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Fundamentals II Test 3 Part 2


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Total destruction of all microbes including bacteria, viruses, mycobacteria, fungi & spores Mechanisms: Physical: Steam under pressure (autoclave), Ionizing radiation (gamma), UV Radiation Gas Vapor: Hydrogen peroxide (instruments), Formaldehyde (carcinogenic) Chemical: Peracetic acid (oxidizing, nontoxic), glutaraldehyde (also toxic)
Destroys most vegetative microbes or viruses; NOT spores Three levels: high, intermediate, low High: req. for surgical instruments, endoscopes- use heat, hydrogen peroxide or chlorine dioxide Intermediate: Utilized when spore presence in unlikely- alcohol or iodine Low: Noncritical instruments, quaternary ammonium compound
Application of agent to living tissue to prevent infection Ex: Povidone-Iodine: prep skin (not as good as iodine for spores) Alcohol-based hand gels
Destruction or marked reduction in number/activity of microorganisms
Reduction of microbial load on inanimate surfaces to level considered acceptable for public health
Hot water or steam to kill non-sporulating bacteria
Antibacterial Therapy: Brainstem approach
Identifying an infection with an antibiotic Problems: multiple drugs available for treatment, some more effective on certain patients than others; promotes antibiotic resistance
Antibacterial Therapy: Thoughtful approach
More integrative- use pharm, micro, etc. to make decision best for patients Questions: Is patient infected? If yes, which bug? only use antibiotic if it is a bacteria
Bacteriostatic Agent
Inhibits bacterial growth
Bactericidal Agent
Kills bacteria Preferred for high inoculum infections
List of all isolated bacteria strains acquired & antibiotics to which they are susceptible for each hospital
Antibiotic Resistance- Contributing Factors
Inappropriate use Animal husbandry- antibiotics given to enhance growth, cultures resistant organisms, undercooked meat = infection in human of resistant pathogen Prolonged hospitalization, esp. ICU Immunocompromised patient pop., esp. organ transplants Invasive device & catheter use
Beta (B)-lactam Antibacterial Resistance Mechanisms
Include: penicillins, cephalosporins MOA: alteration in penicillin-binding proteins (eg Strep. pneumoniae to penicillin, S. aureus to methicillin) Note: S. pyogenes (group A strep) is only strep still susceptible to penicillin MOA2: B-lactamase production hydrolyzes antibiotic (eg E.coli to ampicillin) This also includes extended spectrum B-lactamases- resistance to larger variety of B-lactam antibiotics
Vancomycin (synthetic glycopeptides) Resistance Mechanisms
Intrinsic: ALL gram negative are resistant b/c vancomycin is too large Acquired: Plasmids transferred (eg vancomycin-resistant enterococci [VRE])
Aminoglycosides & Tetracyclines Resistance Mechanisms
Mutation of ribosomal binding site (these agents are bacteriostatic b/c work inside cell) Decreased uptake Increased expulsion Enzymatic modification of antibiotic
Macrolides & Clindamycin Resistance Mechanisms
Methylation of 23S ribosomal RNA Mutations in ribosomal proteins
Quinolones Resistance Mechanisms
Chromosomal mutation in DNA gyrase & topoisomerase IV (these are usually targeted by quinoline)
Antimicrobacterial Therapy
Mycobacteria species are intracellular pathogens that grow slowly & remain dormant Lipid-rich cell wall, impermeable to many agents Capacity for resistance Active disease: treated w/ 2 or more drugs to reduce resistance development Non active, latent: give one drug (eg Isoniazid for TB)
Isoniazid (INH)
For: TB MOA: inhibits biosynthesis of mycolic acids Bacteriostatic for resting cells Bacteriocidal for replicating cells Diffuse readily into all bodily fluids except CSF Excretion: urine as acetylisoniazid & isonicotonic acid Metabolism: acetylation Consider slow (toxicity) vs. fast (undertreatment) Resistance: overexpression of inhA or mutation (katG) of genes Toxicity: Hepatitis- asympt. elevation of liver enzymes, symptomatic hepatitis or liver toxicity (age, alcohol, pregnancy) Neuropathy: Vitamin B6 (pyroxidine) combats neuropathy Interactions: INH & phenytoin co-admin increases phenytoin Indication: prophylaxis, combo therapy (1 of 4)
