibitors that are combined with certain broad or extended spectrum penicillins. What is their action?** - Clavulanic acid is a crucial component in the fight against antibiotic resistance, particularly against bacteria that produce beta-lactamase enzymes. - It is a substrate for beta-lactamase enzymes, meaning it competes with beta-lactam antibiotics for the enzyme\'s attention. However, when the beta-lactamase binds to clavulanic acid, it becomes irreversibly inactivated. Essentially, clavulanic acid \"distracts\" and \"occupies\" the beta-lactamase, preventing it from inactivating the actual antibiotic. By inactivating beta-lactamase, clavulanic acid restores the activity of beta-lactam antibiotics against bacteria that would otherwise be resistant due to beta-lactamase production. - Augmentin is a combination of clavulanic acid and amoxicillin **Describe the general rationale and indications for using both intravenous penicillin and an aminoglycoside.** - The combination of intravenous penicillin and an aminoglycoside is a powerful antibiotic regimen reserved for serious infections where synergy, broad coverage, or overcoming resistance is crucial. Used when infection is unknown - Watch for toxicity and resistance when using this combo - For severe infections such as endocarditis and blood pathogens, neutropenic fever, hospital acquired infections **Discuss resistance develop to penicillins and cephalosporins** - Resistance to penicillins and cephalosporins arises through multiple mechanisms, including beta-lactamase production, PBP modification, reduced permeability, increased efflux, and biofilm formation. Combating resistance requires a multifaceted approach, including antibiotic stewardship, infection prevention, development of new antibiotics, and surveillance. **Identify common drug interactions associated with penicillins and cephalosporins.** - Those who have had anaphylaxis, Stevens-Johnson syndrome or toxic epidermal necrolysis to PCN should not be prescribed cephalosporins - Some cephalosporins can enhance the effect of warfarin and increase the risk of bleeding **What is the spectrum of activity of carbapenems? Who should receive these drugs? Pregnancy category.** - Imipenem (primaxin) prototype given IV - Can be used against gram -- and gram + ; penetrate well into tissues and CSF - Dose reduce in CKD; High levels of this drug can cause seizures, use carefully in PCN allergy - effective against bacteria that are resistant to penicillins, cephalosporins, and other antibiotic classes. - Can treat *Pseudomonas aeruginosa* that are resistant to other antibiotics and hospital acquired infections - Pregnancy category C **What is the difference in the structure of the monobactam- aztreonam (azactam)? What is the spectrum of activity and use of drug?** - **Monobactam**. This means that its beta-lactam ring is not fused to another ring system, unlike other beta-lactam antibiotics like penicillins and cephalosporins which have bicyclic structures. - Gram -- aerobic bacteria! Narrow spectrum - Enterobacteriaceae and pseudomonas - Can be used in those with allergies to PCN, cephalosporins or carbapenems **Glycopeptide/Lipoglycopeptide -- Vancomycin objectives:** **Under what conditions should vancomycin be the drug of choice?** - MRSA infections, covers gram + pathogens. C.diff, MRSE, endocarditis, skin and soft tissue, nosocomial pneumonia **How is it used to treat pseudomembranous colitis and c.diff?** - Must give **orally**; primarily stays in the intestinal tract d/t poor absorption to the blood. **What are the most serious side effects of vanc?** - Nephrotoxicity - Red man syndrome - Ototoxicity **How do drug/drug interactions cause serious side effects?** - Combinging vanc with other nephrotoxic drugs such as aminoglycosides, NSAIDS, diuretics, can cause kidney injury - Vanc can enhance the effects of warfarin and cause bleeding - Ototoxic drugs Why is it important to draw a peak and trough during vancomyacin? Which one is more important? When do you draw them? - Narrow therapeutic window and can cause toxicity - Trough is the most important and reflects the lowest concentration of vancomycin in the blood, just before the next dose is given. A sufficient trough level is necessary to ensure the drug is effective against the bacteria throughout the entire dosing interval. IF not high enough this could cause resistance or bacteria survival - The peak level is the highest concentration of vancomycin in the blood, shortly after the dose is administered. - Trough 30 min before the next dose, Peak 1-2 hours after complete **How does telavancin differ from vancomycin?** - **Telavancin:** Has a dual mechanism of action: Similar to vancomycin, it inhibits bacterial cell wall synthesis by binding to the same target. It disrupts bacterial cell membrane potential, leading to depolarization and cell death. This second mechanism may contribute to its activity against some vancomycin-intermediate strains of *Staphylococcus aureus* (VISA). **Protein synthesis inhibitors Objectives:** **MOA and main indications for aminoglycosides:** - Aminoglycosides are a class of antibiotics that work by **inhibiting bacterial protein synthesis**. - Used for serious gram -- infections, normally part of a combination regimen to treat gram -- pathogens that are resistant. - Pseudomonas aeruginosa, klebsiella pneumonia Enterobacter species **Recognize that nephrotoxicity and ototoxicity are the two main toxicities of aminoglycosides!** **Recognize signs of impending toxicity and describe precautions that need to be taken to prevent.** - Decreased UO, change in electrolytes, fluid retention, weight gain, increased creatinine - Tinnitus, hearing loss, dizziness - Get a baseline kidney function, and only use these meds if needed - Monitor dose and keep pt hydrated - Avoid other nephrotoxic and ototoxic drugs. **Identify other drugs that increase the risk for aminoglycoside-induced nephrotoxicity and ototoxicity and describe the factors that should be considered when deciding whether to use them when aminoglycosides are used.** - Look at the severity of the infection, can you use an alternative, pre-existing kidney or hearing problems, baseline assessment, and drug monitoring - Other nephrotoxic drugs: Vanc, loop diuretics, NSAIDS, ACE, cyclosporin's - Ototoxic drugs: VANC, loop diuretics, erythromycin, aspirin **Tetracycline Objectives:** **Identify the MOA for tetracyclines: (doxycycline/ minocycline)** - MOA: tetracyclines work by **inhibiting protein synthesis** in bacteria **Identify the uses for the various drugs in this class:** - Commonly used to treat chlamydia, treats gram + and -, atypical species, mycobacteria, spirochetes, acne, and rosacea **Identify the differences in pharmacokinetics among the major tetracyclines, lipid solubility, and route of elimination.** - **Tetracycline**- absorbed well orally, binds to teeth/bones and tumors high in ca+, eliminated in urine - **Minocycline**- PO and IV, get to therapeutic levels is CSF (high lipid solubility), high levels is saliva and tears, treat meningococcal carrier states, metabolized in liver - **Doxycycline** -- PO and IV, get to therapeutic levels is CSF (high lipid solubility), preferred in pt with renal disease (eliminated in feces) - ALL tetracyclines cross the placental barrier and concentrate in fetal bone and teeth **Describe the mechanism and potential outcomes of interactions between oral tetracyclines and such minerals as calcium, aluminum, mg, iron, and zinc. Identify common sources of these substances.