Pharmacotherapeutics V Exam I

Principles of Infectious Diseases, Pharmacology & Antibiotic Coverage, Antifungal Pharmacology, and Antifungal Clinical

Infection

Invasion of an organism’s body tissues by disease-causing agents, their multiplication, and the reaction of host tissues to these organisms/toxins

Caused by viruses, prions, bacteria, parasites, fungi, etc.

Transmitted via physical contact with an infected individual ot their body fluid, contaminated food or water or by touching contaminated objects

Normal flora

represents bacteria colonized in areas of the human body

patients with a history of recent antimicrobial use may have this altered

prophylactic or preventative indications

prevent initial infection or its recurrence after infection

limited to patients at high risk of developing infection

immunosuppressed patients, surgical prophylaxis, etc.

primary or secondary infection

empiric therapy indications

infecting organism(s) not yet identified

more “broad spectrum” (i.e. covers more pathogens)

based on data and public health trends → we know the most common cause of pneumonia so we can treat before we know the bacteria and then change

definitive therapy indications

organism(s) identified and specific therapy shosen

more “narrow spectrum” (i.e. covers less pathogens)

specific to the pathogen identified in the patient

colonization

the presence of organisms that are not causing disease

a.

already collected sample (start therapy to likey cover) and not not know what bacteria is causing

JJ is admitted to the hospital with a urinary tract infection. The doctor has collected a clean-catch urine sample. Which of the following type of therapy is good to initiate for JJ?

a. empiric therapy

b definitive therapy

c. prophylactic therapy

d. no therapy is needed

selecting antibiotics

3 things to think about patient, pathogen, and drug

we usually do not know the pathogen right away

• it takes 2-3 days for cultures to finalize

• need to treat empirically and adjust once the pathogen is identified

empiric regimens

are identified based on known information about the infection source

antibiogram

susceptibility rates in a given institution

used to guide empirical therapy

confirm the presence of infection

careful history and physical examination

signs and symptoms

predisposing factors

identify the pathogen

collect infected material

gram stain

culture and sensitivity

select empiric therapy

host factors

drug factors

monitor the therapeutic response

clinical assessment

laboratory test

assessment of therapeutic failure

presence of infection

fever

elevated WBC (greater than 10)

local signs: swelling, erythema, tenderess, purulent drainage, etc.

patient complaints: headache, chest pain, burning while urinating, etc.

avoid using antibiotics when they are not needed (i.e. self-limited conditions or viral infections)

host factors

drug allergies

age

pregnancy

genetic concerns

renal & hepatic function

concomitant drug therapy

underlying disease states

drug factors

pharmacokinetic & pharmacodynamic considerations

tissue penetration & site of infection

drug toxicity

adverse effects

cost and availability

combination antimicrobial therapy

resistance

drug allergies

confirm true allergy over adverse effects → all medications

age

determines the patient’s ability to renally eliminate the medication

neonatal concerns

pregnancy

fetal risk

altered pharmacokinetic disposition of certain medications → all the time or during certain timersters

breastfeeding

genetic or metabolic abnormalities

glucose-6-phosphate dehydrogenase deficiency

HLA-B genes

renal & hepatic functions

reduced function can lead to drug accumulation

concomitant drug therapy/underlying disease states

drug-drug interactions

trauma/burns, immunosuppression, diabetes

time-dependent killing

keep the drug concentration above the MIC for as long as possible

dosing strategies: shorter dosing interval, extended or continuous infusion

real world example: extended infusion piperacillin-tazobactam

concentration dependent

achieve as high of a peak as possible while avoiding drug reactions

dosing strategies: large doses, long intervals

real world example: extended interval aminoglycoside dosing

AUC:MIC

achieve maximum exposure over time

dosing strategies: variable

real world example: AUC:MIC based vancomycin dosing

post antibiotic effect

period where the antibiotic is still killing bacteria AFTER the concentration has dropped below the MIC

real world example: extended interval aminoglycoside dosing

bactericidal

kill bacteria

tend to work on the bacterial cell wall or membrane

preferred for serious infections (i.e. endocarditis, meningitis, osteomyelitis, neutropenic infections)

bacteriostatic

inhibit bacterial growth

tend to work on bacterial ribosomes and protein synthesis

bioavailability

percentage of orally administered drug that enters the bloodstream relative to an IV formulation fot he same drug

