Pharm Exam 2: Infectious disease Flashcards
Adverse effects
Emergence of resistance
Clostridioides (formerly Clostridium) difficile
Drug toxicity
Antibiotic targets
The cell wall
Bacterial protein synthesis
Bacterial DNA replication
Beta-Lactam Antibiotics
Method of Action
Bacteriocydal
Bacterial cell wall is comprised of peptidoglycan strands .
The final step in the synthesis of a bacterial cell wall is a cross-linking of peptidoglycan strands (transpeptidation).
Penicillin-binding protein (PBP) is the enzyme that catalyzes this step in the final stage of cell wall synthesis.
Beta-lactam antibiotics compete for this enzyme since they are similar in chemical structure to the pieces that form the peptidoglycan chain.
Beta-lactam antibiotics inhibit the growth of sensitive bacteria by inactivating enzymes located in the bacterial cell membrane, which are involved in the 3rd stage of cell wall synthesis.
Beta-Lactam
Antibiotics
Grouped together based upon a shared structural feature, the beta-lactam ring.
Beta-lactam antibiotics include: Penicillins Cephalosporins Cephamycins Carbapenems Monobactams Beta-lactamase inhibitors
Mechanism of resistance: production of enzymes that decrease penetration, alteration in PCN binding protein
Beta-Lactams:
Penicillins
Natural penicillins
Penicillin G (broad spectrum)
Penicillin VK
Aminopencillins (2nd gen - broad spectrum)
Ampicillin
Amoxicillin Penicillinase resistant
Dicloxacillin
Naficillin
Carboxypenicillins (3rd gen)
Ticaracillin
Ureidopenicillins (4th gen)
Piperacillin
Inhibit bacterial cell growth by interfering with cell wall synthesis. PCNs bind to and inactivate the penicillin-binding proteins (PBPs)
Sensitivity Natural penicillins: Streptococcus Enterococcus strains Some staphylococcus (non-penicillinase producing)
Aminopenicillins have greater activity against gram-negative bacteria due to enhanced ability to penetrate the outer membrane organisms.
Combination with beta-lactamase inhibitors to broaden their spectrum
Amoxicillin/clavulanate, ampicillin/sulbactam (+haemophilus influenzae)
Pipericillin/tazobactam(+pseudomonas aeruginosa)
Beta-Lactams: Penicillins
Pharmacokinetics
Well absorbed from GI tract, but several are unstable in acid: dicloxacillin, and amoxicillin better absorbed than ampicillin (give IV)
Highly protein bound with good distribution to most tissues
Small amount is metabolized, most excreted as unchanged drug in the urine
Dosing is based upon weight in the pediatric population
Short half life - multiple IV doses
Beta-Lactams: Penicillins
Adverse Reactions
Relative low incidence
Hypersensitivity reactions
IgE mediated hypersensitivity
Maculopapular rash/urticaria
Patients may be given desensitization therapy (time consuming)
GI: most common with oral administration
Loss of normal flora balance
Fungal overgrowth
C. difficile colitis
In rare cases, leukopenia, thrombocytopenia, and hemolytic anemia can occur with penicillin
Beta-Lactams: Penicillins
Clinical Use
Limited bc of resistance
Commonly prescribed for infections such as those of the upper and lower respiratory tract, urinary tract seen in primary care.
Used to treat CNS and infections and sexually transmitted diseases.
Amoxicillin is first line drug for acute otitis media and sinusitis
PCN for streptococcal pharyngitis
Amoxicillin/clavulanate (Augmentin) first line drug for infection following bites including human.
- choice for endocarditis (gram +)
Beta-Lactams: Penicillins Clinical Monitoring and Education
Monitoring
Return to office for evaluation of symptom relief
Acute care setting
May follow up if no symptom resolution
Patient Education
Resistance
ADR’s
Completing course
Beta-Lactam/Beta-Lactamase Inhibitors Information
Prevents the breakdown of the beta-lactam by organisms that produce the enzyme, thereby enhancing the antibacterial activity.