Activity against S. aureus (gram + cocci), N. meningitides (Gram - cocci), Chlamydia & mycobacteria MOA: binds B subunits of bacterial DNA-dep. RNA pol- inhibits RNA synthesis Bactericidal for mycobacteria Well absorbed; penetrates tissue & phagocytic cells (in pus, eg) Highly protein bound- wide distribution, adequate CSF conc. Exretion: mainly liver, into bile via enterohepatic circ.- bulk in feces, some urine Induces Cyt. P450 enzymes- drug interactions = faster metab. Eg: Oral Contraceptives (ineffective), Methadone (decr. levels), Coumadin (red. blood thinning), Phenytoin (no seizure prevention), Protease Inhibitors Indications: Tb- 1 of 4 in combo; Atypical mycobacterial infection combo, Leprosy, Meningococcal carriage Resistance: mutants rapidly selected; never use alone Method: alteration of target polymerase Toxicity: tears, urine, sweat-orange, jaundice, rash, thrombocytopenia, nephritis
Ethambutol (ETB)
Synthetic, water-soluble, heat-stable MOA: inhibits mycobact. arabinsyl transferases involved in cell wall synthesis Aborption: from gut Excretion: urine, some feces Adjust for renal insufficiency Resistant mutants rapidly selected out Indications: combo (1/4) for TB; combo for atypical mycobacterial infection (esp. M avium intracellulare) Toxicity: Optic neuritis Not for children
Pyrazinamide (PZA)
Synthetic analog of nicotinamide MOA: unknown Converted to active form by mycobacterial enzymes Bactericidal at slightly acidic pH (abscesses typically acidic- good for active TB) Activated drug taken up by macrophages; acts against mycobacteria within lysosomes Absorption: from GI-widely distributed, even meninges Metabolism: liver, cleared renally Renal adjustment necessary Resistance due to mutations in pncA gene Toxicity: Hyperuricemia-gout; Hepatotoxicity; GI disturbance
Minimum Inhibitory Concentration (MIC)
Lowest amt. of drug needed to suppress the growth of an organism If a lot of med. needed, org. is somewhat resistance & vice versa Less than 16-susceptible
Pharmacology of antibiotics
Time-Dependent: Have to stay above MIC for as long as possible; needs frequent dosage Concentration-dep: Does NOT depend on frequency or time that conc. is above MIC High doses given at one time & kills bacteria Less frequent dosage Combo: best predictor- AUC/MIC -area under inhibitory curve
Ring structure common to different categories Includes: Penicillins, Cephalosporins, Monobactams, Carbapenems MOA: Inhibits synthesis of bacterial cell wall by inhibiting enzymes that crosslink peptidoglycan = weak cell wall = intolerance to osmotic pressure Enzymes are also called penicillin-binding proteins (PBP) Gram + has lots of PG; Gram - has some PG; penicillin works on both Spectrum: Varies depending on beta lactam DONT cover: atypical organisms (mycoplasma, chlamydia, legionella, rickettsia), MRSA Resistance: B-lactamase, PBP alteration (typical for gram +, eg S. pneumonia, MRSA), Drug doesn\'t reach destination (esp. gram - b/c outer membrane or porin change, eg Pseudomonas) Pharm: Time-dep., some well absorbed; others sensitive to acid; short half-life Elimination: renal, Probenecid blocks renal excretion & incr. penicillin levels Liver: Nafcillin, biliary excretion
Adverse effects to B-lactams
IgE-mediated allergic rxns, esp. w/ IV Skin test or history for dx Vomiting is NOT an allergic rxn Cross reactivity w/ other B-lactams- if allergic to penicillin, chance for other B-lactams Rxn: urticaria, angioedema Serum Sickness: Late allergic rxn, non-IgE, assoc. w/ circulating immune complexes Rash, fever, adenopathy, arthritis Presents 2-3 wks. after tx Dermatologic rxns: Other rashes, not necessarily IgE Stephens-Johnson: rash (mucosal surfaces), Itchy eyes, conjunctivitis, bleeding lesion in mouth, ulcers, genital lesions If milder rash: can sometimes treat through it
General adverse effects to antibiotics
GI-nausea, vomiting, diarrhea Liver- hepatitis, jaundice Hematologic- anemia, neutropenia, thrombocytopenia Renal- allergic interstitial nephritis (assoc. w/ methacillin), renal failure, eosinophils in urine, tx to stop medication CNS- seizures, confusion...