IV=100%

food, gastric acidity, and chelating agents can also influence absorption

tissue penetration

concerning for cerebrospinal fluid (CSF), urine, synovial fluid, peritoneal fluid, and abscesses

parenteral therapy preferred for more serious infections (i.e. meningitis, endocarditis, osteomyelitis)

patients treated in the ambulatory setting generally receive oral therapy

advantages of combining antibiotics

broadens the spectrum of coverage

useful for synergy (example: beta-lactam plus aminoglycoside for endocarditis)

disadvantages of combining antibiotics

increases side effects

increased risk of resistance

increased cost

monitoring for adverse drug reactions

side effects

lab work

vitals

monitoring therapeutic response

review culture and sensitivity reports

temperature (i.e. fever resolves)

WBC trending down and normalizes

renal/hepatic function

symptom improvement

therapeutic drug monitoring → vancomycin, aminoglycosides, etc.

causes of therapeutic failure in infection

non-bacterial

causes of therapeutic failure in drug

not susceptible

does not penetrate site of infection

inadequate does

noncompliance/missed doses

drug interactions

causes of therapeutic failure in host

immunosuppression

inadequate vascular supply to site of infection

peripheral vascular disease, necrotic tissue

causes of therapeutic failure in organism

pre-existing resistance

polymicrobial pathogens

development of resistance on therapy

causes of therapeutic failure in inadequate source control

undrained abscess

biofilm on foreign body

causes of therapeutic failure in laboratory error

identification error

incorrect susceptibility results

immunodeficiency

condition where the body’s immune system is weakened, making it harder to fight off infections and other disease states (i.e. cancer)

causes of immunodeficiency

medications that suppress the immune system → transplant, steroids, cancer therapies, biologics

cancer

congenital disorders

malnutrition

diabetes

consideration of IV to PO medication

clinical improvement

afebrile (not feverish) >24 hours

WBC and other labs improving

functioning GI tract

determine full length of treatment → IV and oral should add to the total length

transition from broad spectrum to narrow spectrum

goals of antimicrobial stewardship

improve patient safety and outcomes

curb resistance

reduce adverse effects

promote cost effectiveness

interventions of antimicrobial stewardship

pharmacokinetic monitoring of aminoglycosides and vancomycin to optimize doses and minimize toxicity

rapid identification of pathogens, shortening time to start effective treatment

preauthorization of select antimicrobials

timely transition from IV to PO (usually transition is from broad to more narrow)

Prevent resistance

First dose of antibiotic kills most of the pathogens

Some pathogens can hang around for a little bit

If pathogens are left behind, they can develop resistance to the antibiotic

Why do we finish all antibiotic therapy? (even if we feel better)

antibiotics usually causes an upset stomach

can impact absorption if an empty stomach is needed

Why do we take antibiotics with food?

a.

MB is a 68 year old female with a past medical history of diabetes and hypertension who is admitted to the hospital with osteomyelitis of the left foot. The team draws blood cultures in the ED and wants to start the patient on therapy right away. What therapy should be initiated at this time?

a. empiric therapy

b. definitive therapy

c. prophylactic therapy

d. colonization therapy

e. none of the above

b.

MB is a 68 year old female with a past medical history of diabetes and hypertension who is admitted to the hospital with osteomyelitis of the left foot. The patient has been receiving ampicillin/sulbactam for 3 days. The bone culture results are listed below. What therapy should be initiated at this time?

a. empiric therapy

b. definitive therapy

c. prophylactic therapy

d. colonization therapy

e. none of the above

a.

Refer to the following culture report.

What sort of pathogen is Staphylococcus aureus?

a. gram positive cocci

b. gram negative rod

c. anaerobe

d. atypical pathogen

a.

b.

d.

e.

Which of the following are host (patient) factors that need to be considered when selecting antibiotics for infections? Select all that apply.

a. drug alleries

b. renal dysfunction

c. tissue penetration

d. drug internations

e. pregnancy

f. resistance

c.

