PHAR 6124

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:

Gram positive

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

Beta-lactamases

Penicillins

Penicillinases

Fluoroquinolones

DNA gyrase alteration

TMP/SMX

Metabolic bypass (folic acid)

Vancomycin

Metabolic bypass

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

PBP-2

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:

Acquired

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:

Cimetidine/rifampin

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!!!