** - Mg (antacids, laxitives), calcium (dairy products, antacids) , aluminum antacids or iron (multivitamins, ceareals), zinc (red meat, poultry, sea food) decrease absorption of tetracyclines. - Separate these at least 2-4 hours before can minimize interactions **Common adverse effects of tetracyclines:** - GI discomfort, esophagitis, always give on empty stomach - [Children in deposits in bones and teeth leading to discoloration, hypoplasia of teeth and temporary growth restriction ] - [Liver toxicity can occur with high doses, especially in pregnant women or with pre-existing liver/kidney disease ] - Eliminated through kindeys so with kidney disease this could cause increase side effects/ failure - Sun sensitivity -- severe sunburn - Dizziness vertigo and tinnitus - Benign intracranial HTN (headache and blurred vision) - NOT to be used in pregnancy (crosses placenta and effects infants' teeth), breastfeeding, or children younger than 8 **Macrolide Objective:** **What is the MOA of Macrolides? (erythromycin, clarithromycin, azithromycin)** - Macrolides are a class of antibiotics that work by **inhibiting bacterial protein synthesis**. **Is the drug cidal or static?** - Bacteriostatic- primarily *inhibit* bacterial growth rather than directly *killing* the bacteria. - They can be bacteriocidal at high doses and against certain bacteria **What is the spectrum of activity? Uses?** - Broad spectrum antibiotics - Gram +, MSSA, atypical bacteria - Used for respiratory tract infections (community pneumonia, pertussis, pharyngitis) - H.flu, chlamydia, h.pylori, Moraxella **What is the most common side effect? Drug specific** - **Erythromycin:** - GI upset - High doses can cause smooth muscle contraction that causes gastric contents to move into the duodenum - Transient deafness - Cholestatic jaundice (other meds as well) - Irreversible hearing loss (azithromycin) - Prolonged Qt intervals - Liver toxicity can occur - Can interfere with liver metabolism and result in toxic levels of other drugs (warfarin) **How does erythromycin and clarithromycin affect other drugs in relation to the p450 system?** - Interferes with the liver metabolism of many other drugs; **inhibitors of CYP450** - Alfuzosin (uroxatrol) - Atorvastatin (Lipitor) - Carbamazepine (Tegretol) - Sildenafil (Viagra) - Warfarin - Change in gut flora can lead to digoxin toxicity **What is the role of fidaxomicin (Dificid)?** - MOA: disrupts bacterial transcription, terminating protein synthesis and causes cell death. - Very narrow spectrum coverage- Gram + aerobes and anaerobes (staph, strep, c.diff) - Has a unique target site different than macrolide (no cross-resistance) - FIRST line agent in severe c-diff; VERY expensive **[Lincosamides-clindamycin objectives:]** **What is the spectrum of activity of clindamycin?** - Treats gram + bugs, MRSA, Streptococcus, and Gram + and - anaerobes - Resistance is increasing with using this drug for gram -- anaerobes **What is it most commonly used for?** - MRSA, streptococcus and + and -- anaerobes. - Skin and soft tissues **What is the most serious side effect? How is it treated?** - Accumulation in those with severe liver/renal disease - Diarrhea (which may be an overgrowth of C. diff) treat this with Vanc or metronidazole! **Identify potential drug interactions.** - Clindamycin is metabolized by CYP3A4, any drugs that inhibit or induce this - Clindamycin may enhance warfarin and cause bleeding **[Oxazolidinones- Linezolid Objectives:]** **Why is this class of drugs important in the treatment of infections? (linezolid (Zyvox))** - Treats Gram + pathogens, including resistant pathogens: - MRSA (not first line) - VRE - Penicillin resistant streptococci **What is the spectrum of activity of Linezolid?** - **narrow spectrum of activity**, focused on **gram-positive bacteria**. - **Streptococci** - **Staphylococci** - **Enterococci** - **Listeriano** **What lab work should be done on a weekly basis?** - A weekly CBC should be done to assess thrombocytopenia and potential bone marrow suppression **What drug interactions should you be alert for in oxazolidinones?** - Can cause a serotonin syndrome with large quantities of tyramine-containing foods, SSRIs, or MAOIs (reversed when the antimicrobial is stopped) - Irreversible peripheral neuropathy (when used for more than 28 days) - Optic neuritis (greater than 28 days) **[Streptogamins- Quinupristin/Dalfopristin Objectives: (Synercid)]** **What is Synercid spectrum of activity?** - Gram + cocci, MRSA, VRE - D/t so many ADEs this agent is reserved for the treatment of severe infections caused by vancomycin-resistant enterococcus faecium when there are not other options. **Is it an alternative drug for patients allergic to which antibiotic?** - It is an alternative for patients who are allergic to **penicillin** and **cephalosporins**. **What is the major side effect? How does that impact the drug interactions?** - Venous irritation - Hyperbilirubinemia - Arthralgias and myalgias at high doses - Inhibits CYP 450 **Prregnancy category? Use in children?** - Category B, only use if clearly needed - Limited data on the use of children **[Folic Acid Inhibitors Objectives:]** **State the antimicrobial mechanism of action of sulfonamides and of trimethoprim and explain why their effects on susceptible bacteria do not affect human cells at the same time.** - **MOA suflonamides:** Sulfonamides act by inhibiting an enzyme called dihydropteroate synthetase. This enzyme is crucial for the bacterial synthesis of tetrahydrofolic acid (THF), also known as folate or folic acid. By interfering with THF production, sulfonamides disrupt bacterial DNA replication and cell growth. - **MOA Trimethoprim:** Trimethoprim inhibits another enzyme in the folate synthesis pathway called dihydrofolate reductase. This enzyme is responsible for converting dihydrofolate to tetrahydrofolate (THF). - Sulfonamides interfere with folic acid *synthesis,* which bacteria perform but humans don\'t. - Trimethoprim interferes with folic acid *utilization* by targeting a bacterial enzyme that is significantly different from the human equivalent. - This selective targeting is why these drugs are effective antibiotics with minimal disruption to human cellular processes. However, it\'s important to note that in cases of severe deficiency, very high doses of these drugs *can* potentially affect human cells, leading to side effects. **Describe the primary uses for sulfonamides,trimethoprim, and the combination of the two drugs. Explain the clinical and biochemical rationales for the common combination of sulfamethoxazole with trimethoprim.