Pharmacology of Antimicrobials
1

Use of chemical agents (natural or synthetic) to destroy or
inhibit the growth of infective agents & cancerous cells
Takes the advantage of biochemical differences b/n
µorganisms & humans
Antimicrobials are effective b/c of selective toxicity
Antibiotics: s/ces produced by µorganisms to suppress the
growth & replication or kill other µorganisms
2
Chemotherapy

Chemotherapy
Antimicrobials
Antibacterials
Antifungals
Antivirals
Antiprotozoals
Anthelmintics
Antineoplastics
3

Antibacterial Agents: ABX
Narrow spectrum: INH, Naldixic acid, Pen-G, Cloxacillin
Broad spectrum: CAPH, TTCs, Rifamycins, FQs
 Bactericidal:
Cell wall synthesis inhibitors, aminoglycosides, metronidazole,
FQs, CAPH (H.influenzae, S.pneumoniae, N.meningitidis)
 Bacteriostatic: TTCs, macrolides, sulphonamides, lincosamides,
aminocyclitoles, CAPH (G-ve bacilli, S.aureus)
4

 Confirm the presence of infection: careful Hx & physical
examination, signs & Sxs, predisposing factors
 Identification of the pathogen: collection of infected material,
stains, serology, culture & sensitivity
 Host & Drug factors:
5
Systematic Approach for the Selection of Antimicrobials

Patient specific considerations
Age: causative agents, contraindication
Disruption of host defenses: compromised  cidal!
Site of infection
History of recent antimicrobial use
Antimicrobial allergies
Renal and/or liver function
Concomitant administration of other medications
Pregnant & nursing women and
Compliance
6

Drug specific considerations
Spectrum of activity: sensitivity testing
Effects on nontargeted microbial flora
Appropriate dosage
Pharmacokinetic & pharmacodynamic properties
Determinants of rational dosing: TDK, CDK, PAE
Safety: ADR & drug-interaction
Cost
7

8

Indication:
 Empiric therapy
Severe infection of unknown etiology
Mixed infection
 Prevention of resistance
 Decreased toxicity
 Enhanced action: penicillin + aminoglycoside = synergism
9
Antimicrobial drug combination

Disadvantages of antimicrobial combination
Increase risk of toxicity/allergy/
Drug interaction:
Antagonism: TTC + Penicillin
Super infection
Resistance
Increased cost
10

✍Prophylactic therapy: dental procedure, surgery, TB, malaria
prophylaxis, meningococcal carriers (Neisseria meningitidis)
✍Empiric therapy: symptomatic management
✍Definitive therapy: identification of pathogen & DST
☞Goal: selective toxicity
11
Use of Antimicrobials

Can be classified in a number of ways e.g. by their;
Chemical structure: β-lactams, aminoglycosides,…
MOA: inhibitors of cell wall synthesis, protein synthesis,…
Activity against particular types of organisms: antibacterial,
antifungal, antiviral,…
12
Classifications of Antimicrobials

13

Mechanisms of Resistance to Antimicrobial Agents
14

15

BETA-LACTAM ANTIBIOTICS
16

Inhibitors of Cell-wall Synthesis
All cell-wall synthesis inhibitors are bactericidal
Beta-Lactam antibiotics 17

 MOA:
Bacterial cell wall is cross-linked polymer of polysaccharides &
pentapeptides
Penicillins interact with cytoplasmic membrane-binding
proteins (PBPs) to inhibit transpeptidation reactions involved in
cross-linking, the final step in cell-wall synthesis
Inhibit inhibitors of autolysins: destroy the existing cell wall
Kill the bacteria in time dependent fashion
18
Penicillins

 Mechanisms of resistance:
β-lactamases break β-lactam ring (Staphylococci)
Structural change in PBPs (e.g., MRSA, penicillin-resistant
pneumococci)
Decreased permeability to the drug:
Lack of high permeability porins (Pseudomonas)
Presence of efflux pump (Klebsiella pneumoniae)
19

Subgroups & antimicrobial activity
Narrow spectrum, β-lactamase sensitive:
PenG (Benzylpenicillin) & Pen. V (Phenoxymethylpenicillin)
Spectrum: streptococci, meningococci, T.pallidum, clostridium
Very narrow spectrum, β-lactamase resistant: nafcillin,
methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin
Spectrum: known or suspected staphylococci (not MRSA)
20

Broad spectrum, aminopenicillins, β-lactamase sensitive:
ampicillin & amoxicillin
Spectrum: G+ve cocci (not staph), E. coli, H. influenzae,
Proteus, L.monocytogenes (ampicillin), Borrelia burgdorferi
(amoxicillin), H. pylori (amoxicillin), Shigella, Salmonella
Extended spectrum, antipseudomonal, β-lactamase sensitive:
Carboxypenicillins: carbenicillin, ticarcillin
Ureidopenicillins: piperacillin, mezlocillin, azlocillin
Spectrum: ed activity against G-ve rods: P. aeruginosa
21

 General considerations:
Activity enhanced if used in combination with β-lactamase
inhibitors: clavulanic acid, sulbactam, avibactam, tazobactam,
vaborbactam
Synergy with aminoglycosides against pseudomonal &
enterococcal species
22

 Penicillin units
Its activity originally defined in units
Crystalline Penicillin G-Na contains 1600 units per mg (1 unit
= 0.6 mcg; 1 million units of penicillin = 0.6 g)
Semisynthetic penicillins prescribed by weight rather than units
23

