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
Sulfonamides
Clinical Use
Active against a wide range of gram +, gram - organisms.
Most commonly used for UTI, pyelonephritis (BACTRIM)
Low cost alternative
PCN allergies
Sulfonamides
Adverse Drug Reactions
Anorexia, n/v, diarrhea, stomatitis
Rash
Stevens-Johnson syndrome/toxic epidermal necrolysis
- Rare
Sulfonamides
Monitoring and Education
Monitoring:
Culture and susceptibility if treating for UTI
long term use check CBC
Resistance potential
* Cx and sensitivity prior to starting abx
Patient Education:
Complete antibiotic course
ADR’s
Glycopeptides (Vancomycin)
Pharmacodynamics/Pharmacokinetics
Pharmacodynamics
- Work by inhibiting the binding of the D-alanyl-D-alanine portion of the cell precursor or by interfering with the polymerization and cross-linking of peptidoglycan.
- Gram + aerobic/anerobic bacteria
- Weight-based dosing
Pharmacokinetics
- IV only for systemic therapy
- PO is reserved for C-Diff treatment
- Poorly absorbed from the GI tract
- Must monitor renal function
Glycopeptides (Vancomycin)
Clinical Use
Empiric therapy for severe infections with risk for gram-positive organisms
- Endocarditis
- Meningitis
- Neutropenic fever with gram-positive risk
- MRSA
- for pt unable to tolerate beta lactams
Clostridium difficile
- PO only
- for those unresponsive to metronidazole
Glycopeptides (Vancomycin)
Adverse Drug Reactions
Fever, chills, phlebitis
Nephrotoxicity/Ototoxicity (transient or permanent)
“Red Man” syndrome Infusion related Prolong infusion time to avoid (i.e. 2 hours) redness, itching, hypotension * stop med * premed w/ Benadryl
Oxalodinones: Linezolid
Pharmacodynamics/Pharmacokinetics
Bacteriostatic
Pharmacodynamics
- Disrupts bacterial protein synthesis
- Most effective against gram-positive aerobic bacteria
- Enterococci, staphylococci, and streptococci
- Resistance emerging
Pharmacokinetics
- Well absorbed orally from the GI tract
- Does not use CYP 450 enzymes
- Considered bacteriostatic agents
Oxalodinones: Linezolid
Clinical Use
Linezolid has been FDA approved for the treatment of:
Community acquired and nosocomial pneumonia
Skin and soft tissue infections
Osteomyelitis
Vancomycin-resistant enterococcus
MRSA
PCN resistant streptococci, VRE
Tedizolid:
Only for treatment of skin and skin structure infections
Oxalodinones: Linezolid
Adverse Drug Reactions
Diarrhea, headache, nausea, vomiting, and taste perversion.
Myelosuppression has been reported, resolves with discontinuation
Decreased blood counts
- Thrombocytopenia, anemia, leukopenia, pancytopenia
- can decrease blood counts over long term
Lincosamides: Clindamycin (Cleocin) Pharmacodynamics/Pharmacokinetics
Pharmacodynamics
- Binds to the 50S subunit of the bacterial ribosome and inhibits protein synthesis.
- Well absorbed and converts to active form in the blood.
Pharmacokinetics
- Metabolized by the liver
- Reaches most tissues/bone, limited distribution into CSF
- Half-life is approximately 3 hours
Lincosamides: Clindamycin (Cleocin
)Clinical Use
Used to treat gram +/- and anaerobic bacterial infections
Toxoplasmosis, PCP, or in combo with other agents to treat PID.
Pregnancy category B
Lincosamides: Clindamycin (Cleocin) Adverse Drug Reactions
Boxed warning for severe colitis-or CDAD
* diarrhea
Skin –pain at the IV site
- Rash , burning, itching, erythema
Hematologic
- Transient eosinophelia, neutropenia, thrombocytopenia
Lincosamides: Clindamycin (Cleocin)
Clinical Monitoring and Education
Monitoring
- Stop medication if significant diarrhea occurs
Patient Education:
- Advise patients to take probiotic with therapy
- Complete therapy
- ADR’s
Metronidazole
Pharmacodynamics
- It is reduced to a toxic product that interacts with DNA, causing stand breakage results in protein synthesis inhibition.
- Metronidazole treats both protozoal and bacterial infections , gram +/- anaerobes
- Active against trichomoniasis, Clostridium difficile, H. Pylori regimen, and bacterial vaginosis.