** - Use for sulfonamides: Gram -- and +, enterobacteriacease, h.flu, streptococcus, nocardia (Sulfadiazine combined with pyrimthamine is DOC for toxoplasmosis) - Uses for trimethoprim: 20-50 fold more potent than sulfonamides (coverage is similar), may be used alone to treat UTI - Combination of these meds are used for UTIs, Respiratory tract, Pneumocystis jirovecii Pneumonia, GI, and skin. - **Biochemical Rationale:** Both drugs inhibit different steps in the bacterial folic acid synthesis pathway. By blocking two steps, the combination has a synergistic effect, meaning it is more effective than either drug used alone. This is because bacteria need folic acid to produce essential components like DNA It also helps to reduce the development of resistance. - Because the combination targets two steps in the same pathway, it is more difficult for bacteria to develop resistance compared to when either drug is used alone. **Recognize the link between sulfonamides and Stevens-Johnson syndrome, hemolytic anemia, and kernicterus. Describe the patient populations who are at the highest risk for these potentially serious disorders.** - SJS is thought to be an immune-mediated reaction, where the drug triggers an abnormal immune response that attacks the skin and mucous membranes. - **Characteristics:** SJS typically begins with flu-like symptoms, followed by a rash that spreads and blisters. It can involve the mouth, eyes, and genitals. - Sulfonamides can cause hemolytic anemia, a condition where red blood cells are destroyed faster than they can be made, leading to anemia (low red blood cell count). Affects those with **G6PD deficiency** - **Mechanism:** In some individuals, sulfonamides can trigger an immune response that attacks red blood cells, causing them to rupture (hemolysis). - Sulfonamides can displace bilirubin from its binding site on albumin (a protein in the blood). This allows bilirubin to cross the blood-brain barrier and deposit in brain tissue, leading to kernicterus. **Explain the general way that sulfonamide-induced crystalluria occurs, and state two simple yet effective and appropriate ways to reduce the risk.** - When urine is acidic (low pH), sulfonamides can precipitate out of solution and form crystals. - Adequate hydration and alkalization of the urine prevent this by reducing concentration of drug and promoting ionization **Compare side effects of trim/sulfa to TCNs (tetracyclines) and macrolides... similarities? Differences?** - Similar side effects: GI disturbance, skin reaction, photosensitivity - **Differences:** - Severity of skin reactions: TMP/SMX is associated with more severe skin reactions (SJS/TEN) compared to tetracyclines and macrolides. - Teeth: Tetracyclines uniquely affect teeth development in young children and in utero. - QTc prolongation: Macrolides (especially erythromycin and clarithromycin) can prolong the QTc interval, a risk not typically associated with TMP/SMX or tetracyclines. - Drug interactions: Macrolides (erythromycin and clarithromycin) are notable for their interactions through CYP450 inhibition, while TMP/SMX and tetracyclines have different interaction profiles. **Name two or three other groups of drugs that might cross-react and cause adverse responses in patients who have had hypersensitivity reactions to sulfonamide antibiotics.** - Do not prescribe sulfonamides to patient on warfarin! If no other alternatives then cut warfarin dose by 50% - Thiazide diuretics - Sulfonylureas - Carbonic anhydrase inhibitors **[Inhibitors of DNA/RNA Synthesis objectives:]** **What is the mechanism of action of fluroquinolones and spectrum of activity?** - Fluoroquinolones inhibit bacterial topoisomerase enzymes, specifically **DNA gyrase** and **topoisomerase IV**. These enzymes are essential for bacterial DNA replication, transcription, and repair. - Broad spectrum antibiotic- gram + and -- (these drugs are now 2^nd^ line for many infections); bactericidal **Discuss the pharmacokinetics of fluoroquinolones.** - Well absorbed after oral dosing (90% bioavalibility) - Antacids, ca++, dairy products reduce absorption - Good penetration into CNS; distributes well into the tissues - Excreted renally; dose adjustment needed for renal disease **What are the various "generations" most useful for treating?** - **First generation**: narrow spectrum, covers gram - , mainly Enterobacteriaceae - **Second Generation:** improved intracellular penetration and broader coverage - **Third generation:** covers same pathogens as second gen. but with expanded coverage of streptococcus species - **Fourth generation**: enhanced gram + coverage and more staph and strep coverage, cover atypical bacteria **Describe the potential adverse effects- what is the basis for the black box warning on this drug class?** - N/V, headache, dizziness, photosensitivity, arthropathy(uncommon) - BB: Tendinitis, tendon rupture, peripheral neuropathy, and CNS effects- hallucinations, anxiety, insomnia, confusion, seizures - May prolong QTc intervals - Cipro inhibits CYP450 **Discuss drug interactions.** - Cipro can inhibit CYP450, so other drugs can be increased (warfarin) - Antacids decrease the absorption - Use of corticosteroids with fluoroquinolones increases the risk of tendon rupture - Avoid in those with arrhythmias or on drugs associated with QT prolongation **Use of fluoroquinalones in pregnancy and children?** - Category C ; risk vs benefit - Children: use in pediatrics should be limited due to cystic fibrosis exacerbations; may also cause tendon rupture **[Cyclic Lipopeptide- Daptomycin Objectives:]** **What is the spectrum of activity and therapeutic use?** - Infections caused by resistant gram + such as MRSA and VRE **What are the side effects and interactions? Renal requirements?** - This drug is inactivated by pulmonary surfactants- so it cannot be used to treat pneumonia; renally eliminated, dose needs to be adjusted - Fever, chills, phlebitis, flushing (red-man syndrome), ototoxicity, and nephrotoxicity **Lab monitoring?** - Kidney function (creatinine, GFR) - Creatine photo kinase weekly, this drug can cause muscle damage and rhabdo - Hepatic transaminases **[Metronidazole -- Flagyl Objectives:]** **What is the MOA of Metronidazole?** - Amoebas possess electron transport proteins; the nitro group of Flagyl is able to serve as an electron acceptor, and forms reduced cytotoxic compounds that cause the death of entamoeba histolytica **What is the antibacterial spectrum?** - Anaerobic gram -- bacilli, anaerobic gram + bacilli (c.diff) - Giardia lambila, trichomonas vaginalis **What are the major uses? Side effects/drug interaction?** - N/V, abdominal pain, metallic taste, oral yeast, neurotoxicity, DO NOT take with alcohol - Bacterial vaginosis, PID, heart and blood infections - Can increase anticoagulant effect of warfarin, lithium, and phenobarbital **[Nitrofurantoin- Macrodantin Objectives]** **Review organisms that cause UTIS.** - E.coli - Enterococcus - Klebsiella - Staphylococcus **Review oral therapy for UTI for non-pregnant women.** - Methenamine - Nitrofurantoin **Discuss the mechanism of action of nitrofurantoin and its antimicrobial spectrum.** - Inhibits DNA and RNA synthesis - Covers E.coli., Klebsiella spp., Enterococcus spp., and staphylococcus spp. **Why should renal function be evaluated before administration?** - Should not be given to patients if GFR is less than 35 - Excreted primarily through the kidneys **What are the possible side effects?** - N/V, diarrhea - Pulmonary fibrosis (do not use in patients with pre-existing lung disease) - Neuropathy and autoimmune hepatitis (complications seen with prolonged use greater than 1 month) **Discuss the use in children and pregnancy.