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. vaginali
s,
　 and used in regimens for H. pylori associated GI ulcers
 Metronidazole

Adverse effects: metalic taste, brown-black urine, glossil

s, stomatitis, urethral burning, dysuria, neurotoxicity (vert
igo, peripheral neuropathy). Disulfram-like interactions wi
th ethanol

Antibiotics for H. pylori GI Ulcers

Amoxicillin, clarithromycin, tetracyclines and metronida
zole: used with H2 blockers, proton pump inhibitors and a
ntacids
 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
 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)
 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)
 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
 Ethambutol

Inhibits synthesis of arabinogalactan (cell wall

component)
Dose- dependent retrobulbar neuritis, causing to
reduce visual acuity
 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
 M. avium – intracellulare (MAC)

Prophylaxis azithromycin (1 x week) or clarithromycin

(daily)
Treatment: clarithromycin + ethambutol +/- rifabutin
 Antifungal Agents

Drug groups: Polyenes ( amphotericin B, nystatin)

Antimetabolite (Flucytosine)

Azoles (ketoconazole, fluconazole,

itraconazole)

Antidermatophytics (griseofulvin,
terbinafine)
 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
 Amphotericin B Characteristics

Given by slow IV infusion – minimal CNS penetretion; slo

w clearance ( halflife > 2 weeks), via metabolism and renal e
limination
Adverse effects: IV infusion – related- fever, chills, muscle
rigor, hypotension (histamine release ) - by pre-treatment wi
th NSAIDs, antihistamines and adrenal steroids
 Amphotericin B Characteristics

Dose – dependent nephrotoxicity includes decrease GF

R, tubular acidosis, decrease K and Mg and anemia throug
h decrease erythropoietin – protect by Na loading use of li
posomal amp B, or drug combinations (eg. + flucytosine)
 Azole Antifungals

Fungicidal reduces synthesis of ergosterol by inhibiting

P-450- dependent demethylation of precursos molecule, la
nosterol
Resistance via decrease intracellular accumulation

Ketoconazole

Co-DOC for Paracoccidodes and back-up for Blastoy

ces and Histoplasma. Rx: mucocutaneous candidasis or
dermatophytoses
 Azole Antifungals

Ketoconazole

Effective orally, but antacids reduce absorption

Adverse effects: reduce synthesis of cortisol and andro
gens, rash, fluid retention, leading to increase BP, hepat
oxicity (rare)
 Azole Antifungals

Fluconazole

DOC for esophagal and invasive candidiasis and cocci

domycoses, prophylaxis and suppression in cryptococcal
meningitis, vaginal candidiasis (single dose)
Oral absorption, penetrates CSF and saliva; renal elim
ination
Adverse effects: similar to ketoconazole but less intens
e
 Azole Antifungals

Itraconazole

DOC in blastomycoses and sporotrichoses – back – up ot

her mycoses and in candidiasis (eg. Fluconazole resistance)
Oral absorption increased by food; hepatic metabolism
Adverse effects: similar to ketoconazole but less P-450 in
hibition
 Flucytosine

Activated by fungal cytosine deaminase to 5 FU, decrease

RNA , thymidine synthase. Rapid resistance
Rx use: with amp B in candidial and cryptococcal infectio
ns – enters CSF. Toxic to bone marrow
 Griseofulvin

Anti-dermatophytic (oral) disrupting microtubule structur

e
Adverse effects: headace, thrush, peripheral neuritis, phot
otoxicity, avoid with history of porphyria

Terbinafine

Anti-dermatophytic-inhibits squalene epoxidase, decrease

ergosterol
Adverse effects: GI distress, rash, headache, increase LF
Ts
 Sites of Antiviral Drug Actions
Viral
adsorption
Enfurvitide Amantadine

penetration
uncoating Polymerase

Viral HOST Nucleic Acid Inhibitors

CELL Synthesis Reverse
release
Viral Transcriptase
Protein synthesis
Inhibitors
Neuraminidase assembly and processing
inhibitors
Protease
Inhibitors
 Acyclovir

