The following objectives are intended to be used as a general guide for focusing your studying for the midquarter examination. This is not all-inclusive but can be used as a general reference. Supplemental study guide materials may be distributed later in the course to augment this guide. Please remember that you are responsible for mechanisms of action and resistance covered in-depth in Dr. Remmel's class. This study guide is NOT intended to replace your notes, readings, lecture handouts. The purpose of this study guide is to assist you in focusing your studying efforts only. PHARMACODYNAMICS Understand: | Pharmacokinetics vs. Pharmacodynamics | | Concentration-dependent killing vs. concentration-independent killing | | Know which drugs are concentration-dependent killers and concentration-independent killers | | MICs, MBCs, SITs, SBTs | | Bacteriostatic | | Bactericidal | | Tolerance | | Synergy | | Antagonism | | Importance of pharmacodynamic outcome predictors (best predictors for each antibiotic class) | AMINOGLYCOSIDES Gentamicin, Tobramycin, Amikacin, Streptomycin | Concentration-dependent killing | | Conventional dosing | | Single daily dosing (rationale, Hartford Nomogram) | | Know average half-life (approx. 2 hours), volume of distribution (0.25-0.35 L/kg) | | Understand peak and trough levels (what levels are you trying to achieve) | | Post-antibiotic effect | | Toxicity: ototoxicity, nephrotoxicity | | Complete computer tutorial modules 1 and 2 | Dosing: | | Conventional dosing | | | Single daily dosing | | Pharmacokinetics: | | Know how to calculate: | | LBW, dosing weight | | | Creatinine clearance | | | | Know how to determine: | | Predicted half-life based on population based data | | | Determine appropriate starting dose, regimen for a patient | | | | Aminoglycoside levels: | | Understand significance of 1st dose levels, 2nd dose levels, and steady-state levels | | | Using logarithmic graph paper, determine patient-specific half-life | | | Determine other patient-specific parameters: volume of distribution | | | Recommend new dose, regimen based on desired peak/trough levels and patient data | | | | Complete modules (AGI, AGII, AG kinetics tutorial, AG study guide, AG study guide 2) | | MICROBIOLOGY Understand chemical tests used to identify organisms: | Catalase | | Coagulase | | Indole | | Glucose fermentation | | Bile-Esculin test | | 6.5% sodium chloride | | Oxidase test | Understand: | | E test | | | MIC/MBC testing | | | Exponential growth (bacterial curve growth) | | | Stationary growth | Gram Positive: | | Understand/Memorize flow chart | | Aerobic/anaerobic/facultative | | | Cocci: Staphylococcus, Streptococcus, Enterococcus | | | Bacilli: Listeria, Clostridium | | | Differentiate types of hemolysis | | Gram Negative: | | Understand/memorize flow chart | | Aerobic/anaerobic/facultative | | | Cocci: Neisseria, Moraxella | | | Bacilli: Enterobacteriaceae group, Pseudomonas, Helicobacter pylori, Stenotrophomonas | | | | Complete microbiology module | VANCOMYCIN Understand: | | Spectrum: | | | Pharmacokinetics: | | No oral absorption | | | Expected half-life | | | Volume of distribution | | | Elimination: renal | | | Concentration independent killer | | | Biexponential decay | | | One compartment vs. multicompartment modeling | | | | Pharmacodynamics: | | Bactericidal/bacteriostatic | | | Synergy with aminoglycosides/rifampin | | | | Appropriate use: (CDC recommendations) | | MRSA/MRSE (present or suspected) | | | PCN allergy | | | PCN-resistant Strep. pneumoniae | | | | Adverse Effects: | | Nephrotoxicity | | | Ototoxicity | | | Phlebitis | | | Red Man Syndrome | | | | Dosing/Monitoring: | | 10 mg/kg/dose (interval based on renal function) | | | Peak/trough levels: | | Usually only monitor trough levels (5 to 10 mcg/mL) | | | | Dosing in renal dysfunction/failure (increased half-life) | | | CDP controversy | | | | Resistance: | | Vancomycin resistance enterococcus (VRE) | | | Plasmid mediated | | | Transfer to Staphylococcus (VISA/GISA) | | | (See BACTERIAL RESISTANCE Lecture) | | | | Complete vancomycin module | BACTERIAL RESISTANCE Understand: | | Different mechanisms of resistance | | Influx alterations: porin channel modification | | | Environmental changes | | | Transport changes | | | Enzyme production: beta-lactamases | | | Chromosomal vs. plasmid mediated | | | Target