Pharmacokinetics
- Metronidazole is well absorbed when taken orally
Metronidazole
Clinical Use and Dosing
Empiric therapy, often in combination with other antibiotics, for infections with risk for anaerobic organisms
Intra-abdominal, aspiration pneumonia, bacterial vaginosis
Adverse Drug Reactions
GI complaints: N/V, abdominal pain, and a metallic taste.
High doses: risk of seizures
Prolonged courses: risk of peripheral neuropath*
pancreatitis
avoid ETOH
can enhance anticoagulation of warfarin
Patient Education
Inhibitor of CYP3A4
Metallic taste with metronidazole
Avoid alcohol due to disulfiram-like reactions
Mycobacteria
Is a type of germ that grows slowly and are relatively resistant to drugs that are largely dependent on how rapidly cells are dividing
Have a lipid-rich cell wall relatively impermeable to many drugs
Are usually resistant to drugs that do not have good intracellular penetration
Have the ability to go into a dormant state
Easily develop resistance to any single drug
Antimycobacterials
Rifampin, typically used in combo w/ Vanco
Pharmacodynamics
- Rifampin suppresses initiation of chain formation for RNA synthesis in susceptible bacteria by inhibiting DNA- dependent RNA polymerase.
- Resistance develops rapidly to monotherapy
- Extremely active against gram + cocci with moderate activity against aerobic gram - bacilli
Pharmacokinetics
- Well absorbed orally
- Metabolism of isoniazid is highly variable
Antimycobacterials
TB guidelines
Clinical Use and Dosing
Follow CDC guidelines
Active TB requires 4 drug therapy
Preventive therapy with INH
Rational Drug Selection
Follow CDC guidelines
Monitoring
Directly Observed Therapy (DOT)
Patient Education
Importance of taking medication daily
Reporting of ADRs
Antimycobacterials
Adverse Drug Reactions
INH: peripheral neuropathy
INH, rifampin & pyrazinamide: hepatotoxicity
Rifampin: red-orange color to body fluids
Monitor LFTS: rare risk of hepatotoxicity
Anemia/thrombocytopenia has been reported
Drug Interactions
Many drug interactions
Rifampin is an inducer of CYP450 enzyme
Antiviral agents
Pharmacodynamics
Viruses are obligate intracellular parasites that consist of a nucleic acid core surrounded by one or more proteins. Several mechanisms exist for replication.
Antivirals work by inhibiting DNA replication.
Acyclovir, valacyclovir, famciclovir: active against HSV 1 and 2; varicella-zoster virus (VZV); Epstein-Barr virus (EBV), herpes B virus
Antiviral agents
Drug selection
Clinical Use and Dosing
Herpes simplex virus: genital herpes both initial outbreak and suppression therapy
Herpes zoster (shingles)
Varicella (chickenpox)
- Not for pt < 12yo
- caution in renal disease
- C/I in CHF and lactation
Antiviral agents
Adverse Drug Reactions
Headache, nausea, rash, nasopharyngitis, ALT/AST increase
Drug interactions
Few
Monitoring
Monitor for improvement and resolution
Patient Education
Drug started at earliest sign of infection
Hydration
Antivirals for Influenza
Pharmacodyanimcs
- Zanamivir and oseltamivir inhibit influenza virus neuraminidase,
- Amantadine and rimantadine inhibit replication of influenza A
- Amantadine, rimantadine (Flumadine) and - - - Oseltamivir (Tamiflu) are used to treat influenza A
- Amantadine (Symmetrel) has been discontinued in the US
- Zanamivir (Relenza) treat influenza A or B (inhaled)
- Sensitivity varies by year
Pharmacokinetics
- Most are well absorbed after oral administration
- Zanamivir is inhaled, 4 – 17% absorbed
Antivirals for Influenza
Adverse Drug Reactions
amantadine and rimantadine: CNS disturbances, abnormal dreams
amantadine : peripheral edema
Zanamivir: nausea, dizziness, headache, bronchitis, cough, nasal symptoms, ear/nose/throat infection, fever, malaise/myalgias, appetite changes
Clinical Use and Dosing
CDC updates recommendations annually.
Amantadine has several drug interactions
Antivirals for Influenza
Monitoring
Resolution of flu symptoms
CNS disturbances
Patient Education
Take full course of therapy
ADRs
Advise annual influenza vaccination
- Encourage flu vaccine and dispel myths
Community Acquired Pneumonia
Most common bacterial cause is Streptococcus pneumoniae
Chest radiograph should be obtained
A sputum gram stain should be obtained
Travel history, local epidemiology, and other epidemiologic and clinical clues should be considered when selecting an empiric regimen.
