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Metronidazole
Mechanism of antibacterial action is unclear, but needs
reductive metabolism of drug bactericidal
DOC for Entamoeba histolytica, Giardial species and T
vaginalis
DOC for anaerobes B fragilis, C. difficile and G. vaginalis,
and used in regimens for H. pylori associated GI ulcers
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Metronidazole
Adverse effects: metalic taste, brown-black urine,
glossils, stomatitis, urethral burning, dysuria,
neurotoxicity (vertigo, peripheral neuropathy). Disulfram-
like interactions with ethanol
Antibiotics for H. pylori GI Ulcers
Amoxicillin, clarithromycin, tetracyclines and
metronidazole: used with H2 blockers, proton pump
inhibitors and antacids
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Antitubercular Drugs
Combinations: Decrease resistance; additive effects
Primary drugs: isoniazid, rifampin, ethambutol, and
pyrazinamide
Regimens usually 2 to 4 of these drugs, but in the case
of highly resistahnt organisms, other agents may also be
required
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Antitubercular Drugs
Prophylaxis usually INH, but rifampin if intolerant, in
suspected multi-drug resistance, both drugs may be
used in combination
Back-up drugs for TB, aminoglycosides (streptomycin,
amikacin, FQs, capreomycin (hearing loss) and
cycloserine (neurotoxic)
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Isoniazid (INH)
Inhibits mycolic acid synthesis. High level resistance
detection in cat K gene (codes for catalase); low level
(changed inhA gene)
Adverse: hepatis (age-dependent), peripheral results (use
B5), hemolysis in G5PD, deficiency, SLE in slow
acetylations (rare)
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Rifampin
Inhibits DNA-dependent RNA polymerase; resistance
(changed enzyme) emerges rapidly if used alone
Adverse: proteinuria, hepatitis ,flu-like syndrome,
induction of P450, throbocytopenia, red-orange metabolites
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Ethambutol
Inhibits synthesis of arabinogalactan (cell wall
component)
Dose- dependent retrobulbar neuritis, causing to
reduce visual acuity
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Pyrazinamide
Mechanism unknown, but metabolically activated bacterial
strains lacking bioactivating enzymes are resistant no cross
resistance
Adverse: polyathralgia, myalgia, hepatitis, rash,
hyperuricemia, phototoxicity, increasing porphyrin synthesis
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M. avium intracellulare (MAC)
Prophylaxis azithromycin (1 x week) or clarithromycin
(daily)
Treatment: clarithromycin + ethambutol +/- rifabutin
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Antifungal Agents
Drug groups: Polyenes ( amphotericin B, nystatin)
Antimetabolite (Flucytosine)
Azoles (ketoconazole, fluconazole,
itraconazole)
Antidermatophytics (griseofulvin,
terbinafine)
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Polyene Antifungals
Amphotericin B and Nystatin
Interact with ergosterol retention, leading to increase
disrupt memebrane permeability
Resistant fungi have low ergosterol content in cell
membranes
Amp B Rx uses: DOC (or co DOC) for infections due to
Aspergillus, Candida, Cryptococcus, Histoplasma,
Mucor and Sporotrichosus
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Amphotericin B Characteristics
Given by slow IV infusion minimal CNS penetretion;
slow clearance ( halflife > 2 weeks), via metabolism and
renal elimination
Adverse effects: IV infusion related- fever, chills, muscle
rigor, hypotension (histamine release ) - by pre-treatment
with NSAIDs, antihistamines and adrenal steroids
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Amphotericin B Characteristics
Dose dependent nephrotoxicity includes decrease GFR,
tubular acidosis, decrease K and Mg and anemia through
decrease erythropoietin protect by Na loading use of
liposomal amp B, or drug combinations (eg. + flucytosine)
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Azole Antifungals
Fungicidal reduces synthesis of ergosterol by inhibiting
P-450- dependent demethylation of precursos molecule,
lanosterol
Resistance via decrease intracellular accumulation
Ketoconazole
Co-DOC for Paracoccidodes and back-up for
Blastoyces and Histoplasma. Rx: mucocutaneous
candidasis or dermatophytoses
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Azole Antifungals
Ketoconazole
Effective orally, but antacids reduce absorption