 PKs:
Most are eliminated via active tubular secretion; blocked by
probenecid; dose reduction needed only in major renal
dysfunction
Nafcillin & oxacillin primarily metabolized in the liver
Ampicillin undergoes enterohepatic cycling
Benzathine PenG: repository form (half-life of 2 wks)
All can cross placental barrier & get access to breast milk
24

 AEs:
Hypersensitivity (10%): rash – angioedema & anaphylaxis
Cross-allergic reactions occur among β-lactam antibiotics
Diarrhea: disruption of the normal balance of intestinal
µorganisms
Pseudomembranous colitis from Clostridium difficile
Nephritis (interstitial nephritis): Methicillin is no longer used
25

Neurotoxicity: provoke seizures if injected intrathecally or if
very high blood levels are reached
Epileptic patients at risk: due to GABAergic inhibition
Hematologic toxicities:  coagulation (inhibit platelet function)
@ high doses of piperacillin, ticarcillin, carbenicillin & nafcillin
(to some extent, with PenG)
Cytopenias with therapy of >2 wks: CBC weekly
26

Cephalosporins
Obtained from Cephalosporium acremonium fungus
MOA & resistance: identical to penicillins
More resistant to β-lactamases than penicillins
Based on their bacterial susceptibility patterns & resistance to
β-lactamases; classified in to 1st, 2nd, 3rd, 4th, 5th generations
Ineffective against L. monocytogenes, atypical (mycoplasma),
MRSA, C. difficile, Enterococci
27

Subgroups & antimicrobial activity:
 1st generation: cefazolin, cephalexin, cephalothin, cephapirin,
cephradine, cefadroxil
Act as penicillin G substitutes
Spectrum: G+ve cocci (not MRSA), E. coli, K. pneumoniae &
some Proteus species
Common use in surgical prophylaxis
PKs: none enter CNS
28

 2nd generation:
True cephalosporins: cefaclor, cefuroxime, cefprozil & Cephamycins
(derived from Streptomyces spp & synthetic derivatives)
Spectrum:
G-ve: H.influenzae, Klebsiella, Proteus, E.coli, M.catarrhalis
Weaker G+ve activity
Anaerobes (B.fragilis): cephamycins; cefotetan, cefmetazole, cefoxitin
Not used as 1st line due to ed resistance
PKs: can’t enter into CNS, except cefuroxime
29

 3rd generation:
Parenteral: ceftriaxone, cefotaxime, ceftazidime
PO: cefdinir, cefditoren, cefixime, cefpodoxime, ceftibuten
Spectrum:
G+ve & G-ve cocci (N.gonorrhea) & many G-ve rods: β-lactamase
producing strains of H. influenza
Enteric organisms: Serratia marcescens & Providencia species
PKs: most enter CNS; important in empiric Rx of meningitis &
sepsis
30

 4th generation: cefepime (IV)
Spectrum:
G+ve: streptococci, staphylococci
G-ve: Enterobacter sps, E. coli, K. pneumoniae, P. mirabilis, P.
aeruginosa
Resistant to most β-lactamases
Enters into CNS
31

 5th Generation: Ceftaroline (active)
Spectrum:
G+ve: broad including MRSA
G-ve (similar to 3rd gen.) & P. aeruginosa, extended-spectrum β-
lactamase (ESBL)-producing Enterobacteriaceae, Acinetobacter
baumannii
Administered IV BID as a prodrug (Ceftaroline fosamil)
Use: complicated skin & skin structure infections & CAP
BID regimen limits use outside of an institutional setting
32

PKs:
Renal clearance similar to penicillins, with active tubular
secretion blocked by probenecid
Dose modification in renal dysfunction
Ceftriaxone is largely excreted through the bile into the feces
33

 AEs:
Hypersensitivity
Cross-allergenicity with penicillins (3-5%): high rate of allergic
cross-sensitivity b/n penicillin & 1st-generation cephalosporins
Avoid cephalosporins in patients allergic to penicillins (for G+ve
organisms, consider macrolides; for G-ve rods, consider
aztreonam)
34

Carbapenems
 Imipenem, meropenem, ertapenem, doripenem
 MOA: same as penicillins & cephalosporins
 Resistant to β-lactamases
 Spectrum: G+ve cocci, G-ve rods (Enterobacter, Pseudomonas) &
anaerobes
Important in-hospital agents for empiric use in severe life-
threatening infections
35

 PKs:
Imipenem is given with cilastatin, a renal dehydropeptidase
inhibitor, w/c inhibits imipenem’s metabolism to a nephrotoxic
metabolite
Both drugs undergo renal elimination:  dose in renal
dysfunction
 AEs:
GI distress
Drug fever (partial cross-allergenicity with penicillins)
CNS effects: seizures (GABA receptor inhibition of β-lactam
ring) with imipenem in overdose or renal dysfunction 36

MONOBACTAMS: Aztreonam
Isolated from Chromobacterium violaceum
 MOA:
Same as for penicillins & cephalosporins
Resistant to β-lactamases
 Uses:
IV drug mainly active versus G-ve rods
No cross-allergenicity with penicillins or cephalosporins 37

Other cell wall synthesis inhibitors:
 Fosfomycin, cycloserine, bacitracin, glycopeptides
 Fosfomycin: bactericidal
Inhibits the first cytoplasmic step in cell wall biosynthesis
Covalently binds with UDP-N-acetylglucosamine enolpyruvyl
transferase (MurA);
Involved in the formation of the peptidoglycan precursor UDP-
N-acetylmuramic acid (UDPMurNAc)
38