** - Do not use in children less than 1 month (risk of hemolytic anemia) - nitrofurantoin is best avoided in the first trimester of pregnancy due to theoretical concerns about potential birth defects. It is also contraindicated near term (during labor and delivery) because of the risk of hemolytic anemia in the newborn. **[Antifungal Agents objective:]** **Define fungus.** - Infections from fungus are called mycoses - Fungi have rigid cell walls composed of chitin rather than peptidoglycan (bacteria) - Fungi are generally resistant to antibiotics, and bacteria are resistant to antifungal agents **Understand the difference between systemic and superficial mycoses.** - May involve the skin only -- cutaneous mycoses extend into the epidermis or may be subcutaneous or systemic - Systemic can be life-threatening - Superficial is limited to the epidermis, nails, and hair **Understand the difference between opportunistic and non-opportunistic pathogen.** - **Non- opportunistic:** Microorganisms that can cause disease in healthy individuals with a normal immune system. They possess virulence factors that allow them to overcome the host\'s defenses and establish infection. High virulence - **Opportunistic:** Microorganisms that typically do not cause disease in healthy individuals with a normal immune system. However, they can cause infections when the host\'s defenses are compromised. Low virulence **Differentiate the polyenes and the imidazole drug groups used to treat fungal infections** - **Polyenes** like amphotericin B are potent, broad-spectrum antifungals reserved for serious systemic mycoses due to their toxicity. Nystatin is used for superficial infections. - **Imidazoles** are commonly used for both superficial and systemic fungal infections, with varying potency and routes of administration depending on the specific drug. They are generally better tolerated than amphotericin B. **Review life span issues of the anti-viral and anti-fungal drugs** - **Compare and contrast the following antifungal clases. Discuss the MOA, uses and side effects.** - **Polyene antifungals** - Amphotericin B (big momma): - DOC for several life threatening mycoses - Given IV infusion; excreted in the urine - LOW therapeutic index - Renal impairment d/t decreased GFR in renal tubule function, normally returns to baseline when drug is stopped (can cause nephrotoxicity) - Fever and chills, hypotension, thrombophlebitis (give heparin during **infusion)** - **Azoles (Imidazoles and triazoles)** - Imidazoles are used for topical for cutaneous infections while the triazoles are given systemically for cutaneous and systemic mycoses - MOA: Inhibits ergosterol biosynthesis and disrupts fungal membrane structure and function - All azoles inhibit CYP450; any CYP450 inhibitors (ritonavir,rifampin,phenytoin) can lead to increased ADEs or failures of the azoles. - TERATOGENIC- avoid in pregnancy - Itraconazole should be avoided in pt with ventricular dysfunction (bb warning in those with HF and ventricular dysfunction) - **Echinocandins (capsofungin, micafungin, anidulafungin)** - MOA- interfere with the synthesis of the fungal cell wall and inhibit the synthesis leading to lysis and cell death - Given slow iv infusion to prevent histamine-induced flushing - Potent against aspergillus and candida ssp. - Capsofungin: cancidas; 1^st^ line with invasive candida, not be given with cyclosporin due to elevated LFTs - Micafungin: 1^st^ line for invasive candidias (candidemia) - **Pyrimidine analogs** - These drugs slow down cell growth and division - Can cause bone marrow suppression - Mainly used in cancer and antiviral - **Sequalene epoxidase inhibitors** - Blocking biosynthesis; terbinafine (Lamisil) - Used for cutaneous mycotic infections **Flucanazole:** - Fluconazole \#1 triazole antifungal (must be reduced in presence of renal disease but not nephrotoxic) - No role in treating aspergillus or zygomycosis - Very active against cryptococcus neoformans, c.albicans, and c. parapsilosis - Effective against most forms of mucocutaneous candidiasis **Itraconazole:** - Synthetic triazole with broad antifungal spectrum compared to fluconazole - DOC in blastomycosis, sporotrichosis, paracoccidioidomycosis, histoplasmosis - Rarely used for candida or aspergillus - Avoid in those with ventricular dysfunction! **Voriconazole:** - DOC for invasive aspergillus **Posaconazole:** - Treats and prevents invasive candida and aspergillus in the immunocomprimised Isavuconazole: - Similar to voriconazole- approved for invasive aspergillus and invasive mucormycosis **[Antiviral agents objective:]** **Define virus and what makes the structure of a virus.** - Viruses are intracellular parasites - They do not have a cell wall or cell membrane and do not carry out metabolic processes - They use much of the metabolic processes of the host, very few drugs are selective enough to prevent viral replication and not injure the host **Discuss acyclovir and valacyclovir as DOC for most herpes simplex and varicella-zoster viruses (action, uses, kinetics, and side effects.)** - **Acyclovir:** (**Zovirax):** covers HSV1,HSV2,VZV and some strains of Epstein bar virus; DOC for HSV encephalitis , genital herpes. Excreted from the urine ( high doses can cause renal dysfunction. - **Valacyclovir:** Valacyclovir is an antiviral medication. It\'s actually a **prodrug** of acyclovir, meaning it\'s converted to acyclovir in the body. Treats HSV, varicella zoster. Valacyclovir, once converted to acyclovir, works by interfering with the herpes virus\'s DNA replication. It\'s a nucleoside analog, meaning it mimics one of the building blocks of DNA. When the virus tries to use it to build new DNA, it gets incorporated and stops the replication process. Monitor kidney function **Understanding drug classes used to treat herpes infections.** **Nucleoside Analog Reverse Transcriptase Inhibitors (NRTIs)** - Acyclovir, valacyclovir, penciclovir, famciclovir **Penciclovir:** HSV-1, HSV-2,VZV; given topically; ½ life longer than acyclovir, minimally absorbed, well tolerated **Famciclovir:** prodrug that is metabolized to the active peniciclovir; treats herpes zoster, genital HSV, and recurrent herpes labialis, taken orally **Trifluridine:** HSV1,HSV2,Vaccinia, indicated to treat HSV keratonconjuntivitis; too toxic for systemic use; short ½ life used in ophthalmic drops **Cidofovir and Ganciclovir:** used for CMV rentinitis **Foscarnet:** **Mechanism of Action:** Inhibits viral DNA polymerase and reverse transcriptase by a different mechanism than NRTIs. **Uses:** Used for resistant herpes infections (e.g., acyclovir-resistant HSV or CMV) or in patients who cannot tolerate other antiviral medications. **Dicuss ganciclovir as the treatment choice for cytomegalovirus. Discuss action, kinetics, and adverse effects.