Adverse effects: reduce synthesis of cortisol and
androgens, rash, fluid retention, leading to increase BP,
hepatoxicity (rare)
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Azole Antifungals
Fluconazole
DOC for esophagal and invasive candidiasis and
coccidomycoses, prophylaxis and suppression incryptococcal meningitis, vaginal candidiasis (single dose)
Oral absorption, penetrates CSF and saliva; renal
elimination
Adverse effects: similar to ketoconazole but less
intense
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Azole Antifungals
Itraconazole
DOC in blastomycoses and sporotrichoses back up
other mycoses and in candidiasis (eg. Fluconazole
resistance)
Oral absorption increased by food; hepatic metabolism
Adverse effects: similar to ketoconazole but less P-450
inhibition
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Flucytosine
Activated by fungal cytosine deaminase to 5 FU, decrease
RNA , thymidine synthase. Rapid resistance
Rx use: with amp B in candidial and cryptococcalinfections enters CSF. Toxic to bone marrow
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Griseofulvin
Anti-dermatophytic (oral) disrupting microtubulestructure
Adverse effects: headace, thrush, peripheral neuritis,
phototoxicity, avoid with history of porphyria
Terbinafine
Anti-dermatophytic-inhibits squalene epoxidase, decrease
ergosterol
Adverse effects: GI distress, rash, headache, increase
LFTs
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Sites of Antiviral Drug Actions
Viral
adsorption
HOST
CELL
Enfurvitide Amantadine
penetrationuncoating
Nucleic Acid
Synthesis
Protein synthesis
and processing
Viral
assembly
Viral
release
Neuraminidaseinhibitors
Protease
Inhibitors
Polymerase
Inhibitors
Reverse
Transcriptase
Inhibitors
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Acyclovir
Monophosphorylated by viral thymidine kinase (TK), then
further bioactivated by host cell kinases to the triphosphate
Acyclovir TP is both at substrate for, and inhibitor of viral
DNA polymerase incorporated into the DNA it acts as a chainterminator, since it lacks the 3 hydroxyl group
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Acyclovir Characteristics
Rx uses: HSV, VZV and Vanicella : decrease viral
shedding in general herpes and decrease acute neuritis
in shingles no effect on postherpetic neuralgia
Prophylaxis; immunocompromised patients
Topical, oral and IV forms short halflife
Adverse Effects: crystaluris (maintain full hydration)
and neurotoxicity (agitation, headache, confusion seizures in OD), NOT hematotoxic
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Acyclovir Characteristics
Famciclovir and Valacyclovir
Approved for HSV infection similar
mechanism to acyclovirActive vs strains resistant to acyclovir; but not
TK
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Gancyclovir
Mechanism similar to acyclovir, 1st phosphorylation
viral-specific via a phosphotransferase, Gancyclovir-TP
inhibits viral DNA polymerase, but does not cause chain
termination
Resistance mechanisms similar to acyclovir
Rx uses: HSV, VZV and CMV. Mainly prophylaxis and
treatment of CMV including retinitis, oral, IV and retinal
implant forms
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Gancyclovir
Adverse Effects: dose-limiting hematotoxicity, mucositis,
fever, rash and crystaluria (maintain hydration); seizures
in OD
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Foscarnet
Not an antimetabolite, inhibits viral DNA and RNA
polymerases
Rx uses identical to ganciclovir, plus activity versus
acyclovir resistant strains of HSV
Adverse effects: dose-limiting nephrotoxicity with
tubular necrosis, electrolyte imbalance with hypocalcemia,
and then tremors and seizures. Avoid pentamidine (IV)
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Drugs Active Against HIV
HAART can reduce viral mRNA, reverse decline in
CD4 cells and decrease opportunistic infections
Non-nucleoside RTIs (NNRTIs), which do not require
bioactivation (eg. Nevirapine, efavirenz) are also used in
combination with NRTIs
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Zidovudine (AZT)
Prototype, orally actve, hepatic metabolism, increase
ZDV toxicity with acetaminophen, ASA, cimetidine,
probenecid and sulfonamides
Dose-limiting hematotoxicity (neuropenia, anemia,
granulocytopenia), headache, asthenia, myalgia,
myopathy and peripheral neuropathy
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Specific Features of Other NRTIs
Didanosine pancreatitis, peripheral neuropathy,
hyperuricemia, increasing LFTs