Fosfomycin uses two mechanisms for cellular entry;
L – alphaglycerophosphate & hexose-6-phosphate transporter
systems
Fosfomycin reduces adherence of bacteria to urinary epithelial
cells
It also suppresses PAF receptors in respiratory epithelial cells 
reducing adhesion of S.pneumoniae & H.influenzae
39

 Has oral & parenteral forms
Dose:
3g Stat PO (FDA) for uncomplicated UTI, OR
3g Q10 days for UTI prophylaxis
The oral formulation is a powder (fosfomycin tromethamine) &
BA is approximately 40%, with a t½ of 5-8 h
 Distribution: low in blood but highly concentrated in urine
 AEs: well tolerated; GI distress, vaginitis, headache, dizziness
40

Cycloserine
 D-4-amino-3-isoxazolidone
 Broad-spectrum, produced by Streptococcus orchidaceous
41

 MOA:
Acts within the cytoplasm to prevent the formation of D-
alanine-D-alanine
It does this by mimicking the structure of D-alanine &
inhibiting;
L-alanine racemase: racemizing L-alanine to D-alanine
D-alanine-D-alanine ligase: linking the two D-alanine units
together
Spectrum: against MAC, MTB, Enterococci, S. aureus, S.
epidermidis, Nocardia & Chlamydia
42

Bacitracin
An antibiotic produced by the Tracy-I strain of Bacillus subtilis
Bacitracins are a group of polypeptide antibiotics; multiple
components have been demonstrated in the commercial pdts
The major constituent is bacitracin A; its probable structural
formula is:
43

✍Bacitracin:
 Inhibits the recycling of pyrophosphobactoprenol to the inner
leaflet
Bactoprenol is a lipid synthesized by three d/t species of
lactobacilli. It is a hydrophobic C55 isoprenoid.
BPP transports NAM & NAG across the cell membrane during
the synthesis of peptidoglycan, by flipping the repeating
monomer units from the cytoplasm to the periplasm
Bactoprenol remains in the membrane at all times
 Since it is associated with severe nephrotoxicity, not given
systemically rather used topically
44

 Clinical Use:
Alone or in combination with polymyxin or neomycin: Rx of
mixed skin, wound or mucous membrane infections
 AEs:
Significant nephrotoxicity limits systemic administration
Skin sensitization: on topical use
45

Glycopeptides
 Vancomycin, Teicoplanin, Telavancin, Oritavancin, Dalbavancin
 Vancomycin
A tricyclic glycopeptide produced by Streptococcus orientalis
 MOA:
Binding to peptidoglycan pentapeptide  Transglycosylase
inhibition  inhibition of elongation of peptidoglycan
(glycosylation)  no cross linking
46

Doesn’t bind with PBPs
 Spectrum: MRSA, enterococci, C.difficile (backup drug)
 Resistance: VRSA & VRE strains emerging
Enterococcal resistance involves change in the muramyl
pentapeptide target; the terminal D-ala is replaced by D-
lactate
47

 PKs:
Used IV & orally (not absorbed) in colitis
Enters most tissues (e.g., bone), but not CNS
Eliminated by renal filtration (dose in renal dysfunction)
48

 AEs:
Red man syndrome (histamine release)
Ototoxicity (usually permanent, additive with other drugs)
Neutropenia: antibody-mediated destruction of neutrophils
Nephrotoxicity (rare & minor): due to drug induced oxidative
stress on the proximal renal tubule  renal tubular ischemia
(additive with other drugs)
49

 Telavancin, Oritavancin, Dalbavancin
Structurally different from vancomycin
More potent than vancomycin
Spectrum: same as vancomycin + vancomycin resistant strains
Oritavancin & dalbavancin have t½ of (245 & 187 hrs,
respectively)
Telavancin has limited use b/c of ADRs: nephrotoxicity, risk of
fetal harm & interactions with medications known to prolong
the QTc interval (fluoroquinolones, macrolides)
50

Summary
51

Protein Synthesis
Simplified schematic of mRNA translation 52

Protein synthesis inhibitors
Substances that stop or slow the growth or proliferation of
cells by blocking the generation of new proteins
Act at the ribosome level (either the ribosome itself or the
translation factor), taking advantages of the major d/ces b/n
prokaryotic & eukaryotic ribosome structures
Toxins: ricin also function via protein synthesis inhibition
Ricin acts at the eukaryotic 60S
53

Protein synthesis inhibitors…
Aminoglycosides
Aminocyclitols: spectinomycin
Tetracyclines & Amphenicols: broad spectrum
Macrolides: moderate spectrum
Lincosamides (clindamycin, lincomycin): narrow spectrum
Streptogramins (Quinupristin, Dalfopristin): narrow spectrum
Oxazolidinones (Linezolid, Tedizolid, Sutezolid): narrow
spectrum
Mupirocin: G-ve & G+ve
54

55

Mechanism
 Work at different stages of prokaryotic mRNA translation into
proteins, like;
Initiation
Elongation: aminoacyl tRNA entry, proofreading, peptidyl
transfer & ribosomal translocation &
Termination
56