alteration: penicillin binding alteration | | | | Beta-Lactamases: | | Mechanism of resistance | | | Chromosomally mediated, plasmid mediated | | | Induction: What organisms can be induced to produce beta-lactamases | | | Classification schemes: Richmond Sykes (esp. Type I/Type IIIs) | | H. influenzae: beta-lactamase producers (> 90%) | | | Moraxella catarrhalis: beta-lactamase producers (> 90%) | | | | | Specific Antibiotic Destruction: | | Aminoglycosides | | Adenylation/Acetylation/Phosphorylation | | | | Macrolides | | 50s ribosome alteration | | | Resistance to one, means resistance to all | | | | Cephalosporins | | | Penicillins | | | Fluoroquinolones | | | TMP/SMX | | Metabolic bypass (folic acid) | | | | Vancomycin | | | | Penicillin binding alteration: | | PCN resistance Strep. pneumoniae | | Sensitive MIC less than or equal to 0.6 mg/L/ Nonsusceptible MIC 0.12 to 1.0 mg/L/Resistant greater than or equal to 2mg/L | | | Prevalence | | | Drugs of choice based on sensitivities | | | | MRSA/MRSE | | | | Enterococcus: | | Mechanisms of resistance: | | PBP (approx. 98%) | | | Tolerance | | | Beta-lactamase production: PCN resistance (approx. 2%) | | | High level gentamicin, streptomycin resistance | | | Vancomycin resistance (alteration of amino acid) | | E. faecium > (vanco/ampicillin) resistance than E. faecalis | | | Van A, Van B, Van C | | Van A: high level resistance vanco/teicoplanin; transferable/inducible/transposon | | | Van B: Moderate vanco resistance/susceptible teicoplanin; Chromosomal/transferable | | | Van C: Low level resistance vanco/susceptible teicoplanin | | | | | Therapeutic options based on mode of resistance | | | H. fluenzae | | Mechanisms of resistance | | | Prevalence | | | | M. catarrhalis | | Mechanisms of resistance | | | Prevalence | | | | MACROLIDES (not lectured on, but may be included in the midquarter) (Erythromycin, Azithromycin, Clarithromycin, Dirithromycin, Roxithromycin) Understand: | | Spectrum: Strep/H. flu/M. catarrhalis/H. pylori/Gr. A. Strep/Chlamydia/Legionella/Mycoplasma/ Mycobacterium | | | Mechanism of action: binds 50s ribosome | | | Bacteriostatic antibiotics | | | Good intracellular/tissue penetration | | | Antimicrobial action: pH sensitive | | | Concentration dependent/independent ?? | | | Difference between products: dosing/side effects/half-lives/drug interactions | Resistance: | | Gram positive: | | Methylates 23S of the 50S ribosome | | | | Gram negative: | | Unable to penetrate cell wall | | Erythromycin: | | T1/2: 2 hours | | | Intravenous product: Lactobionate | | Side effects: QTc prolongation, Torsades des pointes | | | | Oral products: | | Acid labile: food effects absorption | | | High GI side effects | | | Use (only) erythromycin base in pregnancy | | Clarithromycin: | | Metabolized to 14-OH clarithromycin (active) | | | Take with food | | | T1/2 2.5 to 6 hours | | | H. pylori treatment | | | MAC prophylaxis | Azithromycin: | | Large volume of distribution, good tissue penetration, low serum levels | | | Food inhibits absorption | | | Used in treatment of C. trachomatis (1gm x 1) | | | T1/2: 11 to 60 hours | | | Fewer GI side effects | | | MAC prophylaxis | KNOW DRUG INTERACTIONS *Also responsible for all antibiotics listed under the background expectations section of the syllabus* QUINOLONES Ciprofloxacin, Ofloxacin, Levofloxacin, Sparfloxacin, Trovafloxacin, Norfloxacin, Moxifloxacin, Gatifloxacin, Clinafloxacin, Gemifloxacin, Sitafloxacin Understand: | | Spectrum: BROAD (depends on product): gram positive, gram negative (pseudomonas), anaerobic (new products: trovafloxacin) | | | Mechanism of action: inhibits DNA gyrase | | | PO = IV | | | Bactericidal antibiotics (active both stationary/exponential growth) | | | Good intracellular/tissue penetration | | | Concentration dependent: Proven for gram negative infections | | | Outcome predictors: AUC/MIC ratios, break point: 100-125 | | | Pharmacokinetics: Large Vd, long T1/2 (BID or QD dosing), low protein binding | | | Difference between products: dosing/side effects/half-lives/drug interactions/spectrums | | | Difference between old products and advanced generation products with regards to coverage, characteristics, and uses | | | Higher cost in comparison to Bactrim/macrolides/PCNs | New Products/Advanced Generation: | | Recently approved, QD dosing, broad spectrum, URTIs, UTIs, skin/soft