Zalcitabine peripheral neuropathy, GI distress,
pancreatitis, neutropenia
Stavudine peripheral neuropathy, myelosuppression
(< ZDV)
Lamivudine GI effects and neutropenia (minor);
active hepatitis B
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Mechanism of Action of Protease Inhibitors (PIs)
Aspartate protease (pol gene encodes) cleaves precursor
polypeptides in HIV buds proteins of mature virus core
PIs bind to a unique dipeptide structure inhibiting the
enzyme
Resistance via specific point mutation in the pol gene, such
that there is not complete cross-resistance between
different PIs
In HART regimens, indinavir and ritonavir have been
most commonly used (with 2 NRTIs)
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Adverse Effects of Protease Inhibitors
Indinavir: nephrolithiasis (maintain hydration), GI
distress, thrombocytopenia, inhibition of P-450
Ritonavir: GI distress, asthenia, paresthesias and
drug interactions induces CYP1A2 and inhibits majorP450 isoforms, increase effects of dronabiol,
erythromycin, ketoconazole and rifampin
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Adverse Effects of Protease Inhibitors
PI use is associated with disordered lipid and CHO
metabolism with central adiposity and insulin resistance
HAART regimen where PI is replaced by efavirenz ( a
NNRTI) are highly effective with deduce drug interactions
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HIV Prophylaxis
Needle stick
ZDV + 3TC, 1 month but in high risk (eg. High
HIV RNA copies) a combination of ZDV + 3TC +
indinavir is recommended
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HIV Prophylaxis
Pregnancy
ZDV, trimester 2 and 3,+ 6 weeks to neonate, reduces
vertical transmission by 80% - possible combinations if
high maternal viral RNA
ZDV restricted to intrapartum period, or nevirapine
(NRRTI) one dose at onset of delivery + one dose to
neonate and reduces transmission by 50% to 60%
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Amantadine
Blocks attachment and penetration and uncoating of
influenza A virus
Prophylaxis mainly, but may decrease duration of flu
symptoms by 1-2 days
Adverse: CNS effects include nervousness, insomnia and
seizures in OD. Causes atropin-likeperipheral effects and
livedo reticularis
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Zanamivir and Oseltamivir
Inhibit neuraminidases of influenza A and B, enzymes which
prevent clumping of virions, so that more particles are available of
infecting host cells. This inhibition decreases the likehood that the
virus will penetrate uninfected cells
Prophylaxis mainly, but may reduce duration of flu symptoms
by 2-3 days
Adverse: nausea and vomitting and zanamivir (via inhalation)causes nasal and throat irritation
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Ribavirin
Monophosphorylated form inhibits IMP dehydrogenase,
triphosphate form inhibits viral RNA polymerase and end-
capping of viral RNA
Rx uses: management of RSV, influenzae A and B, Lassa
fever
Hantavirus and as adjunct to alpha-interferons in hepatitis
C
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Ribavirin
Adverse: hematotoxic, upper airway irritation, tetratogenic
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Antiprotozoal Drugs of Choice
Amebiasis: metronidazole or Diloxanide for noninvasive
intestinal amebiasis
Giardiasis: metronidazole for diarrhea from
contaminated water or food
Leishmaniasis : stibogluconate
Pneumocystosis: TMP-SMX for Atovaquone or
pentamidine IV are backups
Toxoplasmosis: pyrimethamine + sulfadiazine
Trypanosomiasis: nifurtimox, arsenicals
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Antiprotozoal Drugs of Choice
Prophylaxis Pymethamine + sulfadoxine
Mefloquine
Treatment Falciparum Chloroquine
Malariae Chloroquine
Vivax Chloroquine + primaquine
Ovale Chloroquine + prmaquine
Chloroquine-resistance
Prophylaxis mefloquine
Treatment quinine +/- pyrimethamine or clindamycine
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Drugs for Helminthic Infections
Most Intestinal Nematodes (Worms)
Mebendazole ( reduces glucose uptake and
microtubular structure) , or pyrantel pamoate (NM
blocker and spastic paralysis)
Most Cestodes (Tapeworms and Trematodes )
Praziquantel ( increase Ca influx, vacuolization)
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Vaccination Strategies
Mechanisms of Protection within the Immune System
Divided into innate or primitive and adaptive or
acquired, against variety of bacterial and viral agents.