** **Ganciclovir:** Used in the treatment of CMV retinitis in the immunosuppressed to prevent CMV in the transplant patient - Given iv and excreted through the urine (accumulates in those with CKD) - Severe dose-dependent neutropenia; carcinogenic and teratogenic; BB for pregnancy! **Know drug options for treating influenza and respiratory viral infections** - Influenza A &B, and RSV - Neuraminidase inhibitors (oseltamivir (Tamiflu) and zanamivir); do not interfere with immune response to the flu vaccines and givern 24-48hrs after symptoms occur **Discuss the action, kinetics, and side effects of drugs used to treat influenza (neuraminidase inhibitors and adamantanes)** - **Neuraminidase Inhibitors:** given prior to exposure, this drug prevents spreading of the virus - Eliminated in the urine; can cause GI discomfort and cause bronchospasms **(zanamivir is an inhalant)** - **Amantadine antivirals**: (amantadine (Symmetrel), rimantadine) ONLY flu A - **Ribavirin: Virazole**; synthetic guanosine analog; effective against broad spectrum of RNA and DNA viruses; used in treatment of immunosuppressed children with RSV; effective with chronic hep C **Discuss drugs used to treat hepatitis infections.** **-Hep B:** - Chronic heb B can be treated with Peginterferon-a-2a injected SQ weekly - Oral therapy for chronic hep B can be Lamivudine, adenovir and tenoforvir - **Adenovir:** nephrotoxicity can occur in chronic use. use with caution in those with CKD, no longer first line treatment - **Entecavir**- used in those lamivudine resistant strains of hep B; adjustments needed for CKD - Treating hep B- interferons- naturally occurring inducible glycoproteins that interfere with the virus to infect the host cell; not understood - Chronic hep c is treated with a combo of direct acting antivirals - **Ns3/NS4A protease inhibitors**; without these serin protiens, RNA replication does not occur and the HEP c life cycle is stalled (paritaprevir,grazoprevir, etc) - **Ribavarin**- chronic hep C when used in combination with standard pegylated interferon or with DDAs There are several classes of DAAs, each targeting a different part of the HCV life cycle:   1. **NS3/4A Protease Inhibitors:** These drugs block the viral protease enzyme, which is essential for processing viral proteins.   - Examples: Grazoprevir, Glecaprevir, Voxilaprevir (often used in combination with other DAAs)   2. **NS5A Inhibitors:** These drugs target the NS5A protein, which plays a crucial role in viral replication and assembly.   - Examples: Ledipasvir, Daclatasvir, Velpatasvir (often used in combination with other DAAs)   3. **NS5B Polymerase Inhibitors:** These drugs inhibit the viral polymerase enzyme, which is responsible for replicating the viral RNA.   - Examples: Sofosbuvir (often used in combination with other DAAs) **[Additional objectives:]** **What are common gram +, gram -, and atypical organisms and the disease they cause?** **Gram-Positive Bacteria (Gram +)** - Staphylococcus aureus: - Diseases: Skin infections (boils, impetigo, cellulitis), pneumonia, bacteremia, endocarditis, toxic shock syndrome, food poisoning. - Streptococcus pyogenes (Group A Strep): - Diseases: Strep throat, scarlet fever, skin infections (impetigo, cellulitis, erysipelas), rheumatic fever, post-streptococcal glomerulonephritis. - Streptococcus pneumoniae: - Diseases: Pneumonia, meningitis, otitis media, sinusitis. - Enterococcus faecalis/faecium: - Diseases: Urinary tract infections, endocarditis, intra-abdominal infections. - Clostridium difficile: - Diseases: *C. difficile*-associated diarrhea, pseudomembranous colitis. **Gram-Negative Bacteria (Gram -)** - Escherichia coli (E. coli): - Diseases: Urinary tract infections, sepsis, pneumonia, diarrhea. - Klebsiella pneumoniae: - Diseases: Pneumonia, urinary tract infections, bloodstream infections. - Pseudomonas aeruginosa: - Diseases: Pneumonia (especially in cystic fibrosis or ventilator-associated), skin infections (e.g., burn wounds), bacteremia. - Neisseria gonorrhoeae: - Diseases: Gonorrhea (a sexually transmitted infection). - Neisseria meningitidis: - Diseases: Meningitis, sepsis. - Haemophilus influenzae: - Diseases: Respiratory tract infections (especially in children), meningitis. - Salmonella species: - Diseases: Salmonellosis (food poisoning), typhoid fever. **Atypical Organisms** - Chlamydia trachomatis: - Diseases: Chlamydia (a sexually transmitted infection), pelvic inflammatory disease, trachoma (eye infection). - Mycoplasma pneumoniae: - Diseases: \"Walking pneumonia\" (a mild form of pneumonia). - Legionella pneumophila: - Diseases: Legionnaires\' disease (a severe form of pneumonia). **Discuss how bacteria develop resistance to antimicrobials and how prescribers can prevent or reduce the resistance.** **How Bacteria Develop Resistance** Bacteria can develop resistance to antimicrobials through various mechanisms: 1. **Enzymatic Inactivation:** Bacteria produce enzymes that inactivate the antimicrobial by chemically modifying it (e.g., beta-lactamases that break down beta-lactam antibiotics like penicillin). 2. **Target Modification:** Bacteria alter the target site where the antimicrobial binds, reducing its ability to interact effectively (e.g., mutations in ribosomal RNA leading to macrolide resistance). 3. **Efflux Pumps:** Bacteria increase the expression of efflux pumps, which actively pump the antimicrobial out of the cell, reducing its intracellular concentration. 4. **Reduced Permeability:** Bacteria decrease the permeability of their cell membrane, preventing the antimicrobial from entering the cell. 5. **Target Bypass:** Bacteria develop alternative metabolic pathways that bypass the step inhibited by the antimicrobial. 6. **Horizontal Gene Transfer:** Bacteria can acquire resistance genes from other bacteria through plasmids, transposons, or other mobile genetic elements. This allows resistance to spread rapidly within and between bacterial populations. **How Prescribers Can Prevent or Reduce Resistance** Prescribers can play a crucial role in preventing and reducing antimicrobial resistance by implementing the following strategies: 1. **Judicious Use of Antimicrobials:** - **Avoid unnecessary use:** Don\'t prescribe antimicrobials for viral infections (e.g., common cold, flu) or when there is no clear evidence of a bacterial infection. - **Use the right drug:** Choose the most appropriate antimicrobial based on the suspected pathogen, local resistance patterns, and patient-specific factors. - **Use the correct dose and duration:** Follow recommended guidelines for dosage and duration of therapy to ensure effective treatment and minimize selection pressure for resistance. - **Consider narrower spectrum agents:** When possible, use a narrow-spectrum antimicrobial that targets the specific pathogen rather than a broad-spectrum agent. 2. **Accurate Diagnosis:** - **Obtain cultures:** When appropriate, obtain cultures before starting antimicrobial therapy to identify the causative organism and its susceptibility patterns. - **Use rapid diagnostic tests:** Utilize rapid diagnostic tests when available to differentiate between bacterial and viral infections and guide treatment decisions. 3. **Antimicrobial Stewardship Programs:** - **Implement guidelines:** Adhere to evidence-based guidelines for antimicrobial use. - **Monitor antimicrobial use:** Track antimicrobial prescribing practices and provide feedback to prescribers. - **Educate healthcare professionals:** Educate healthcare professionals about antimicrobial resistance and appropriate prescribing practices. - **Promote de-escalation:** Encourage switching from broad-spectrum to narrow-spectrum therapy once culture results are available. **Discuss the advantages and disadvantages of using narrow, extended, or broad spectrum antibiotics.