Summary of MOA of Protein Synthesis Inhibition
57

Aminoglycosides
 Activity & clinical uses:
Bactericidal, accumulated intracellularly in µorganisms via an
O2-dependent uptake  anaerobes are innately resistant
Spectrum: aerobic G-ve rods (P.aeruginosa, K. pneumoniae,
Enterobacter sps)
With β-lactam ABX: for Rx of Enterococcus faecalis &
Enterococcus faecium infective endocarditis
Streptomycin used in TB; is the DOC for bubonic plague &
tularemia (Francisella tularensis)
58

 PKs:
Highly polar & polycationic structure; not absorbed orally
Must be given parenterally except neomycin
Distribution: variable (due to their hydrophilicity)
Does not cross blood-brain barrier into CNS
May accumulate in fetal plasma & amniotic fluid; streptomycin &
tobramycin can cause hearing loss in children born to women who
receive the drug during pregnancy: megalin transporter
Excretion: >90% of the parenteral agents unchanged in the urine
Dose adjustment needed in renal dysfunction
Neomycin is primarily excreted unchanged in the feces 59

 AEs:
Nephrotoxicity: proteinuria, hypokalemia, acidosis & acute
tubular necrosis; usually reversible, but enhanced by
vancomycin, amphotericin B, cisplatin & cyclosporine
Ototoxicity from hair cell damage; includes deafness
(irreversible) & vestibular dysfunction (reversible); toxicity may
be enhanced by cisplatin or loop diuretics
Neuromuscular paralysis: release of ACh; may enhance
effects of skeletal muscle relaxants: Rx is calcium gluconate or
neostigmine
Skin rash (contact dermatitis): topical neomycin
60

Tetracyclines
 Activity & clinical uses:
Bacteriostatic drugs, actively taken up by susceptible bacteria
Broad-spectrum: good activity versus chlamydial &
mycoplasmal species, H. pylori, Rickettsia, Borrelia burgdorferi,
Brucella, Vibrio & Treponema (backup drug), mycobacteria, G-
ve & G+ve, protozoa
61

Doxycycline: more activity overall than tetracycline HCl & has
particular usefulness in prostatitis b/c it reaches high levels in
prostatic fluid
Minocycline: in saliva & tears at high concentrations & used in
the meningococcal carrier state
Tigecycline: used in complicated skin, soft tissue & intestinal
infections due to resistant G+ve (MRSA, VRE), G-ve & anaerobes
62

 PKs:
Adequately absorbed after PO
TTCs bind with di-& tri-valent cations (Ca++, Mg++, Al3+, Fe++),
which  their absorption
Distribution: concentrate well in the bile, liver, kidney, gingival
fluid, skin
Bind to tissues undergoing calcification (teeth & bones) or to
tumors that have high Ca++content
63

Only minocycline & doxycycline achieve therapeutic levels in
the CSF
All TTCs cross the placental barrier & concentrate in fetal
bones & dentition
Most are excreted via kidney:  dose in renal dysfunction
Doxycycline eliminated by liver
Doxycycline & minocycline available in PO & IV
64

Pharmacokinetics…
65

 AEs:
Gastric discomfort: epigastric distress due to irritation of
gastric mucosa
Tooth enamel dysplasia & possible bone growth in children
(avoid)
Phototoxicity (more frequent with tetracycline, demeclocycline)
Superinfections  candidiasis or colitis
66

Vestibular dysfunction (minocycline): dizziness, vertigo, tinnitus
Pseudotumor cerebri: benign, intracranial hypertension
☞Contraindication:
Pregnancy: cause hepatotoxicity @ very high doses
Breast-feeding women & children <8 years old
67

Chloramphenicol
 Activity & clinical uses:
Broad spectrum with bacteriostatic activity, may be cidal
depending on dose & organism
Spectrum: chlamydiae, rickettsiae, spirochetes, anaerobes
Restricted to life-threatening infections for w/c no alternatives
exist
68

 PKs:
Available PO, IV & topical (e.g., ophthalmic) preparations
Oral capsule is absorbed rapidly from the GI tract
Widely distributed throughout the body (including CSF)
Metabolized by hepatic Glucuronidation & dose reductions are
needed in liver dysfunction or cirrhosis
Secreted into breast milk: avoided in breastfeeding mothers
69

 AEs:
Anemias: dose-related anemia, hemolytic anemia (in G6PDH
deficiency), aplastic anemia
Gray baby syndrome in neonates: UDP-glucuronyl transferase
 DDI:
Inducer of CYP450s
Concurrent administration of phenobarbital or rifampin:
shortens the t½ of CAPH
70

Macrolides
 Erythromycin, azithromycin, clarithromycin, telithromycin,
fidaxomicin
Erythromycin has similar spectrum with PenG; alternative
Clarithromycin: spectrum of erythromycin PLUS;
H.influenza, atypicals: Chlamydia, Mycoplasma & Ureaplasma
Legionella pneumophila, Campylobacter jejuni, Moraxella catarrhalis
Mycobacterium avium-intracellulare (MAC), H. pylori
Azithromycin: more active against H. influenzae & M.catarrhalis, less
active versus streptococci & staphylococci
Telithromycin (ketolide): active vs macrolide-resistant organisms
71

 PKs:
Inhibit CYP450s, except azithromycin
72

 AEs:
GI distress & motility: stimulate motilin receptors
(erythromycin, azithromycin > clarithromycin)
Ototoxicity: reversible deafness at high doses
Cholestatic jaundice: estolate form of erythromycin
Increased QT interval
 CI: hepatic dysfunction cautiously with erythromycin,
telithromycin, or azithromycin, b/c these drugs accumulate in
the liver
 DDI: digoxin reabsorption from enterohepatic circulation
73