Examples Amoxicillin-clavulanic acid Ampicillin-sulbactam Piperacillin-tazobactam Ticarcillin-clavulanic acid
Because these drugs are eliminated by glomerular filtration, renal dysfunction necessitates dosage changes.
tx: intrabd, bites, foot infection (DM), lung abscessed
Beta-Lactams: Cephalosporins
Pharmacodynamics
Structurally and chemically similar to PCN’s. Interfere with bacterial cell wall synthesis by binding to and inactivating the PBPs.
First-generation (i.e. cefazolin and cephalexin)
- Used for skin and soft tissue infections
- Primarily active against gram-positive bacteria, S. aureus and S. epidermidis
Second-generation (i.e. cefaclor)
- Active against same as 1st generation, plus Klebsiella, Proteus, E. coli
Third-generation (ceftriaxone)
- Used for broader indications
- More active against gram-negative bacteria
Fourth-generation (i.e. cefipime, ceftazidime)
- Resistant to beta-lactamase
- Antipseudomonal
Fifth-generation (i.e. ceftaroline)
- Active against MRSA
Beta-lactam: Cephalosporins
Pharmacokinetics
Oral formulations absorbed from GI tract, enhanced by food
Widely distributed to most tissues
Some highly bound to proteins
Some are metabolized to less active compounds
Most excreted via kidneys, in various degrees as unchanged drug
Beta-Lactams: Cephalosporins
Clinical Use
Used for therapeutic failure in acute otitis media
Cellulitis, erysipelas
1st generation: Strep pharyngitis
Cephalexin, cefpodoxime, cefixime can be prescribed for UTI
Ceftriaxone and cefixime used for Gonococcal infection
Cefpodoxime, cefuroxime, or parenteral ceftriaxone for community-acquired pneumonia in combination with azithromycin for atypical coverage
Not for use in CNS bc don’t penetrate CNS
Tx: UTI, surgical prophylaxis, skin infections, Respiratory inf
Beta-lactam: Cephalosporins
Adverse Drug Reactions
Hypersensitivity reactions
* maculopapular rash, itching
3-10% cross reactivity between PCNs and cephalosporins
Transient GI effects
Fluoroquinolones
Pharmacodynamics-
THEY ARE BACTERICIDAL
- Floxacin
Interferes with bacterial enzymes required for the synthesis of bacterial DNA.
Inhibit two bacterial enzymes which have essential and distinct roles in DNA replication
Provides extensive gram-negative activity
Avoid in general pediatric population Tendon rupture (low risk) Exceptions exist
Avoid in Pregnancy/breast feeding
Increasing resistance due to overprescribing
Can no longer be used for GC
Resistant TB
Fluoroquinolones
Pharmacokinetics
Well absorbed, take on empty stomach for best absorption
Half life of 4 – 12 hours
Removed by dialysis
Excellent bioavailability
Fluoroquinolones
Clinical Use
Complicated UTI, pyelonephritis infections, chronic bacterial prostatitis
No longer effective in gonorrhea
Pneumonia/chronic bronchitis exacerbation
PCN resistant S. pneumoniae, skin infections, bone/joint infections, complicated intra-abdominal, infectious diarrhea, travelers diarrhea
Meningitis prophyxlaxis (ciprofloxacin)
Fluoroquinolones Adverse
Drug Reaction
Relatively low ADR profile
Black Box warning for tendonitis/tendon rupture
- Elderly at higher risk
- Can have delayed onset, 120 days to months after administration
Pseudomembranous colitis and transient GI effects
QTc prolongation (rare)
Do not prescribe to children < 18 yrs
Fluoroquinolones
Clinical Monitoring and Education
Monitoring
- Watch for prolonged use
- QT prolongation
- ECG in patients taking QT prolonging drugs (i.e. amiodarone)
Patient Education:
- Food delays absorption (concentration dependent killing)
- Many drug interactions
- Take with full glass of water
- May cause dizziness, palpitations, nervousness
- If tendon tenderness occurs stop medication and notify provider
Macrolides, Azalides, Ketolides Pharmacodynamics
Inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit.