JB is being treated for a urinary tract infection in the hospital and has received 3 days worth of IV Ceftriaxone. The plan is to treat the urinary tract infection for a total of 7 days. The patient is evaluated and appears to be improving. The medical team plans for discharge today. How many additional days of oral cefdinir should the patient receive to complete treatment for the urinary tract infection.

a. 2 more days

b. 3 more days

c. 4 more days

d. 5 more days

capsule and glycocalyx (polysaccharides or hyaluronic acid)

causes protection from desiccation (drying), attachment to surfaces

cell wall

peptidoglycans made of N-acetyl muramic acid and N-acetyl glucosamine crosslinked with tetrapeptides

it is porous to allow nutrients and water flow

peptide contains glutamate, alamine, and lysine

different in gram (-) and gram (+) bacteria

• gram (+) is thicker causing a purple color upon staining due to stain not being able to leave

cell membrane

can be a drug target or barrier to drug penetration

gram (-) has 2

gram (+) has 1

genetic material and ribosomes

major drug target

gram-negative bacteria

3 components outside the peptidoglycan layer

1. lipopolysaccharide (LPS): a.k.a endotoxin

2. external membrane (phospholipid) → second cell membrane

3. periplasm

gram-positive bacteria

no lipopolysaccharide, external membrane, or periplasm

much thicker peptidoglycan layer

list of gram-negative bacteria

Enterobacteriaceae

Escherichia coli

Helicobacter

Haemophilus

Klebsiella

Legionella

Neisseria

Pseudomonas

Salmonella

Shigella

Vibrio

Brucella

Acinetobacter

list of gram-positive bacteria

Cocci

• staphylococcus aureus

• streptococcus pyogenes

• streptococcus pneumonia

• streptococcus viridans

Bacilli

• Corynebacterium

• Listeria

• Bacillus

DNA/RNA Inhinitors

Quinolones (DNA gyrase, topoisomerase IV)

Metronidazole, tinidazole

Rifampin

Cell Membrane Inhibitors

Polymyxins

Daptomycin

Telavancin

Oritavancin

Protein Synthesis Inhibitors

Aminoglycosides

Macrolides (erythromycin, azithromycin, and clarithromycin)

Tetracyclines

Clindamycin

Linezolid, tedizolid

Quinupristin/Dalfopristin

if cells cannot produce RNA, they die

Cell Wall Inhibitors

Beta-lactams (penicillins, cephalosporins, carbapenems)

Monobactams (aztreonam)

Vancomycin, dalbavancin, telavancin, oritavancin

Folic Acid Synthesis Inhibitors (DNA Synthase Inhibitors)

Sulfonamides

Trimethoprim → often combined with sulfamethoxazole to overcome resistance

Dapsone

class of beta-lactams

penicillins

cephalosporins

carbapenems

aztreonam (Azactam) → stand alone (only one in class)

side effects of beta-lactams

Hypersensitivity reactions - ranging from mild rashes to drug fever and interstitial nephritis

central nervous system issues (confusion, dizziness, seizures at high concentration, etc.)

GI upset, diarrhea

drug interactions of beta-lactams

probenecid increases drug concentration by interfering with renal excretion

can enhance the anticoagulant effect of Warfarin by inhibiting the production of vitamin K-dependent clotting factors (except for Nafcillin and Dicloxacillin)

Most require renal dose adjustment

derivatives of β-lactam

all agents contain the β-lactam ring

spectrum of activity enhanced due to protection from β-lactamases

difference in route of administration and cost

β-lactamases

bacterial enzymes that provide antibiotic resistance by breaking the beta-lactam ring in beta-lactam antibiotics

β-lactams overall major target

to block transpeptidation

Vancomycin and derivatives major target

block terminal alanine removal, which prevents transpeptidation

Fosfomycin major target

to block MurA, which prevents transpeptidation

Cycloserine major target

to block Alr and Ddl, which prevents transpeptidation

Bacitracins major target

to block C55-PP (bactoprenol pyrophosphate), which prevents transpeptidation

β-lactams mechanism of action

prevents the cross-linking peptides from binging to the retrapeptide side-chains

inhibit the enzyme of penicillin-binding protein/PBP that crosslinks peptide chains

the cell wall starts to lyse (disintegrate) itself, destroying the bacterium (bactericidal)

however if the cell wall is already created there is nothing the antibiotic can do → used to prevent not remove

4 major β-lactam resistance mechanisms

1. destruction of the β-lactam by β-lactamases

2. modification of penicillin binding proteins (PBP) to reduce affinity of the drug for the target