Lincosamides: Clindamycin & lincomycin
Not macrolides, but has the same PK & PD
Narrow spectrum: G+ve cocci (including community-acquired
MRSA) & anaerobes: B. fragilis (backup drug)
Concentration in bone has clinical value in osteomyelitis due to
G+ve cocci
 AEs: pseudomembranous colitis/C. difficile
74

Oxazolidinones: Linezolid, Tedizolid, Sutezolid
 MOA:
Inhibits the formation of the initiation complex in bacterial
translation systems by preventing formation of the N-
formylmethionyltRNA – ribosome – mRNA ternary complex
 Spectrum:
Rx of VRSA, VRE & drug-resistant pneumococci
75

 AEs:
Serotonin syndrome: MAO-A & B inhibition  levels of 5-HT
activity in the brain
Hyperlactatemia & metabolic acidosis: due to mitochondrial
inhibition
Nerve damage (CNS & PNS): due to mitochondrial suppression
Hematologic: bone marrow suppression (myelosuppression) 
low blood counts (platelets, RBCs, or WBCs) in patients treated
with linezolid for at least 21 days. Not common & reversible
76

Streptogramins: quinupristin, dalfopristin
 MOA: via several mechanisms
Binding to sites on 50S ribosomal subunit, they prevent the
interaction of amino-acyl-tRNA with acceptor site & stimulate
its dissociation from ternary complex
May also the release of completed polypeptide by blocking its
extrusion
77

 Spectrum:
Used parenterally in severe infections caused by VRSA & VRE,
as well as other drug resistant G+ve cocci
Streptogramins for E. faecium, including VRE faecium, but not
for E.faecalis
Linezolid for both types of enterococci
 AEs: toxic potential remains to be established
78

Summary
79

80

 Activity & clinical uses:
Sulfonamides alone are limited in use b/c of multiple resistance
Sulfasalazine is a prodrug used in ulcerative colitis &
rheumatoid arthritis
Ag sulfadiazine used in burns
81

5-ASA: 5-aminosalicylic acid, SP: sulfapyridine
Metabolism & Uses of Sulfasalazine
82

Combination with DHFR inhibitors: resistance & synergy
 Uses of TMP-SMX (co-trimoxazole): dose (1:5 ratio)
Bacteria:
DOC in Nocardia, Listeria (backup)
G-ve: E. coli, Salmonella, Shigella, H. influenzae
G+ve: Staph. (community acquired MRSA, Strep.)
Fungus: PCP (back-up drugs are pentamidine & atovaquone)
Protozoa: T. gondii (sulfadiazine + pyrimethamine)
83

 PKs:
Sulfonamides are hepatically acetylated (conjugation)
Renally excreted metabolites cause crystalluria (older drugs)
High protein binding
 Drug interaction:
Kernicterus in neonates (avoid in 3rd trimester)
84

 AEs:
Sulfonamides:
Hypersensitivity: rashes, SJS
Hemolysis in G6PD deficiency
Phototoxicity
Trimethoprim or pyrimethamine:
Bone marrow suppression (leukopenia)
85

Direct Inhibitors of Nucleic Acid Synthesis:
Quinolones, FQs, Rifamycins
 Drugs: ciprofloxacin, levofloxacin, “−floxacins”; bactericidal
 MOA: block DNA replication by inhibit the ligase domains of;
Topoisomerase II (DNA gyrase): in G-ve bacteria  relaxation
of super coiled DNA  DNA strand breakage &
Topoisomerase IV: G+ve bacteria  impacts chromosomal
stabilization during cell division, thus interfering with the
separation of newly replicated DNA
Resistance is increasing
86

 Activity & clinical uses:
UTIs, particularly when resistant to Cotrimoxazole
STDs/PIDs: chlamydia, gonorrhea
Skin, soft tissue & bone infections by G-ve organisms
Diarrhea to Shigella, Salmonella, E. coli, Campylobacter
Drug-resistant pneumococci (levofloxacin)
87

 PKs:
Iron, Ca++ limit their absorption
Eliminated mainly by kidney by filtration & active secretion
(inhibited by probenecid)
Reduce dose in renal dysfunction
Moxifloxacin: through liver
 AEs:
Tendonitis, tendon rupture
Phototoxicity, rashes, CNS effects (insomnia, dizziness, headache)
 CI: pregnancy & children (inhibition of chondrogenesis)
88

Unclassified Antibiotic: Metronidazole
In anaerobes, converted to free radicals by ferredoxin, binds to DNA
& other macromolecules, bactericidal
Antiprotozoal: Giardia, Trichomonas, Entamoeba
Antibacterial: strong activity against most anaerobic G-ve Bacteroides
sps, G+ve Clostridium sps (DOC in pseudomembranous colitis),
Gardnerella vaginalis & H. Pylori (G-ve)
Used topically for rosacea: antiinflammatory & immunesuppressant
 AEs: metallic taste, disulfiram-like effect
89

ANTITUBERCULAR DRUGS
Combination drug therapy is the rule to delay or prevent the
emergence of resistance & to provide additive (possibly
synergistic) effects against Mycobacterium tuberculosis
The primary drugs: H, R, Z, E
Regimens may include 2 – 4 of these drugs, but in the case of
highly resistant organisms, other agents may also be required
90