tissue infections | | | Marketed for upper respiratory tract infections/community-acquired pneumonia | | | Trovafloxacin/Grepafloxacin/Sparfloxacin/Levofloxacin | | | Moxifloxacin/Gatifloxacin/Clinafloxacin/Gemifloxacin/Sitafloxacin | | | More potent against gram-positive pathogens | Resistance: | | PCN-resistance Strep. pneumoniae | | Cipro is not useful | | | New products with marked activity | | | | Target alteration | | DNA gyrase alteration | | | Topo IV alteration | | | Understand 1-step/2-step mutations and consequences | | Adverse Reactions: | | Depends on product | | | Drug/food/drug interactions (many): | | Theophylline: interferes drug metabolism | | | Trovafloxacin & morphine | | | Interferes quinolone absorption: sucralfate, antacids | | | | Phototoxicity: (esp. sparfloxacin, ciprofloxacin) | | | Prolongation QTc interval (understand significance) | | | Anthropathy: animal model (use in children when benefits outweigh risks, most agents currently seeking pediatric indication) | | | Tendon rupture | ANTIFUNGALS (Amphotericin B, Liposomal Amphotericin B, Nystatin, Griseofulvin, Terbinafine, Flucytosine) Azoles (Ketoconazole, Fluconazole, Itraconazole) Amphotericin B | | Mechanism of action: | | pH dependent: fungicidal/fungistatic | | | Binds cell membrane ergosterol: affinity > fungus vs. host | | | | Resistance: | | | Pharmacokinetics: | | Highly protein bound: 91-95% | | | T1/2 - 15 days | | | Renal elimination | | | High tissue binding, low CSF | | | | Adverse effects: | | Nephrotoxicity: increase SCr, K, Mg wasting | | Sodium Loading: | | 500 mL NS prior/after dose | | | | Every other day dosing | | | | Hypo- potassium/magnesium (monitor) | | | Anemia | | | Fever/chills/nausea/vomiting/thrombophlebitis | | Pre-medicate to avoid SEs | | Acetaminophen or aspirin/hydrocortisone or benadryl/meperidine | | | | | | Drug interactions: cyclosporin, aminoglycosides, antineoplastic agents | | | Clinical uses: | | Effective against most fungal pathogens: except Pseudoallescheria boydii | | | Limited activity: Trichosporin beigellei, Fusarium, Actinomyces, Mucorales | | | Candidiasis: invasive, systemic infections | | | Cryptococcal meningitis: drug of choice | | | | Bladder irrigation: continuous/intermittent | | | Dosing: | | Test dose? (do not premedicate) | | | 0.5 to 1 mg/kg IV QD (infuse over 60 min, unless renal dysfunction the 4 to 6 hrs) | | | Liposomal may decrease renal toxicity | | Flucytosine (5-FC): | | Mechanism of action: Inhibits DNA synthesis | | | Resistance: | | Loss/mutation of enzymes | | | Occurs frequently when used as monotherapy (Candida spp) | | | | Adverse effects: | | Concentration-dependent: bone marrow suppression | | | Nausea/vomiting/diarrhea/increased hepatic transaminases | | | Monitor: renal function, hematology, LFT's | | | | Clinical uses: Use only in COMBO with Ampho B | | Cryptococcus, Candida, Aspergillis | | | | Dosing: 100-150 mg/kg/day PO q6h, ADJUST BASED ON RENAL FUNCTION | AZOLES: | Ketoconazole | Fluconazole | Itraconazole | | PO pH dependent Protein binding > 90% Hepatic metabolism Reports of resistance Adverse effects: -N/V -Hepatotoxicity -Inhibits testosterone synthesis Clinical Uses: -Mucosal Candidiasis Histoplasmosis Blastomycoses Paracoccidiomycosis Dosing: 800mg/d po - serious 200-400mg/d | PO & IV Protein binding low Renally eliminated CSF penetration Absorption not dependent on food/pH Reports of resistance Adverse effects: -N/V -Rash -Increased transaminases Clinical Uses: -Candidiasis: (mucosal/ vulvovaginal/ systemic/ invasive) -C. krusei, C. glabrata Blastomycosis Histoplasmosis Aspergillosis Dosing: 100-200mg/d 400mg/d serious infections Adjust based on renal function | PO & IV Protein binding > 90% Hepatic metabolism pH dependent (improved w food) Adverse effects: -N/V -Increased transaminases -Hypokalemia Clinical Uses: -Blastomycosis -Candida -Hidtoplasmosis -Aspergillosis -Coccidiomycosis -Sporothrichosis Dosing: -600mg /d x 3, then 100-200/qd-bid (serious) No renal adjustment | | | Drug interactions: | | All inhibit P450IIIA4 enzyme: Ketoconazole > Itraconazole > Fluconazole | | | Many drug interactions (SEE ANTIFUNGAL lecture) | | Terbinafine: | | Mechanism of action: inhibits fungal squalene epoxidase | | | May be more effective than azoles in treatment toe/nail infections | | | Pharmacokinetics: | | Hepatic metabolism/renal