** **1. Narrow-Spectrum Antibiotics** - **Definition:** These antibiotics are specifically effective against a limited range of bacteria, typically either gram-positive or gram-negative. - **Advantages:** - **Targeted Therapy:** Highly effective against the specific pathogen while minimizing disruption to the normal microbiota (the beneficial bacteria in your body). - **Reduced Resistance Risk:** Less likely to contribute to antibiotic resistance compared to broad-spectrum agents. - **Fewer Side Effects:** May cause fewer side effects as they have a more targeted impact. - **Disadvantages:** - **Requires Identification:** Need to know the exact bacterial cause of the infection before using a narrow-spectrum antibiotic. This often requires culture and sensitivity testing, which takes time. - **Ineffective if Unknown:** If the causative organism is unknown or is resistant to the narrow-spectrum agent, the treatment will fail. **2. Extended-Spectrum Antibiotics** - **Definition:** These antibiotics have a broader range of activity than narrow-spectrum but are still not effective against all types of bacteria. They may cover some gram-positive and some gram-negative bacteria. - **Advantages:** - **Broader Coverage:** Offer a wider range of activity compared to narrow-spectrum antibiotics, making them useful when the exact bacterial cause is not yet known. - **May Be Effective Against Some Resistant Strains:** Some extended-spectrum antibiotics are effective against certain bacteria that are resistant to narrow-spectrum agents. - **Disadvantages:** - **Increased Resistance Risk:** Contribute more to antibiotic resistance compared to narrow-spectrum drugs. - **More Disruption to Microbiota:** Affect a wider range of bacteria in the body, potentially leading to side effects like *C. difficile* infection. **3. Broad-Spectrum Antibiotics** - **Definition:** These antibiotics are effective against a wide range of bacteria, including both gram-positive and gram-negative, and sometimes atypical bacteria. - **Advantages:** - **Empiric Therapy:** Useful for empiric therapy (treatment started before culture results are available) when a serious infection is suspected, and the causative organism is unknown. - **Coverage of Mixed Infections:** Can be used to treat infections caused by multiple types of bacteria. - **Disadvantages:** - **Highest Resistance Risk:** Carry the highest risk of contributing to antibiotic resistance. - **Significant Microbiota Disruption:** Significantly disrupt the normal microbiota, leading to increased risk of secondary infections (like *C. difficile* infection) and other side effects. - **May Mask Infection:** Can suppress but not eliminate the causative organism, making it difficult to identify the true pathogen. **Explain the difference between a bactericidal or bacteriostatic antibiotic. Under what conditions does each work best?** **Bactericidal Antibiotics** - **Definition:** Antibiotics that **kill** bacteria directly. - **Mechanism of Action:** Interfere with bacterial cell wall synthesis, protein synthesis, or DNA replication in ways that are lethal to the bacteria. - **Examples:** Penicillins, cephalosporins, aminoglycosides, fluoroquinolones, vancomycin. **Bacteriostatic Antibiotics** - **Definition:** Antibiotics that **inhibit** bacterial growth and replication, preventing them from multiplying. They don\'t kill the bacteria directly. - **Mechanism of Action:** Interfere with bacterial protein synthesis, metabolism, or DNA replication in a way that stops growth but doesn\'t kill the bacteria. The host\'s immune system then plays a crucial role in eliminating the inhibited bacteria. - **Examples:** Tetracyclines, macrolides, sulfonamides, clindamycin, trimethoprim. **When to Use Bactericidal vs. Bacteriostatic Antibiotics** **Bactericidal are generally preferred in these situations:** - **Serious Infections:** Infections that are life-threatening or involve critical organs (e.g., meningitis, endocarditis, sepsis, pneumonia). Rapidly killing the bacteria is crucial in these cases. - **Immunocompromised Patients:** Patients with weakened immune systems rely more on the antibiotic to eliminate the infection since their immune defenses are compromised. - **Infections in Sites with Poor Blood Flow:** Areas with poor blood flow (e.g., abscesses, infected heart valves) may be difficult for the immune system to reach, making bactericidal agents more important. - **Infections Caused by Certain Bacteria:** Some bacteria are more effectively eradicated with bactericidal antibiotics. **Bacteriostatic may be appropriate in these situations:** - **Less Severe Infections:** Infections that are not immediately life-threatening and in patients with intact immune systems. - **When Bactericidal are Contraindicated:** If a patient has allergies or other contraindications to bactericidal antibiotics. - **Long-term Therapy:** Some infections requiring long-term treatment may be more manageable with bacteriostatic agents. **Differentiate between microbial colonization and infection based on patient history, physical exam, and laboratory and culture results.** - **Microbial colonization:** The presence of microorganisms (bacteria, fungi, viruses) on or in a host **without causing disease**. The microbes are living and sometimes even multiplying at the colonized site, but the host does not experience any negative health impact. Often asymptomatic - **Infection:** The invasion and multiplication of microorganisms in body tissues, leading to a **disease state** characterized by signs and symptoms. The host experiences a negative impact. **Identify causes of patients failing to improve while on antimicrobials and recognize other less common but potential reasons for antimicrobial failure.** 1. **Incorrect Diagnosis:** - The initial diagnosis may be wrong. The patient might have a non-infectious condition mimicking an infection or an infection caused by a different pathogen than initially suspected. 2. **Antibiotic Resistance:** - The bacteria causing the infection may be resistant to the prescribed antibiotic. This is a growing problem due to overuse and misuse of antibiotics. 3. **Inadequate Drug Levels:** - The antibiotic may not be reaching the site of infection in sufficient concentrations due to factors like poor absorption, inadequate dosing, or the presence of barriers (e.g., abscess, foreign body). 4. **Non-Adherence to Therapy:** - The patient may not be taking the antibiotic as prescribed (e.g., missing doses, stopping early). This can lead to treatment failure and contribute to resistance development. 5. **Superinfection:** - A new infection may develop during antibiotic therapy, caused by a different organism (often drug-resistant). This is common with broad-spectrum antibiotics that disrupt the normal microbiota. 6. **Persistent Source of Infection:** - The infection may persist due to an undrained abscess, infected foreign body, or other structural issues requiring intervention (e.g., surgical drainage). 7. **Drug Interactions:** - Other medications the patient is taking may interfere with the absorption or effectiveness of the antibiotic. **Describe the general characteristics and mode of action of antibiotics commonly used.