Backup drugs: aminoglycosides (streptomycin, amikacin,
kanamycin), fluoroquinolones, Capreomycin (marked hearing
loss) & cycloserine (neurotoxic; “psych-serine”)
Prophylaxis: usually INH, but rifampin if intolerant
In suspected MDR, both drugs may be used in combination
91

92

93

94
Antifungal Drugs & Their Targets
Naftifine
Terbinafine

Polyenes: Amphotericin B (AmB), Nystatin
 MOA:
Amphoteric compounds with both polar & nonpolar structural
components: interact with ergosterol in fungal membranes to
form artificial “pores,” which disrupt membrane permeability
Resistant fungal strains appear to have low ergosterol content
in their cell membranes
95

 Activity & clinical uses:
AmB has wide fungicidal spectrum; remains the DOC (or co-
DOC) for severe infections caused by Cryptococcus & Mucor
AmB: synergistic with flucytosine in cryptococcosis
Nystatin (too toxic for systemic use): topically for localized
infections (e.g., candidiasis)
96

 PKs:
AmB given by slow IV infusion: poor penetration into the CNS
(intrathecal possible)
Slow clearance (t½ >2 wks) via both metabolism & renal
elimination
 AEs:
Infusion-related:
Fever, chills, muscle rigor, hypotension (histamine release)
occur during IV infusion (a test dose is advisable)
Can be alleviated partly by pretreatment with NSAIDs,
antihistamines, meperidine & adrenal steroids 97

Dose-dependent:
Nephrotoxicity (AmB binds to cholesterol of kidney cells):
GFR, tubular acidosis,  K+ & Mg++ & anemia through 
erythropoietin
Protect by Na+ loading, use of liposomal amphotericin B, or by
drug combinations (e.g., + flucytosine), permitting  in
amphotericin B dose
98

Azoles: Imidazole, Triazole, Tetrazole
Imidazole: Clotrimazole, Econazole, Miconazole, Ketoconazole,
Tioconazole, Fenticonazole
Triazole: Fluconazole, Itraconazole, Posaconazole, Voriconazole
Tetrazole: Oteseconazole (selective)
 MOA:
Azoles are fungicidal & interfere with the synthesis of
ergosterol by inhibiting 14--demethylase, a fungal CYP450
enzyme, which converts lanosterol to ergosterol
Resistance: ed intracellular accumulation of azoles (efflux)
99

 Activity & clinical uses:
Ketoconazole:
Co-DOC for Paracoccidioides & backup for Blastomyces &
Histoplasma
Oral use in mucocutaneous candidiasis or dermatophytoses
Fluconazole:
DOC for esophageal & invasive candidiasis &
coccidioidomycoses
Prophylaxis & suppression in cryptococcal meningitis
100

Itraconazole & Voriconazole:
DOC in blastomycoses, sporotrichoses, aspergillosis
Backup for several other mycoses & candidiasis
Clotrimazole & miconazole:
Used topically for candidal & dermatophytic infections
101

 PKs:
Effective orally
Absorption of ketoconazole  by antacids
Absorption of itraconazole  by food (fatty meal)
Only fluconazole penetrates into the CSF & can be used in
meningeal infection
Fluconazole is eliminated in the urine, largely unchanged form
Ketoconazole & itraconazole are metabolized by liver enzymes
Inhibition of hepatic CYP450s
102

 AEs:
 synthesis of steroids: cortisol & testosterone  libido,
gynecomastia, menstrual irregularities
 liver function tests & rare hepatotoxicity
103

 Flucytosine:
Activated by fungal cytosine deaminase to 5-FU, w/c after tri-
phosphorylation is incorporated into fungal RNA  inhibition of
protein synthesis
5-FU also forms 5-Fd-UMP, w/c inhibits thymidylate synthase
 thymine  inhibit DNA synthesis
Resistance emerges rapidly if flucytosine is used alone
Use in combination with AmB in severe candidal & cryptococcal
infections: enters CSF
Toxic to bone marrow
104

105
(uracil
phosphoribosyltransferase)

 Griseofulvin:
Active only against dermatophytes (orally, not topically) by
depositing in newly formed keratin & disrupting microtubule
structure
 AEs: disulfiram-like reaction
106

 Terbinafine:
Active only against dermatophytes by inhibiting squalene
epoxidase  ergosterol
Possibly superior to griseofulvin in onychomycoses
 AEs: GI distress, rash, headache,  liver function tests 
possible hepatotoxicity
107

 Echinocandins: caspofungin & other “fungins”
Inhibit the synthesis of β-1,2 glucan, a critical component of
fungal cell walls
Back-up drugs given IV for disseminated & mucocutaneous
Candida infections or invasive aspergillosis
Monitor liver function
108

ANTIVIRAL AGENTS
 Introduction:
Viruses are obligate intracellular parasites, rely on host
biosynthetic machinery to reproduce
They are simple organisms consist of;
Genetic material (DNA or RNA)
Lipid envelope derived from the infected host cell
109

Viral replication has distinct stages: antiviral drug intervention
Completely unaffected by antibiotics: no cell wall, ribosome,…
Do not carry out metabolic processes, use much of the host’s
metabolic machinery
Few drugs are selective enough to prevent viral replication
without injury to the infected host cells
110

Therapy for viral diseases is further complicated by the fact
that the clinical sXs appear late in the course of the disease, at
a time when most of the virus particles have replicated
At this stage of viral infection, administration of drugs that
block viral replication has limited effectiveness
However, some antiviral agents are useful as prophylactic
agents
111

