Lecture 3 - Cells of immune system & Glycopeptides/Lipoglycopeptides Flashcards
Two distinct systems of immunity
Innate (non-specific)
Adaptive (specific)
Innate (non-specific) Immunity
- Physical barriers, phagocytes (Neutrophils + macrophages), proteins
- Strategically redeployed and prepositioned to prevent and/or quickly neutralize infection
Adaptive (Specific) Immunity
- Evolves and adapts against invading pathogens
2. Divided into humoral (B Lymphocytes) and cellular (T lymphocytes) mediated arms
Functional Divisions of Immune System: Innate
Exterior defenses: Skin, mucus, cilia, normal flora, etc
Specificity: Limited + fixed
Memory: none
Time to response: hours
Soluble factors: Lysozymes, complement, C-reactive protein, interferons
Cells: Neutrophils, monocytes, macrophages, NK cells, eosinophils
Functional Divisions of Immune System: Adaptive
Exterior defenses: none
Specificity: Extensive
Memory: yes
Time to response: days
Soluble factors: Antibodies, cytokines
Cells: B + T lymphocytes
Barriers of entry to microorganisms into the body
Skin Mucous Membranes Respiratory Tract GI tract Genitourinary Tract
Skin info
Physical + immunologic barrier to invasion
Dryness, salinity, mild acidity, combined w/ normal skin flora help make inhospitable for invading pathogens
Mucous Membranes info
Most pathogens enter through mucosal surfaces of respiratory, GI and urogenital tracts
Mucus, formed by highly glycosylated proteins called mucins
Respiratory Tract info
Trachea, bronchi, and bronchioles are lined with a ciliated epithelia surface that propels mucus upward
GI Tract info
Acidic pH of stomach and antibacterial effect of pancreatic enzymes, bile, and intestinal secretions are effective, non-specific, antimicrobial defense factors
Small intestine = mucus limit number of bacteria that can reach epithelium + Peyer patches
Large intestine = inner mucus layer relatively free of bacteria, outer layer supports commensal flora
Genitourinary Tract info
Lactobacillus spp. lowers pH of vagina = restricts growth of invading organisms
Vaginal flora prevents bacterial vaginosis, yeast infections, UTI and HIV
Urine is bactericidal for some strains of bacteria
Uromodulin (glycoprotein) made by kidneys, protects against kidney stones and binds to E.coli preventing them from attaching to cellular lining of urinary tract
Eye info
constant bathing of eye by tears effective means of protection
Foreign substances are diluted and washed away via tear ducts into nasal cavity
What is an elevated WBC?
> 10,000
Blood work signs of infection?
High % of Poly PMNs
What is a Left shift?
Bands increased ~5% during acute infection and shift to the left
Gram positive Antibiotics
Glycopeptides & Lipoglycopeptides
Oxazolidinones
Misc
Glycopeptides & Lipoglycopeptides
Vancomycin Daptomycin Telavancin Dalbavancin Oritavancin
Oxazolidinones
linezolid
Tedizolid
Miscellaneous Gram + antibiotics
Clindamycin
Lefamulin
Vancomycin MOA
- Inhibit late stage of cell wall synth
- Forms complex with carboxyl-terminal D-ala residues of peptidoglycan precursors
* 1st line MRSA *
Vancomycin resistance is valued by….
D-Ala residue turning into D-Lac
Most common Vancomycin Resistance?
Vancomycin A
thought to have picked it up from another bacteria
Vancomycin has no activity in….
Gram -
Gram - anaerobes
Atypical
Vancomycin Spectrum of Activity Gram +
- Broad gram + activity
- Txm of choice for MSSA + coagulase negative Staphylococci.
- Worse outcome compared to beta-lactams in MSSA (oxacillin/nafcillin or cefazolin)
- Covers all Streptococci species, used if resistant or beta-lactam intolerant/allergic
Vancomycin + ceftriaxone combo used for…
S. Pneumoniae meningitis
Vancomycin Gram + Anaerobes Spectrum of activity
Txm of choice for Clostridioides difficile (Oral)**
also covers Peptostreptococci + P.acnes
Oral vs IV Vancomycin
Cant use IV Vanco for C.dif
Cant use oral vancomycin for systemic infection
Vancomycin absorption
Can be given bunch of ways, but IM not recommended
Poor systemic absorption when given PO
Vancomycin Elim
Excreted primarily unchanged via kidney
1/2life = 4-6hrs w/ normal renal fxn
non renal clearance ~ 5-10% loss per day
Vancomycin efficacy is associated with….