Classes of Beta Lactams
Penicillins: Natural: narrow spectrum (tx for strep throat & other streptococci, as well as syphilis), oral form not absorbed well but good for mild infection Penicillinase resistant penicillins: tx of choice against staph that is still susceptible to beta-lactams, not MRSA Includes: methicillin, nafcillin,oxacillin, dicloxacillin Extended spectrum penicillins: Aminopenicillins: ampicillin, amoxicillin- for resp. pathogens Carboxypenicillins: incr. activity against gram negatives Ureidopenicillins: Piperacillin Beta-lactamase inhibitors: combine w/ beta-lactam- recover some activity against anaerobes & gram negatives Ex: amoxicillin + clavulanate PO (Augmentin) NOT for MRSA
Four generations: 1: gram positive, skin & urine infections; Cefazolin, cephalexin 2: respiratory pathogens; Cefuroxime, Cefoxitin & cefotetan have incr. activity against anaerobes 3: Hospital (eg ceftriaxone, cefotaxime), broader activity for gram positives (less for staph), abdominal, resp, urinary infections; Ceftazidime active against pseudomonas Orally: cefpodoxime, cefixime 4: Broader than all; decent against gram + & -, no activity against abdominal anaerobes Used in neutropenia & hospital acquired infections from resistance Reactive against Pseudomonas
Very broad spectrum: gram +, gram -, anaerobes Used as last resort Ex: imipenem, meropenem, doripenem, ertapenem Imipenem given w/ cilastatin- prevents inactivation by kidneys (alone, imipenem won\'t work; causes renal toxicity)
Aztreonam is only one Active against: gram - aerobic orgnaisms Only B-lactam for patient w/ IgE-mediated allergic reaction to other beta lactam
Glycopeptide MOA: Blocks cell wall synthesis by inhibiting synthesis of PG chains by binding murain monomers Spectrum: Gram + bacteria, MRSA, C. difficile, allergy to penicillin Mechanisms of resistance: modification of cell wall precursors = loss of binding & antibacterial activity NO cross resistance w/ B-lactams Pharm: Activity- area under curve AUC/MIC, minimal oral absorption (give IV, except C. diff. b/c need high conc. in gut) Half-life: 6 hrs. Limited tissue penetration due to size Excretion: kidneys (adjust for renal dysfunction) Monitor trough levels; modify does to remain therapeutic Adverse effects: RED MAN SYNDROME- flushing, pruritus, rash secondary to histamine release (Not IgE)-- due to rate of giving drug NOT concentration; Allergy: rare, causes different rxn w/ edema; Hematologic: leukopenia, thrombocytopenia; Renal probs; Ototoxicity- hearing & balance
Cyclic lipopeptide Large molecule MOA: Binds bacterial cell membr. & creates transmemb. channels; electrolytes flow out of cell through membranes =depol. that leads to inhibition of RNA, DNA & protein synthesis Bactericidal Req. Ca+2 Spectrum: Gram + aerobic orgs., MRSA Also some vancomycin-resistant orgs. like VRE Indications: skin infections, MRSA, VRE NOT for pneumonia b/c de-activated by lung surfactant Mechanisms of resistance: not understood, rare Pharm: concentration, dosage not frequent, only IV, renal elimination Adversity: Nausea, vomiting, diarrhea, rash, muscle toxicity (myopathy) = pain, weakness, elevation of muscle enzymes, peripheral neuropathy
Linezolid- oxazolidinone
MOA: blocks protein synthesis by binding to 50S ribosomal subunit near interface w/ 30S = no 70S Bacteriostatic except w/ pneumococcus (bactericidal) Spectrum: gram +, some atypical bacteria like mycoplasma Also covers: VRE, MRSA Indication: skin infection, pneumonia Mechanism of resistance: Mutation in gene for 23S ribosomal RNA of 50S subunit, no cross resistance Pharm: time-dep.. half-life of 5 hrs, good bioavailability (given orally and barring GI prob, get good bl. levels) Elimination: renal & non-renal; no adjustment needed Adversity: Nausea, vomiting, diarrhea, headache Unique adversities: After 2 wks- anemia, thrombocytopenia, some bone marrow toxicity Optic neuritis, peripheral neuropathy, lactic acidosis Serotonin syndrome: seen when combined w/ med w/ serotonin acitivty- lethality, or fever, tremor, delirium
Nitroimidazole MOA: Inhibits DNA synthesis; toxic against anaerobic bacteria due to presence of ferrodoxins in these bacteria (ferrodoxins donate electrons to metronidazole, creating highly reactive free radicals which damage bacterial DNA & other macromolecules Bactericidal Spectrum: anaerobes, activity against non-bacterial organisms such as protozoa- Trichomonas, Giardia, Entamoeba Indication: interabdominal infections, some protozoa Mechanisms of resistance: rare; altered ferredoxins Pharm: Conc.-dep., good bioavailability, good tissue distribution Elimination: liver (reduce w/ liver disease) Adversity: Gi effects, metallic taste Disulfiram (Antabuse) effect- terrible effects w/ alcohol; side effects: flushing, tachycardia, palpitations, nausea, vomiting Rash CNS toxicity

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