Classification of Viruses
 Based on their genomic content, viruses can be:
 DNA viruses:
Poxviruses  smallpox
Herpesviruses  chickenpox, shingles, oral & genital herpes
Adenoviruses  conjunctivitis, sore throat
Hepadnaviruses  hepatitis B (HBV)
Papillomaviruses  warts 112

 RNA viruses: complete their replication in the cytoplasm, but
influenza are transcribed in the host cell nucleus
Rubella virus  German measles
Rhabdoviruses  rabies
Picornaviruses  poliomyelitis, meningitis, colds, hepatitis-A
Arenaviruses  meningitis, Lassa fever (by Lassa virus)
113

RNA viruses…
Flaviviruses  West Nile meningoencephalitis, yellow fever,
hepatitis C
Orthomyxoviruses  influenza
Paramyxoviruses  measles (rubeola), mumps
Coronaviruses  colds, severe acute respiratory syndrome
(SARS)
 Retroviruses (a special group of RNA viruses): HIV 114

ANTIVIRAL AGENTS
Many antiviral drugs are antimetabolites that resemble the
structure of naturally occurring purine & pyrimidine bases or
their nucleoside forms
Antimetabolites are usually prodrugs requiring metabolic
activation by host-cell or viral enzymes;
Commonly, bioactivation involves phosphorylation reactions
catalyzed by kinases
115

Site of action of Antiviral drugs
116

MOA of Antiviral Drugs
117

ANTIHERPETICS
 Acyclovir:
 MOA:
Mono-phosphorylated by viral thymidine kinase (TK), then
further bio-activated by host-cell kinases to the triphosphate;
Acyclovir-triphosphate is both a substrate for & inhibitor of viral
DNA polymerase
118

When incorporated into the DNA molecule, acts as a chain
terminator b/c it lacks the equivalent of a ribosyl 3′-OH group
Resistance possibly due to changes in DNA polymerase or to
ed activity of TK
>50% of HSV strains resistant to acyclovir completely lack
thymidine kinase (TK– strains)
119

Common Mechanism for “ovirs” and NRTIs
120

 Activity & clinical uses:
Activity: against HSV & VZV
There are topical, oral & IV forms; has a short t½
Reduces viral shedding (expulsion & release of virus progeny)
in genital herpes;  acute neuritis in shingles but has no effect
on postherpetic neuralgia
Reduces symptoms if used early in chickenpox; prophylactic in
immunocompromised patients
121

 AEs:
Minor with oral use, more obvious with IV
Crystalluria (maintain full hydration) & neurotoxicity (agitation,
headache, confusion: seizures in over dose)
Is not hematotoxic
122

 Newer drugs: famciclovir & valacyclovir
Have same MOA with acyclovir
Approved for HSV infection
Activity against strains resistant to acyclovir, but not TK– strains
A longer t½ than acyclovir
123

 Ganciclovir:
MOA: similar to that of acyclovir
First phosphorylation step is viral-specific; involves TK in HSV
& a phosphotransferase (UL97) in cytomegalovirus (CMV)
Triphosphate form inhibits viral DNA polymerase & causes
chain termination
Resistance mechanisms similar to acyclovir
124

 Activity & clinical uses:
HSV, VZV & CMV
Mostly used in prophylaxis & Rx of CMV infections, including
retinitis, in AIDS & transplant patients: relapses & retinal
detachment occur
 AEs:
Dose-limiting hematotoxicity (leukopenia, thrombocytopenia),
mucositis, fever, rash & crystalluria (maintain hydration)
Seizures in overdose
125

Phosphonoformic acid (PFA, Foscarnet)
Is a pyrophosphate analogue
 MOA & clinical uses:
Not an antimetabolite, but still inhibits viral DNA & RNA
polymerases noncompetitively
Uses identical to ganciclovir, plus > activity versus acyclovir-
resistant strains of HSV
126

 AEs:
Dose-limiting nephrotoxicity with acute tubular necrosis,
electrolyte imbalance with hypocalcemia (tremors & seizures)
Avoid pentamidine IV:  nephrotoxicity & hypocalcemia
127

Drugs for Hepatic Viral infections
Identified hepatitis viruses are A, B, C, D & E, [F, G(orphan)]
Each has a pathogenesis specifically involving replication in and
destruction of hepatocytes
Hepatitis A: a common infection due to ingestion of the virus
but not a chronic disease
HBV & HCV: the most common causes of chronic hepatitis,
cirrhosis & hepatocellular carcinoma
Currently therapy is available for HBV & HCV infections
128

HCV enters into hepatocyte following interaction with cellular
entry factors
Then, a viral genome is released from the nucleocapsid & an
HCV polyprotein is translated using the internal ribosome entry
site
Cleavage of polyprotein by cellular & viral proteases to yield
structural & nonstructural proteins
129

The core NS3 & NS5A proteins form the replication complex on lipid
droplets & serve as a scaffold for RNA polymerase to replicate the
viral genome
Then packaged in envelope glycoproteins before noncytolytic
secretion of mature virions
Direct-acting antiviral agents (DAAs): target the NS3/NS4A protease,
NS5B polymerase & NS5A involved in HCV replication & assembly
Combination with DAAs: to optimize HCV Rx response rates
130