** **1. Cell Wall Synthesis Inhibitors** - **Mechanism of Action:** Interfere with the synthesis of the bacterial cell wall, a structure essential for bacterial survival. This leads to bacterial cell lysis (bursting) and death. - **Examples:** - **Beta-lactams:** Penicillins (e.g., amoxicillin, penicillin G), Cephalosporins (e.g., cefazolin, ceftriaxone), Carbapenems (e.g., imipenem, meropenem), Monobactams (e.g., aztreonam). - **Glycopeptides:** Vancomycin, Teicoplanin. - **Characteristics:** - Often bactericidal (kill bacteria). - Time-dependent killing (effectiveness depends on the duration of exposure above a certain concentration). - Beta-lactams have a beta-lactam ring crucial for their activity. - Glycopeptides bind to cell wall precursors, preventing their incorporation. **2. Protein Synthesis Inhibitors** - **Mechanism of Action:** Inhibit bacterial protein synthesis by binding to bacterial ribosomes (cellular structures responsible for protein production), thus preventing bacterial growth and replication. - **Examples:** - **Macrolides:** Erythromycin, Clarithromycin, Azithromycin. - **Tetracyclines:** Tetracycline, Doxycycline, Minocycline. - **Aminoglycosides:** Gentamicin, Tobramycin, Amikacin. - **Lincosamides:** Clindamycin. - **Oxazolidinones:** Linezolid, Tedizolid. - **Characteristics:** - Often bacteriostatic (inhibit growth) but can be bactericidal at high concentrations or against certain bacteria. - Macrolides bind to the 50S ribosomal subunit. - Tetracyclines block tRNA binding to the ribosome. - Aminoglycosides bind to the 30S ribosomal subunit, affecting protein synthesis and causing misreading of mRNA. - Oxazolidinones interfere with the formation of the initiation complex in protein synthesis. **3. DNA Replication Inhibitors** - **Mechanism of Action:** Interfere with bacterial DNA replication or repair, preventing bacterial cell division. - **Examples:** - **Fluoroquinolones:** Ciprofloxacin, Levofloxacin, Moxifloxacin. - **Characteristics:** - Bactericidal. - Inhibit topoisomerase enzymes (DNA gyrase and topoisomerase IV) involved in DNA supercoiling and replication. - Concentration-dependent killing (higher concentrations lead to more rapid bacterial killing). **4. Metabolic Pathway Inhibitors** - **Mechanism of Action:** Interfere with essential metabolic pathways in bacteria, such as folic acid synthesis. - **Examples:** - **Sulfonamides:** Sulfamethoxazole. - **Trimethoprim:** Trimethoprim. - **Characteristics:** - Bacteriostatic individually but often bactericidal in combination (e.g., trimethoprim-sulfamethoxazole). - Sulfonamides block the synthesis of dihydrofolic acid. - Trimethoprim inhibits dihydrofolate reductase. **5. Cell Membrane Disruptors** - **Mechanism of Action:** Damage the bacterial cell membrane, leading to leakage of cellular contents and bacterial death. - **Examples:** - **Polymyxins:** Colistin, Polymyxin B. - **Lipopeptides:** Daptomycin. - **Characteristics:** - Bactericidal. - Polymyxins interact with lipopolysaccharide (LPS) on the bacterial cell membrane. - Daptomycin inserts into the cell membrane, causing depolarization and cell death. **Discuss mechanism of action, pharmacokinetics, and spectrum of activity of natural and extended spectrum penicillins.** **Natural Penicillins (e.g., Penicillin G, Penicillin V)** - **Mechanism of Action:** - Inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), which are enzymes involved in peptidoglycan synthesis (a component of the bacterial cell wall). - This leads to bacterial cell lysis (bursting) and death. - **Pharmacokinetics:** - **Absorption:** - Penicillin G: Primarily administered intravenously or intramuscularly due to poor oral absorption. - Penicillin V: Can be administered orally. - **Distribution:** Distributes well to most body tissues except for the brain and cerebrospinal fluid (unless the meninges are inflamed). - **Metabolism:** Minimal metabolism in the liver. - **Excretion:** Primarily excreted unchanged in the urine via tubular secretion. - **Spectrum of Activity:** - Primarily active against gram-positive bacteria (e.g., streptococci, some staphylococci) and some gram-negative cocci (e.g., Neisseria gonorrhoeae). - Also active against some spirochetes (e.g., Treponema pallidum, the cause of syphilis). - Narrow spectrum of activity compared to other penicillins. **Extended-Spectrum Penicillins (e.g., Ampicillin, Amoxicillin, Ticarcillin, Piperacillin)** - **Mechanism of Action:** - Same as natural penicillins -- inhibit bacterial cell wall synthesis by binding to PBPs. - **Pharmacokinetics:** - **Absorption:** - Ampicillin and Amoxicillin: Can be administered orally and have better oral absorption compared to penicillin G. - Ticarcillin and Piperacillin: Primarily administered intravenously or intramuscularly. - **Distribution:** Similar to natural penicillins. - **Metabolism:** Similar to natural penicillins. - **Excretion:** Primarily excreted unchanged in the urine. - **Spectrum of Activity:** - **Ampicillin and Amoxicillin:** - Broader spectrum compared to natural penicillins. - Retain activity against most gram-positive bacteria susceptible to penicillin G. - Also active against some gram-negative bacteria (e.g., Haemophilus influenzae, Escherichia coli, some strains of Salmonella and Shigella). - **Ticarcillin and Piperacillin:** - Extended spectrum, including activity against Pseudomonas aeruginosa (especially Piperacillin). - Used in combination with a beta-lactamase inhibitor (e.g., clavulanate, sulbactam, tazobactam) to enhance their activity against bacteria that produce beta-lactamase enzymes (which inactivate penicillins). **Select the most appropriate, cost-effective cephalosporin based on generational characteristics and spectrum of activity** -   **1st Generation Cephalosporins:** - **Characteristics:** Primarily active against gram-positive bacteria. Some activity against certain gram-negative bacteria. - **Examples:** Cefazolin, Cephalexin, Cefadroxil. - **Common Uses:** Skin and soft tissue infections, surgical prophylaxis. - **2nd Generation Cephalosporins:** - **Characteristics:** Expanded gram-negative coverage compared to 1st generation. - **Examples:** Cefuroxime, Cefaclor, Cefprozil. - **Common Uses:** Respiratory tract infections, some intra-abdominal infections. - **3rd Generation Cephalosporins:** - **Characteristics:** Increased gram-negative coverage, including activity against some resistant organisms. Some can cross the blood-brain barrier. - **Examples:** Ceftriaxone, Cefotaxime, Ceftazidime. - **Common Uses:** Serious infections, meningitis, pneumonia, some drug-resistant infections. - **4th Generation Cephalosporins:** - **Characteristics:** Broad spectrum activity, similar to 3rd generation but with increased resistance to some beta-lactamases. Can cross the blood-brain barrier. - **Examples:** Cefepime. - **Common Uses:** Febrile neutropenia, serious infections caused by resistant organisms. - **5th Generation Cephalosporins:** - **Characteristics:** Active against MRSA (methicillin-resistant Staphylococcus aureus). - **Examples:** Ceftaroline, Ceftobiprole. - **Common Uses:** MRSA infections, complicated skin and soft tissue infections. **Answering the Question** To select the most appropriate, cost-effective cephalosporin, consider these steps: 1. **Identify the Suspected Pathogen:** - What type of bacteria is likely causing the infection (gram-positive, gram-negative, or both)? - Are there any concerns about resistance? 