Atypical organisms commonly resistant to beta-lactam antibiotics are often susceptible
Cross resistance seen to all in class
Well absorbed from the GI tract
Macrolides and Ketolides Pharmacokinetics Erythromycin Azithromycin Clarithromycin
Weak bases, activity increases in alkaline media, rapidly absorbed from duodenum
Exhibit enterohepatic recycling
- May contribute to GI side effects
- Tissue levels are higher than serum levels
Potent inhibitors of CYP 450 3A4
½ life for azithromycin: 50-72 hours
Macrolides and Ketolides
Clinical Use
Broad spectrum
First line option for outpatient community acquired pneumonia
+/- ceftriaxone for drug-resistant streptococci
Chlamydia
Pertussis
H. Pylori infections (clarithromycin)
Legionella
PNA and COPD: Combo med use with macrolide AND beta-lactamase inhibitior
Macrolides, Azalides, Ketolides
Adverse Drug Reactions
Relatively safe and effects are dose related
Erythromycin : nausea, vomiting, abdominal pain, cramping, and diarrhea
Hepatotoxicity (rare)
Ototoxicity
Macrolides, Azalides, Ketolides
Clinical Monitoring and Education
Monitoring
- Monitored for altered response to concurrent medications metabolized by - CYP450 3A4 or 2C9
- Hepatic/renal impairment
- Hearing loss (rare)
Patient Education
- ADR’s
- Drug interactions
Aminoglycosides Pharmacodynamics mono therapy no recommended Gentamicin Amikacin Tobramycin Neomycin Streptomycin
They are actively taken up by bacteria and subsequently bind to the smaller 30S subunit of the bacterial ribosome, thus inhibiting bacterial protein synthesis.
Active against gram negative bacilli
e.coli, clebsiella, enterobacter
Must be used in combination with a cell wall agent for gram+ activity
Staph, enterococcus, strep
Aminoglycosides
Pharmacokinetics
IV administration only, poorly absorbed GI
Weakly serum protein bound and excreted by kidneys
Adjust dose in renal patients – removed by hemodialysis
Monitor renal function and serum levels
* narrow therapeutic range
Aminoglycosides
Clinical Uses
Drug-resistant gram-negative infections
Synergy against gram positive cocci in combination with cell-wall agent (i.e. gentamicin)
Empiric treatment in combination with other abx for hospital acquired infections
- UTI, pneumonia
Aminoglycosides
Adverse Drug Reactions
Mild and transient GI and CNS effects
Rare hypersensitivity
Nephrotoxicity and ototoxicity
- Accumulation of drug in the proximal tubule cells
- Otoxicity may be irreversible and Is associated with high serum trough levels.
Extended interval dosing (i.e. 6mg/kg q24hr) associated with lower risk of renal and ototoxicity (may be irreversible)
Tetracyclines
Pharmacodynamics/Pharmacokinetics
Pharmacodynamics
- Inhibits bacterial protein synthesis by binding to the 30S subunit of the ribosome.
Pharmacokinetics
- Food decreases absorption (take on empty stomach)
- Highly protein bound
- Renally excreted (except doxycycline)
- Milk and dairy products impair absorption
Tetracyclines
Clinical Use
Possess activity against gram +/- and atypical organisms
Doxycycline is considered first-line therapy for
Chlamydia trachomatis and the drug of choice for early Lyme disease, Community acquired PNA
Tetracycline and minocycline used to treat P. acnes
Minocycline/doxycycline-community-acquired MRSA infections
Patient Education
Administration, ADRs, avoid pregnancy
Tetracyclines
Adverse Drug Reactions
Do not prescribe to pregnant women, lactating women or children < age 8 yrs
Drug-drug CYP3A4 interactions
Anorexia, nausea, vomiting, epigastric pain
Thrombophlebitis
Hepatotoxicity
Tooth discoloration
Sun sensitivity (avoid the sun)
- infuse slowly w/ large volume
Sulfonamides
Pharmacokinetics /Pharmacodynamics
Bactrim
Work by inhibiting the incorporation of paraaminobenzoic acid used by bacteria to synthesize dihydrofolic acid, the first step leading to folic acid synthesis, which is required for bacterial cell growth.
Readily absorbed in the GI tract and well distributed
Metabolized by the liver and eliminated by the kidneys
Half lives vary from hours to days