Monophosphorylated by viral thymidine kinase (TK), then f

urther 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 chain
terminator, since it lacks the 3’ hydroxyl group
 Acyclovir Characteristics

Rx uses: HSV, VZV and Vanicella : decrease viral sh

edding 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 hydratio
n) and neurotoxicity (agitation, headache, confusion – s
eizures in OD), NOT hematotoxic
 Acyclovir Characteristics

Famciclovir and Valacyclovir

Approved for HSV infection – similar mechanis

m to acyclovir
Active vs strains resistant to acyclovir; but not T
K
 Gancyclovir

Mechanism similar to acyclovir, 1st phosphorylation vira

l-specific via a phosphotransferase, Gancyclovir-TP inhibit
s viral DNA polymerase, but does not cause chain terminat
ion
Resistance mechanisms similar to acyclovir
Rx uses: HSV, VZV and CMV. Mainly prophylaxis and
treatment of CMV including retinitis, oral, IV and retinal i
mplant forms
 Gancyclovir

Adverse Effects: dose-limiting hematotoxicity, mucositi

s, fever, rash and crystaluria (maintain hydration); seizur
es in OD
 Foscarnet

Not an antimetabolite, inhibits viral DNA and RNA pol

ymerases
Rx uses identical to ganciclovir, plus activity versus acy
clovir resistant strains of HSV
Adverse effects: dose-limiting nephrotoxicity with tubu
lar necrosis, electrolyte imbalance with hypocalcemia, an
d then tremors and seizures. Avoid pentamidine (IV)
 Drugs Active Against HIV

Nucleoside reverse transcriptase (NRTIs, eg. Zidovudi

ne)
Antimetabolites, converted to active forms via phosph
orylation
Commonly, two NRTIs (2 drugs) plus a protease inhib
itor (PI) are the components of HAART (highly active a
ntiretrovivral therapy) drug regimens
 Drugs Active Against HIV

HAART can reduce viral mRNA, reverse decline in CD

4 cells and decrease opportunistic infections
Non-nucleoside RTIs (NNRTIs), which do not require b
ioactivation (eg. Nevirapine, efavirenz) are also used in co
mbination with NRTIs
 Zidovudine (AZT)

Prototype, orally actve, hepatic metabolism, increase Z

DV toxicity with acetaminophen, ASA, cimetidine, probe
necid and sulfonamides
Dose-limiting hematotoxicity (neuropenia, anemia, gra
nulocytopenia), headache, asthenia, myalgia, myopathy a
nd peripheral neuropathy
 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
 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)
 Adverse Effects of Protease Inhibitors

Indinavir: nephrolithiasis (maintain hydration), GI di

stress, thrombocytopenia, inhibition of P-450
Ritonavir: GI distress, asthenia, paresthesias and dru
g interactions induces CYP1A2 and inhibits major P450
isoforms, increase effects of dronabiol, erythromycin, ke
toconazole and rifampin
 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
 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
 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%
 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
 Zanamivir and Oseltamivir

Inhibit neuraminidases of influenza A and B, enzymes which p

revent 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 b
y 2-3 days
Adverse: nausea and vomitting and zanamivir (via inhalation) c
auses nasal and throat irritation
 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
 Ribavirin

Adverse: hematotoxic, upper airway irritation, tetratogenic

 Summary of Mechanisms of Action of Antiviral Drugs

Mechanism of Action Major Drugs

Block viral penetration/uncoa Amantadine, rimantadin
ting e
Inhibit viral DNA Acyclovir, foscarnet, gan
polymerases ciclovir
Inhibit viral RNA polymerase Foscarnet, ribavirin
s
Inhibit viral reverse Zidovuline, didanosine, z
transcriptase alcitahine, lamivudine
Inhibit viral aspartate protea Indinavir, ritonavir, saqu
se inavir, nelfinavir
Inhibit viral neuraminidase Zanamivir, oseltamivir
 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
 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
 Drugs for Helminthic Infections

Most Intestinal Nematodes (Worms)

Mebendazole ( reduces glucose uptake and microtubul

ar structure) , or pyrantel pamoate (NM blocker and spas
tic paralysis)

Most Cestodes (Tapeworms and Trematodes )

Praziquantel ( increase Ca influx, vacuolization)

 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.