2. **Consider the Site of Infection:** - Where is the infection located? (e.g., skin, lungs, blood, CSF). - Does the antibiotic need to cross the blood-brain barrier? 3. **Choose the Narrowest Spectrum Possible:** - Select a cephalosporin that covers the likely pathogen but has the narrowest spectrum of activity. This helps reduce the risk of resistance and side effects. **Describe the characteristics, expected toxicities, and indications for the use of aminoglycosides, macrolides, and sulfonamides.** The image asks: **Describe the characteristics, expected toxicities, and indications for the use of aminoglycosides, macrolides, and sulfonamides.** Let\'s break down these aspects for each class of antibiotics: **1. Aminoglycosides (e.g., Gentamicin, Tobramycin, Amikacin)** - **Characteristics:** - Bactericidal (kill bacteria) - Inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit - Concentration-dependent killing (higher concentrations = more rapid killing) - Poor oral absorption, typically administered intravenously or intramuscularly - Narrow therapeutic index (the difference between effective and toxic levels is small) - **Expected Toxicities:** - **Nephrotoxicity:** Can damage the kidneys, especially with prolonged use or high doses. Monitor kidney function (BUN, creatinine). - **Ototoxicity:** Can damage the auditory (hearing) and vestibular (balance) nerves, potentially leading to hearing loss, tinnitus, or vertigo. Risk increases with prolonged use, high doses, and pre-existing renal impairment. - **Neuromuscular Blockade:** Can interfere with nerve transmission to muscles, potentially causing muscle weakness or respiratory paralysis (rare). - **Indications for Use:** - Serious gram-negative bacterial infections (e.g., sepsis, pneumonia, complicated UTIs) - Synergy with beta-lactam antibiotics for certain infections (e.g., endocarditis) - Treatment of infections caused by some drug-resistant bacteria **2. Macrolides (e.g., Erythromycin, Clarithromycin, Azithromycin)** - **Characteristics:** - Primarily bacteriostatic (inhibit bacterial growth) - Inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit - Can be administered orally - Broad spectrum of activity, including some gram-positive, gram-negative, and atypical bacteria - **Expected Toxicities:** - **Gastrointestinal:** Nausea, vomiting, diarrhea are common. - **QTc Prolongation:** Can prolong the QT interval on an electrocardiogram (ECG), potentially leading to dangerous heart rhythm problems (torsades de pointes). - **Liver Toxicity:** Can cause liver enzyme elevations and, rarely, hepatitis. - **Drug Interactions:** Inhibit cytochrome P450 enzymes, leading to potential interactions with many other drugs. - **Indications for Use:** - Respiratory tract infections (e.g., pneumonia, bronchitis, sinusitis) - Skin and soft tissue infections - Sexually transmitted infections (e.g., chlamydia) - Infections caused by atypical bacteria (e.g., Legionella, Mycoplasma) - Alternative to penicillin in patients with penicillin allergy **3. Sulfonamides (e.g., Sulfamethoxazole-Trimethoprim (Bactrim))** - **Characteristics:** - Bacteriostatic (inhibit bacterial growth) - Inhibit bacterial folic acid synthesis, which is essential for bacterial growth and replication - Broad spectrum of activity, including some gram-positive, gram-negative, and some protozoa - **Expected Toxicities:** - **Hypersensitivity Reactions:** Rash, fever, Stevens-Johnson syndrome (a severe skin reaction) are possible. - **Hematologic:** Can affect blood cell production, potentially leading to anemia, leukopenia, or thrombocytopenia. - **Renal:** Can cause kidney damage, especially in patients with pre-existing kidney disease or dehydration. - **Photosensitivity:** Can make the skin more sensitive to sunlight. - **Drug Interactions:** Interact with warfarin and other drugs. - **Indications for Use:** - Urinary tract infections (UTIs) - Respiratory tract infections (e.g., bronchitis, sinusitis) - Skin and soft tissue infections (e.g., MRSA infections) - Pneumocystis jirovecii pneumonia (PCP), especially in HIV/AIDS patients - Nocardiosis **Outline the MOA, pharmacokinetics, and advantages inherent to quinolones and tetracyclines.** **Quinolones (e.g., Ciprofloxacin, Levofloxacin, Moxifloxacin)** - **Mechanism of Action:** - Inhibit bacterial DNA replication by targeting topoisomerase enzymes (DNA gyrase and topoisomerase IV). - These enzymes are essential for DNA unwinding and supercoiling during replication. - **Pharmacokinetics:** - **Absorption:** Well absorbed orally, with good bioavailability. - **Distribution:** Distribute widely to various body tissues and fluids, including bone, joints, and prostate. - **Metabolism:** Varying degrees of hepatic metabolism depending on the specific quinolone. - **Excretion:** Primarily renal excretion, with some biliary excretion for certain quinolones. - **Advantages:** - **Broad Spectrum:** Effective against a wide range of gram-positive and gram-negative bacteria, as well as some atypical bacteria. - **Oral Administration:** Allows for convenient outpatient treatment of many infections. - **Excellent Tissue Penetration:** Makes them useful for treating infections in various sites, including those difficult to reach with some other antibiotics. - **Potent Activity:** Often bactericidal (kill bacteria) and effective against many resistant strains. **Tetracyclines (e.g., Tetracycline, Doxycycline, Minocycline)** - **Mechanism of Action:** - Inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit, preventing tRNA from attaching to the ribosome during translation. - **Pharmacokinetics:** - **Absorption:** Variable oral absorption, affected by divalent cations (calcium, magnesium, iron) and food. Doxycycline has the best oral absorption. - **Distribution:** Distribute widely to various body tissues and fluids. Can accumulate in teeth and bones. - **Metabolism:** Varying degrees of hepatic metabolism and some enterohepatic recycling. - **Excretion:** Primarily renal excretion, with some biliary excretion for doxycycline. - **Advantages:** - **Broad Spectrum:** Effective against a wide range of bacteria, including gram-positive, gram-negative, atypical bacteria (Chlamydia, Mycoplasma, Rickettsia), and some protozoa. - **Oral Administration:** Allows for convenient outpatient treatment. - **Useful for Certain Infections:** Particularly useful for infections caused by atypical bacteria, acne, and some tick-borne illnesses (e.g., Lyme disease, Rocky Mountain spotted fever). - **Availability in Various Formulations:** Includes intravenous formulations for severe infections. **Key Differences and Considerations:** - **Quinolones:** - More potent activity against gram-negative bacteria, including Pseudomonas aeruginosa. - Associated with some serious adverse effects, including tendon rupture, QTc prolongation, and peripheral neuropathy (black box warnings). - Increased risk of *C. difficile* infection. - **Tetracyclines:** - Effective against a wider range of atypical bacteria. - Can cause tooth discoloration in children \