AUC / MIC ratio
Target goal is 400 - 600
Vancomycin ADR
- Nephrotoxicity
- Infusion-related reaction
- Hematologic effects
- Delayed hypersensitivity reactions
Risk factors for Vancomycin associated nephrotoxicity
AUC > 650-1300 or trough > 14mc/ml Dose > 4g/day Duration > 7 days Wt > 101.4 kg Renal impairment > 65yrs old Critically ill using other nephrotoxic agents same time
Infusion-related reaction vancomycin
Most common SE
Rapid onset of rash, itchy skin, etc
Premeditate w/ Benadryl + slow infusion rate = will be fine
Hematologic effects Vancomycin
Leukocytoclastic Vasculitis (rare)
Thrombocytopenia
Pancytopenia
Neutropenia 1-2%
Daptomycin MOA
A Lipopeptide
Ca-dependent insertion of lipophilic tail into cytoplasmic membrane….causes Oligomerization and disruption of cell membrane….release of intracellular ions and cell death
Daptomycin Spectrum of Activity Gram +
** Txm of choice for Vancomycin-resistant Enterococci VRE ***
Covers MSSA/MRSA
Covers most Streptococci species, gaps in S.anginosus + Viridians Streptococci
Daptomycin + Vancomycin MRSA Cross Resistance
- Exposure of vancomycin causes MRSA to inc the cell wall
- MICs to vancomycin and daptomycin increase simultaneously
- Oxacillin MICs decrease = improved oxacillin susceptibility
Daptomycin and Enterococci
Treatment for E.faecium (VRE) is dose dependent.
Have to give a certain dose or no point in using to treat
Daptomycin Spectrum of Activity Gram + anaerobes
Covers Peptostreptococci and P. acnes
What does Daptomycin not have activity for?
Gram -
Gram - anaerobes
Atypical
Daptomycin Distribution
** Cannot be used for pneumonia, becomes inactivated by surfactant **
1/2life = 7.3-9.6hrs
little pen across uninflamed meninges
Daptomycin Elimination
unchanged via kidney
1/2life = 8-9hrs
Risk factors for CPK elevations in Daptomycin
Concomitant statin use, obesity, critically ill pt, higher doses, and severe renal impairment
Daptomycin ADR
CPK elevations ( Do baseline + wkly lvls)
Eosinophilic pneumonia = rare
Hepatic
GI
Lipoglycopeptides MOA
- Differ from vancomycin by presence of lipophilic side chain
- Bind to d-ala-d-ala portion of cell wall, blocking cross-linking of peptidoglycans
- Side chains enhance MOA by 2 mechanisms
Long 1/2 life
Where do Lipoglycopeptides not have activity?
Gram -
Gram - anaerobes
Atypical
Lipoglycopeptide drugs
Dalbavancin
Oritavancin
Telavancin
Lipoglycopeptides Spectrum of activity Gram +
All provide coverage against E.faecalis, MSSA, MRSA
Cover Streptococci species
Oritavancin coverage against VRE
Dalba + Telavancin active against Van-B/Van-c resistant enterococci strains but not Van-A
Which Lipoglycopeptides lack S.pneumoniae coverage?
Oritavancin
Dalbavancin
Lipoglycopeptides Spectrum of activity Gram + anaerobes
Very good gram + anaerobic activity
Not active against Actinomyces spp.
Covers Peptostreptococci, P.acne
used in setting of polymicrobial infections or beta-lactam intolerance
Lipoglycopeptides Elim & 1/2 lives
Tela = 7-10hrs Dalbavancin = 346hrs** Oritavancin = 245hrs**
** useful for bone infections…req way fewer doses due to 1/2 life **
Lipoglycopeptides ADR
CNS Hematologc GI Injection site reaction Nephrotoxicity (Telavancin)
Renal monitoring Telavancin
Monitor renal function prior to, during (atleast every 48/72hrs, more if needed) and following therapy in all patients