Drug-resistant Streptococcus pneumoniae complicates the use of empiric treatment.
Initiation of Drug Therapy
Provide adequate hydration (replace losses).
Bronchodilators for dyspnea.
Fever control.
Supplemental oxygen for hypoxia.
Early identification of causative microorganism.
Community Acquired Pneumonia
No requirement for hospitalization, have no major co-morbidities, and have not used antibiotics within the last 3 months, and reside in a region in which there is not a high prevalence of macrolide-resistant S. pneumoniae (<25 percent)
Treatment: advanced macrolide-Azithromycin (500 mg on day 1 followed by four days of 250 mg a day or 500 mg daily for 3 days), clarithromycin (500 my twice daily), or clarithromycin XL (two 500 mg tablets once daily).
For non pregnant patients with CAP who do not require hospitalization, have no major co-morbidities, and have not used antibiotics within the last 3 months but cannot take a macrolide due to a high local rates (> 25%) of macrolide-resistant S. pneumoniae or a contraindication and who live in a region in which the local rate of doxyclcyine-resistant S. pneumonia is 25% or is unknown-
Treatment: doxycycline 100 mg PO twice daily.
Most outpatients with CAP should be treated for 5 days, including those receiving azithromycin 500 mg on the first day followed by 250 mg daily on subsequent days and those receiving any other antibiotic. Because of its long half-life, patients receiving azithromycin at a dose of 500 mg daily can usually be treated for 3 days. Patients should be afebrile for >48 hours and clinically stable before therapy is discontinued.
Patients who have not responded to therapy after 48 to 72 hours should be re-evaluated
CURB-65 Pneumonia Severity Score
A clinical prediction tool validated to predict mortality from CAP
Assists with the decision to admit to hospital vs. outpatient management
Confusion BUN > 20 RR > 30 SBP < 90 DBP < 60 > 65
CURB-65 is only used as a guide to decision making
PNA s/s: cough, sputum production, chills, SOB, chest pain
Physiologic exam: fever, tachycardia, crackles, tachypnea, decreased breath sounds
Agent selection
Community acquired pan
1st line: <60 yo, no comorbidities
Macrolide
Fluorquinolone
2nd line: comorbidities, > 60 yo
Beta-lactam
Beta-lactamase inhibitor
3rd line
If no improvement
Tx for 5-10 days
HIV
Induces defects in the immune response system.
Patient is susceptible to various infections and neoplasms.
Transmitted via blood, sexual contact and mother to child (vertical transmission).
Prevention is the key to avoiding transmission.
HIV is the virus that causes acquired immunodeficiency syndrome (AIDS).
- primarily in lymph node and genital secretion
Stages of HIV Infection
Stage I: Acute HIV infection
2-4 weeks after exposure
Flu like illness with fever, rash, pharyngitis, adenopathies and myalgias
Very contagious
Stage 2: Clinical latency (HIV inactivity or dormancy) sometimes called asymptomatic HIV infection or chronic HIV infection.
HIV is still active but reproduces at very low levels. Patients may or may not have any symptoms.
Stage 3: Acquired immunodeficiency syndrome (AIDS)AIDS is the most severe phase of HIV infection.
Advanced HIV/AIDS: CD4 below 200 cells/mm3
- very infectious; high viral load
Develop common opportunistic infections
s/s: chills, fever, swollen lymph glands, sweats, wt loss, weakness,
Diagnostic Criteria and CD4+ T-Cell Count
Diagnosis of HIV is based on the presence of:
RNA or p24 antigen in serum/plasma
Often with a negative/indeterminate HIV antibody test
The CD4+ T-cell count indicates the extent to which HIV has damaged the immune system.
Normal: 500-1600/mm3
- viral load tells how much HIV is reproducing
- successful tx: rise in CD4 count and decrease in viral load to undetectable amount
Goals of Anti-retroviral therapy(ART)
Maximal suppression of viral load
Also diminishes spread of virus.
Restoration and preservation of immune system function.
Enhancement of quality and duration of life.
Reduction in morbidity and mortality from HIV-related complications.
Prevention of HIV transmission
Reverse Transcriptase Inhibitors: Nucleoside and Non-Nucleoside
Work in the target cells to interfere with the transcription of RNA to DNA.
Break into the chain of the RNA and replace a nucleoside analog or another non-nucleoside component so that the DNA is not produced.
Many drug interactions due to CYP450.