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.

 Activation of Innate Immunity: Sensing the Enemy

 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 structur
es on invading microorganisms (‘detection phase’)

(2) a phase of translating this sensory information into a lang

uage understood by the cells of the adaptive immune syste
m, e. g., chemokines and cytokines (‘transmission phase’)
 Some key elements of the adaptive immune system

B lymphocytes, their precursors and progeny, and their produc

ts – 8 different classes of antibody
T lymphocytes with / receptors, their precursors and progeny, t
heir lymphokine products,
and specifically CD4+ regulatory (suppressor) Tcells; CD8+ cyt
otoxic and cytokine secretory
cells; 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, imm
ature dendritic cells, B cells,
polymorphonuclear leukocytes, NK cells, mast cells, and platele
ts, as well as soluble Fc receptors
 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 release
Defensins
The complement cascade
Non-immunoglobulin opsonins, e. g., collectins such as m
annose-binding protein or C-reactive
protein, lectins, fibronectin, etc.
 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
Overall view of innate immunity shaping adaptive immune
responses. Cells of the innate immune system(DC = dendritic
cells; MC = mast cells) detect the presenceof foreign structures,
such as pathogen-associated molecular patterns, by surface expressed pat
tern-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
 Pathogen-associated Molecular Patterns

Required for differentiation of adaptive immune response

s when cells of the innate defense system interact with patho
gen-associated molecular patterns (PAMPs, i. e., highly cons
erved structures that are necessary for the survival of micro
organisms)
 Pathogen-associated Molecular Patterns

Pattern-recognition receptors primarily serve the purpose o

f enhancing phagocytosis.

Example, the macrophage mannose receptor (recognizin

g terminal mannose and fucose residues on microbial cell wall
s) or the macrophage scavenger receptor (recognizing polyani
onic ligands such as double stranded RNA, lipopolysaccharid
e, and lipoteichoic acid) are mainly involved in clearing patho
gens from the site of invasion
 Pathogen-associated Molecular Patterns

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

 Recognition of pathogen structures via surface receptors
on innate immune cells
Pattern-recognition receptors Pathogen-associated molecular patterns on innate i
une 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 Lipopolysaccharides
TLR5 Flagellin
TLR7 and TLR8 Imidazoquinoline Derivatives
TLR9 Unmethylated CpG-motif oligonucleotides
 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 aci
d,
double-stranded RNA, lipopolysaccharide
Mannose–fucose receptor Terminal mannose and fucose on microbial
glycoproteins/glycolipids
CD14 Monomeric lipopolysaccharides
CD48 Fimbrial protein FimH on enterobacteria
CD91 Heat-shock proteins 70, 90, gp 96; calreticulin
IgE/FceR-crosslink Parasitic lectins
unknown Allergens
 Host Cellular Sensors

At the immunological level, innate defenses rely mostly on gr

anulocytes, mast cells (MC), macrophages, dendritic cells (DC),
natural killer (NK), NKT, and T cells - a bridge between PAMP
s and the antigen-specific cells of adaptive immunity, translatin
g the sensory input of pattern-recognition receptors into soluble
mediators that communicate with T and B cells via specific cyto
kine/chemokine receptors.
 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 o
f the adaptive immune system

Continuously produced from hematopoietic stem cells within t

he bone marrow
 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, C
D80, 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 c
ytokines by infected cells, thus integrating different signals of da
nger
 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
 Host Cellular Sensors

Mast Cells
Activation is followed by de novo synthesis of numerous cytokin
es (TNF-alpha, interleukins 1-10, IL-12, IL-13, IL-15, IL-16, IL-1
8, IL-25, and GM-CSF) and chemokines (CCL2–5, CCL8, CCL11,
IL-8). Mast cells are long-lived and therefore able to respond repe
atedly to the same stimulus

In addition to their well-established central role in the pathogen

esis of allergic disorders, MCs are now also appreciated as key eff
ector cells in the induction of protectiveimmune responses to bacte
ria