elimination | | | Not affected by food | | | Large Vd - lipophilic | | | T1/2 at steady-state 10-14 days | | | | Dosing: | | 250 mg/d 6 weeks fingernail | | | 250 mg/d 12 weeks toenail | | | | Adverse effects: | | No interference with testosterone/cortisol production | | | N/V | | | | Drug interactions: | | | Understand: | | Prophylaxis of candidal infections in neutropenic patients | | | Prophylaxis of opportunistic infections in patients with AIDS | | | Risk factors for serious candidal infections | | STAPHYLOCOCCUS | | Understand: | | Staphylococci infections | | | Pathogenesis | | | Catalase positive: S. aureus | | | Coagulase negative: S. epidermidis, S. saprophyticus and S. haemolyticus | | | Colonization | | | Sites of infection: soft tissue/GI/prosthetic devices/osteomyelitis/bacteremia/ surgical wound | | | Toxins: Alpha, Beta, Delta, Gamma, TSST-1, Enterotoxin A, B, C | | | | Resistance: | | Methicillin-sensitive Staph. aureus (MSSA) | | | MRSE (40-80%) prosthetic devices/MRSA (2-20%): alteration PBP2 | | | Vancomycin-resistance: S. haemolyticus common, S. aureus recently reported GISA/CDC guidelines for prevention and control of GISA | | | | Treatment: | | S. aureus: | | Vancomycin vs. nafcillin (endocarditis) | | Vancomycin slower killer up to 7 days to sterilize blood, approx. 3 days for nafcillin | | | Use nafcillin if no PCN allergy | | | | Synercid (Quinupristin & Dalfopristin) synergistic effects (alternative treatment) | | | Adjunct therapy (Rifampin, Gentamicin) | | | ENTEROCOCCUS | | Understand: | | Pathogenesis | | | Enterococcal infections (endocarditis, UTI, bacteremia) | | | | Resistance: | | VRE | | Mechanism of resistance (VanA, VanB, VanC) | | | Risk factors | | | Treatment | | | | Beta-lactam and aminoglycoside resistance | | Mechanism of resistance | | | Treatment | | | | | Therapy: | | Synercid | | Spectrum (E. faecium, not faecalis) | | | MOA | | | Adverse reactions | | | | Linezolid | | Oxazolidinone class | | | MOA | | | Spectrum (MRSA, MRSE, PCN-R S. pneumo, VRE, Enterococcus species) | | | RESPIRATORY TRACT INFECTIONS Epidemiology •Majority of respiratory tract infections have viral etiology •A leading cause of death and major cause of morbidity in US •Major cause of death from infectious diseases (50,000 to 60,000 deaths / year) in the US Pharyngitis, Sinusitis, Acute Otitis Media, and Bronchitis Understand Principles of judicious antibiotic use Etiology Clinical presentation Diagnostic criteria Treatment Know Pneumonia Definitions Nosocomial pneumonia: acquired in the hospital after 72 hours Community- acquired pneumonia: colonization occurs outside hospital or prior to admit Understand treatment recommendations provided by the various organizations Clinical Presentation •elevated WBC with left shift may signify bacterial pneumonia •relies on clinical findings of fever, cough, and rhonchi, together with a new infiltrate on chest films and documentation of pathogen Causative Organisms Bacterial/ Typical •'typical' generally refers to extracellular organisms •Streptococcus pneumoniae and Haemophilus influenzae are most common organisms in community acquired- pneumonia •Pseudomonas aeruginosa common cause of nosocomial pneumonia Atypical 'atypical' generally refers to intracellular organisms Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella species Know how to identify and recommend DOC and alternative therapy for common pathogens (i.e. smokers - H. influenzae; aspiration - anaerobes) Streptococcus pneumoniae •aerobic, gram-positive coccus in pairs •causes >70% of all pneumonias in the US •36% non-susceptible to penicillin DOC: Penicillin (based on susceptibilities) Alternatives: macrolides, newer fluoroquinolones, cephalosporins, clindamycin, TMP/SMZ Haemophilus influenzae •gram negative, small pleomorphic coccobacillus •nonencapsulated strain causes pneumonia- not covered by vaccine •encapsulated strain causes invasive meningitis and septic arthritis DOC: cefotaxime or ceftriaxone Alternatives: TMP/SMX, cefuroxime, amoxicillin/ clavulanate (Augmentin) Pseudomonas •cause of nosocomial pneumonia •aerobic, gram negative rod •mortality 50-70% DOC: Anti-pseudomonal PCN (piperacillin) plus aminoglycoside (tobramycin, etc) Alternatives:ceftazidime, ciprofloxacin *You are also responsible for the heuristics and background expectations. DONT FORGET!!* GOOD LUCK!!! |