Reverse Transcriptase Inhibitors: Nucleoside
Truvada
Renally excreted. Need dose adjustment in renal failure.
Lactic acidosis with hepatic steatosis. Decrease in bone mineral density. Hypersensitivity reaction. Headache, malaise, GI disturbances.
Some dosing schedules are based on weight.
Combination drugs: Truvada
Reverse Transcriptase Inhibitors: Nonnucleoside
By binding to reverse transcriptase, NNRTIs also interfere with the conversion of RNA to DNA.
Adverse effect: GI disturbances. Rash. Elevated hepatic transaminases.
All of the NNRTIs are metabolized by the cytochrome P-450 3A4 isoenzyme system in the liver.
Caution w/ liver disease
Proteases Inhibitors
Ritonavir
Activity late in the reproduction phase of the HIV virus, inhibiting the ability of the polyprotein chains to break apart and create new chains of the virus.
Ultimately this decreases the production of viral RNA.
Food decreases absorption unless boosted with another PI, Ritonavir.
Proteases Inhibitors
N/V/D
Increase in hepatic transaminases.
Monitor for hepatotoxicity
Fat maldistribution: Fat lipodystrophy
Hyperlipidemia
Hyperglycemia -> DM
Management: diet and exercise
Fusion Inhibitor
Fuzeon
Fuzeon (Enfuvirtide)-injected subcutaneously BID.
Prevents fusion of the virus to the cell membrane of the CD4 host cell.
Often useful in patients with other drug resistance.
Local injection site reactions. <1% experience hypersensitivity reactions (rash/fever).
Integrase Inhibitors
dolutegravir
elvitegravir
raltegravir
Prevents integration of viral DNA into the host cell’s genome.
Includes dolutegravir, elvitegravir, and raltegravir
Used in drug resistance/earlier treatment naïve patients.
CCR5 Antagonists
Maraviroc
Maraviroc
Blocks the CCR5 receptor on the CD4 cell membrane.
Not all viruses use this receptor for cell entry
Co-receptor tropism must be performed to determine if pt virus enters via CCR5
BLACK BOX WARNING: Hepatotoxicity.
Numerous drug interactions
Requires dose adjustments
s/s: cough, orthostatic hypotension, rash, fever
Initiating and Monitoring Therapy
Adherence is the most crucial factor to success.
ART is recommended for all patients with HIV.
Recommended initial therapy is comprised of 2 NRTIs plus a third drug, either a boosted PI or INSTI.
Evaluate HIV RNA and CD4+ count.
LFTs, CBC with diff, CMP
Special Population Considerations: Pediatrics
Infant testing can start at birth and by age 4 months
Initial test negative: repeat at age 1-2 months and age 4-6 months.
CD4+ T cell counts in children <5 years higher than adult counts.
Use CD4+ T cell count and viral load to accurately predict prognosis/survival.
An HIV expert should manage pediatric patients.
Special Population Considerations: Women/Pregnancy
ART thresholds same for men and women.
ART selection in childbearing women-balance efficacy/potential of teratogenicity
ART reduces efficacy of many PO contraceptives
In pregnancy: 1. ART of HIV in the mother. 2. Prophylaxis to reduce risk of perinatal HIV infection.
During Labor: ART chemoprophylaxis IV zidovudine
* recommended for pregnant women w/ viral load > 1000 copies/mL during late pregnancy
Postnatally: infant receives oral chemoprophylaxis
Post Exposure Prophylaxis (PEP)
Post Exposure Prophylaxis (PEP)
Occupational O-Pep-begin as soon as possible.
Non-occupational N-Pep
Begin within 72 hours of exposure for 28 days
Preferred regimen: tenofovir/emtricitabine (TRUVADA) tablet PO daily PLUS raltegravir 400 mg PO BID
Pre exposure prophylaxis (PrEP)
Pre exposure prophylaxis (PrEP)
Truvada once daily
44% relative risk reduction in HIV infection incidence
ADHERENCE IS IMPORTANT! Must receive safer sexual practices counseling.
Must test negative for HIV within 1 week of PrEP initiation and every 3 months during treatment -> to prevent resistance
90 day supply, follow-up every 3 months.
HIV
Retrovirus
Each molecule has 2 single strands of RNA
Virus is transcribed, via reverse transcriptase, into DNA that inserts into DNA host cell -> replication
Host cells: CD4, T-lymphocytes, WBC
Host cell destruction -> immunocompromised stated
- increase in CD4 may indicate noncompliance with medication