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Activation of Innate Immunity: Sensing the Enemy
Innate defenses are primarily aimed at recognizing
foreign structures and eliminating them.
Since infectious pathogens have often evolved to subvert
these mechanisms, specialized cells of the innate immune
system are also capable of presenting digested antigen to
T cells in a context and environment appropriate for
optimal effector cell development.
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Activation of innate immunity to provide this context may
be conceptually divided into two stages :
(1) a phase of antigen sensing during which a combination of
surface receptors detects the presence of non-self
structures on invading microorganisms (detection phase)
(2) a phase of translating this sensory information into a
language understood by the cells of the adaptive immune
system, e. g., chemokines and cytokines (transmission
phase)
Activation of Innate Immunity: Sensing the Enemy
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Some key elements of the adaptive immune system
B lymphocytes, their precursors and progeny, and their
products 8 different classes of antibodyT lymphocytes with / receptors, their precursors and progeny,
their lymphokine products,
and specifically CD4+ regulatory (suppressor) Tcells; CD8+
cytotoxic and cytokine secretorycells; and CD1-specific CD4+ or double negative NK-1 Tcells
T lymphocytes with / receptors, their various subsets, and their
lymphokine products
Other atypical Tcells
Fc receptors of various types on monocytes, macrophages,immature dendritic cells, B cells,
polymorphonuclear leukocytes, NK cells, mast cells, and
platelets, as well as soluble Fc receptors
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Some key elements of the innate defense system
Cilia
Enzymes in mucous secretions, e. g., lysozyme
Repair mechanisms of damaged anatomical barriers, e. g.
the clotting cascade or growth factor
and chemokine releaseDefensins
The complement cascade
Non-immunoglobulin opsonins, e. g., collectins such as
mannose-binding protein or C-reactive
protein, lectins, fibronectin, etc.
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Some key elements of the innate defense system
Recognition receptors on dendritic cells, macrophages,
NK cells, and mast cells including Tolllike receptors,
scavenger receptors, or integrin
Phagocytosis by polymorphonuclear leukocytes, monocytes,
or macrophages
Cytokines, including interferons , , and tumor necrosis
factor
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Overall view of innate immunity shaping adaptive immune
responses. Cells of the innate immune system(DC = dendriticcells; MC = mast cells) detect the presenceof foreign structures,
such as pathogen-associated molecular patterns, by surface expressed
pattern-recognition receptors,and translate this sensory
input into a language (cytokines,chemokines) understood by cells
of the adaptive immune system,skewing the response to either T
helper 1 (Th1)/T cytolytic 1 (Tc1) or Th2/Tc2-type immunity
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Pathogen-associated Molecular Patterns
Required for differentiation of adaptive immune
responses when cells of the innate defense system interact
with pathogen-associated molecular patterns (PAMPs, i. e.,
highly conserved structures that are necessary for thesurvival of microorganisms)
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Pattern-recognition receptors primarily serve the purpose
of enhancing phagocytosis.