3. impaired penetration of drug to the bacterium (a gram (-) issue)

4. antibiotic efflux out of the bacterial cell (a gram (-) issue)

β-lactamase inhibitors

stop bacteria from deactivating the antibiotic with their enzymes

are not administered alone, and must be given with a β-lactam drug

cannot be mixed with any random β-lactam drug, but are combined with drugs that are sensitive to the β-lactamase of targeting

EX: clavulanic acid (clavulanate) → narrow, sulbactam, tazobactam, avibactam, avibactam, and relebactam → broad and strong

Penicillin-Binding Protein (PBP)

the pharmacological target of β-lactams

the enzymes that catalyze the transpeptidation reaction

Modification:

• Staphylococci has caused methicillin resistance

• pneumococci and enterococci has caused penicillin resistance

impaired penetration of β-lactams

only in gram (-)

caused by the peptidoglycan layer where this class of drug work is covered by the lipopolysaccharide layer

porins are required for the class to enter the periplasmic space of the gram (-) bacteria

• proins can be downregulated

antibiotic efflux

membrane proteins that actively pump antibiotics and other toxic substances out of bacterial cells

only gram (-) bacteria exhibit this resistance

pumps in the outer membrane

β-lactams absorption

highly variable from drug to drug

• variability partly based on acid stability

• Nafcillin is not suitable for oral use due to highly erratic absorption

• Most penicillins have impaired absorption with food (except amoxicillin)

IM administration of penicillin G can cause pain, whereas IV is less bothersome

Penicillins vary in their protein binding (nafcillin > penicillin G or ampicillin), affects free drug concentration

β-lactams distribution

most distribute thoroughly into extracellular space in tissue throughout the body → do not go intracellular but can freely move throughout the body

do not accumulate in intracellular fluid owing to their hydrophilic nature

CNS penetration is poor for PCNs, except when the meninges are inflamed (bacterial meningitis)

Certain cephalosporins (cefotaxime, cefuroxime, and ceftriaxone) and aztreonam enter CSF without inflamed meninges

β-lactams excretion

most are highly renally eliminated, and dependent on renal secretion (transporters)

For PCN G, 90% of renal excretion is through tubular secretion

Nafcillin and ceftriaxone have substantial hepatic elimination compared to most

inhibitors do not affect half-life significantly

probenecid

a prescription medication primarily used to treat chronic gout and gouty arthritis by helping the body eliminate excess uric acid

used with Penicillin G (PCN G) to block its kidney excretion (OAT1 & OAT3 transporters), significantly increasing penicillin's blood levels and duration

Highly bound drugs will only exhibit rapid renal clearance if they have high affinity for renal organic anion transporters

What does plasma protein binding have to do with β-lactam elimination?

glomerulus

High binding β-lactam means poor filtration at the ______?

Only the unbound, or "free," drug can pass through the filtration barrier into the renal tubules. The glomerulus is a selective filter that is passive and acts by pressure control across capillary walls. Factors that determine what can pass through are based on size, charge, and its affinity for plasma proteins (albumin).

Why does high binding β-lactam means poor filtration at the glomerulus?

They are transported due to being lipophilic.

Despite high protein binding, these 3 drugs have short half-lives, Oxacillin, Flucloxacillin, and Dicloxacillin. Why?

Natural Penicillins

Penicillin VK (Pen VK) - PO

Penicillin G Benzathine/Penicillin G Procaine (Bicillin CR) - IM

Penicillin G Benzathine (Bicillin LA) - IM

Aqueous Penicillin G -IV

Pencilln VK

Pen VK generic name

Pen VK

Penicillin VK brand name

PO Natural Penicillins

Penicillin VK (Pen VK)

Bicillin CR

Penicillin G Benzathine/Penicillin G Procaine brand name

Penicillin G Benzathine/Penicillin G Procaine

Bicillin CR generic name

Bicillin LA

Penicillin G Benzathine brand name

Penicillin G Benzathine

Bicillin LA generic name

IM Natural Penicillins

Penicillin G Benzathine/Penicillin G Procaine (Bicillin CR)

Penicillin G Benzathine (Bicillin LA)

IV Natural Penicillins

Aqueous Penicillin G