Example, the macrophage mannose receptor
(recognizing terminal mannose and fucose residues on
microbial cell walls) or the macrophage scavenger receptor
(recognizing polyanionic ligands such as double stranded
RNA, lipopolysaccharide, and lipoteichoic acid) are mainlyinvolved in clearing pathogens from the site of invasion
Pathogen-associated Molecular Patterns
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PAMPs have multiple effects on the signals generated by
cells of the innate immune system and may therefore be
useful as natural adjuvants in driving adaptive responses
Pathogen-associated Molecular Patterns
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Recognition of pathogen structures via surface receptors
on innate immune cells
Pattern-recognition receptors Pathogen-associated molecular patterns on innateimmune cells or similar insults
TLR1/TLR2 Triacylated lipopeptides
TLR2 Lipoproteins, lipoteichoic acid,
glycolipids,modulin,arabinose-capped lipoarabinomannan,
GPI-anchored molecules from parasites
TLR2/TLR6 Diacylated lipopeptides, zymosan
TLR3 Double-stranded RNA
TLR4 LipopolysaccharidesTLR5 Flagellin
TLR7 and TLR8 Imidazoquinoline Derivatives
TLR9 Unmethylated CpG-motif oligonucleotides
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Recognition of pathogen structures via surface receptors
on innate immune cells
Pattern-recognition receptors Pathogen-associated molecular patterns
on innate immune cells or similar insults
Complement receptors Activated components of complement coating
microbial surface
Scavenger receptors Polyanionic compounds, e. g., lipoteichoic acid,double-stranded RNA, lipopolysaccharide
Mannosefucose receptor Terminal mannose and fucose on microbial
glycoproteins/glycolipids
CD14 Monomeric lipopolysaccharides
CD48 Fimbrial protein FimH on enterobacteriaCD91 Heat-shock proteins 70, 90, gp 96; calreticulin
IgE/FceR-crosslink Parasitic lectins
unknown Allergens
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Host Cellular Sensors
At the immunological level, innate defenses rely mostly on
granulocytes, mast cells (MC), macrophages, dendritic cells
(DC), natural killer (NK), NKT, and T cells - a bridge between
PAMPs and the antigen-specific cells of adaptive immunity,translating the sensory input of pattern-recognition receptors
into soluble mediators that communicate with T and B cells via
specific cytokine/chemokine receptors.
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Host Cellular Sensors
Dendritic Cells
The most potent type of any antigen-presenting cell,which is
able both to sense a foreign insult and to orchestrate the cells
of the adaptive immune system
Continuously produced from hematopoietic stem cells within
the bone marrow
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Host Cellular Sensors
Dendritic Cells
Maturing DCs lose the ability to take up and process antigen,
but they up-regulate surface expression of MHC class I and II, as
well as of costimulatory and adhesion molecules such as CD86,
CD80, CD40, and CD54.
Mature DCs express proinflamatory cytokines like IL-6, IL-12,
IL-18, IL-23, and IL-27 and are able to detect the expression of
cytokines by infected cells, thus integrating different signals ofdanger
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Host Cellular Sensors
Mast Cells
Mast cells (MC) are derived from CD34+ stem cells
Initiate their differentiationin the bone marrow under the
influence of stem cell factor and interleukin-3
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Host Cellular Sensors
Mast Cells
Activation is followed by de novo synthesis of numerous
cytokines (TNF-alpha, interleukins 1-10, IL-12, IL-13, IL-15, IL-
16, IL-18, IL-25, and GM-CSF) and chemokines (CCL25, CCL8,
CCL11, IL-8). Mast cells are long-lived and therefore able to
respond repeatedly to the same stimulus
In addition to their well-established central role in the
pathogenesis of allergic disorders, MCs are now also appreciatedas key effector cells in the induction of protectiveimmune
responses to bacteria
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