131

NS3/NS4A protease inhibitors: -previr end
Paritaprevir (requires ritonavir boosting), grazoprevir,
voxilaprevir, glecaprevir, Boceprevir & Telaprevir
MOA: covalently & reversibly bind to the HCV NS3/4A serine
protease active site & inhibiting viral replication in host cells
The viral NS3/NS4A serine protease is crucial for processing the
single polyprotein encoded by HCV RNA into individually active
proteins: NS4A, NS4B, NS5A & NS5B
132

Without these serine proteins, RNA replication does not occur
& HCV life cycle is disrupted
These drugs have a lower barrier to resistance than sofosbuvir
Metabolized by CYP3A: significant potential for DDIs
 AEs: rash, pruritus, nausea, fatigue, anemia
133

Boceprevir & Telaprevir
PO DAAs for Rx of chronic HCV
High risk of resistance in monotherapy
Used in combination with interferon- & ribavirin
Food enhances the absorption of both drugs
Metabolized via CYP450 & are strong inhibitors of CYP3A4/5
 AEs: anemia, rash & anorectal discomfort
134

NS5B RNA polymerase inhibitors: -buvir end
NS5B: RNA dependent RNA polymerase responsible for HCV
replication
Processed with other HCV proteins into an individual
polypeptide by the viral NS3/NS4A serine protease
Two types of NS5B RNA polymerase inhibitors:
Nucleoside/nucleotide analogues, compete for active site &
Nonnucleoside analogues; target allosteric sites
Sofosbuvir: nucleotide & dasabuvir: nonnucleoside
AEs: few & well tolerated
135

NS5A replication complex inhibitors: -asvir end
Ledipasvir, ombitasvir, elbasvir, velpatasvir, pibrentasvir, daclatasvir
NS5A: essential for HCV RNA replication, assembly & release
Provides a platform for replication by forming a membranous
web along with viral protein NS4B
NS5A inhibitors are co-formulated with other DAAs; except
daclatasvir
They are inhibitors of P-gp & metabolized by CYP450
136

Daclatasvir: extensively metabolized by CYP3A4;
Not administered with strong CYP3A4 inducers
Dose ↓ed when with strong CYP3A4 inhibitors
Dose ↑ed when with moderate CYP3A4 inducers
Absorption of ledipasvir is reduced when gastric pH is ↑ed
Patients receiving PPIs should either stop these agents during
HCV therapy with ledipasvir or
Take PPI with ledipasvir-containing regimens under fasted
conditions to ensure that gastric pH is at its lowest point
137

Cyclophilin inhibitors
Derived from cyclosporine A, but lack calcineurin-binding
properties; don’t exhibit immunosuppressive effects
Alisporivir the first agent on a phase III trial
Binds to cyclophilin A, an essential cofactor for HCV replication
& shows additive antiviral effect with pegIFN in pts with
genotype 1 & 4 HCV
Sometimes referred to as host-targeted agents, but can also be
part of the DAAs b/c interact with the NS5A protein
138

Interferons
A family of naturally occurring, inducible glycoproteins
(cytokines) that interfere with the ability of viruses to infect
cells
Trigger the protective defences of the immune system that
help eradicate pathogens
Three types of interferons exist: α(15), β & γ
Synthesized by recombinant DNA technology
139

 MOA:
Interfere with RNA & DNA polymerases & activate viral RNases
 degradation of mRNA & tRNA
Inhibition of transcription:
Activates Mx protein (human protein), blocks mRNA synthesis
Mx genes are induced exclusively by type I IFNs (INF/) or
type III INF (INF ), & possess antiviral activity
140

Inhibition of translation:
Activates methylase, thereby reducing mRNA cap methylation
Activates 2’5’ oligoadenylate synthetase  2’5’A  inhibits
mRNA splicing and activates RNaseL  cleaves viral RNA
Activates phosphodiesterase  blocks tRNA function
Activates protein kinase P1  blocks eIL-2a function 
inhibits initiation of mRNA translation
141

Inhibition of post-translational processing
Inhibits glycosyltransferase, thereby reducing protein
glycosylation
Inhibition of virus maturation
Inhibits glycosyltransferase, thereby reducing glycoprotein
maturation
Inhibition of virus release: causes membrane change  blocks
budding
142

 PKs:
Not active in PO, so; administer SC, or IV
Highly metabolised by liver
 AEs: flu-like symptoms: fever, chills, myalgias & GI
disturbances
Bone marrow suppression, fatigue & weight loss, neurotoxicity
are common
143

 Therapeutic use:
Interferon-α: chronic hepatitis B & C, genital warts by HPV,
melanoma, condylomata acuminate, leukemia (hairy cell, CML),
Kaposi sarcoma
Interferon-: relapsing remitting multiple sclerosis
Interferon-: chronic granulomatous disease   TNF
144

Lamivudine: 3TC
A cytosine analog, an inhibitor of both HBV & HIV RTs
Must be phosphorylated by host cellular enzymes to the
triphosphate (active) form
Competitively inhibits HBV RNA-dependent DNA polymerase
Rate of resistance is high following long-term therapy
145

 PKs:
Well absorbed orally & is widely distributed
Mainly excreted unchanged in urine
Dose reductions are necessary in renal problem
 AEs: well tolerated, headache & dizziness less common
146

Adefovir
A nucleotide analog, phosphorylated by cellular kinases, which
is then incorporated into viral DNA → termination of chain
elongation & prevents replication
Administered once a day
Excreted via urine
Nephrotoxicity in chronic use
Cautiously use in patients with existing renal dysfunction 147

Entecavir
A guanosine nucleoside analog for the Rx of HBV infections
 MOA: phosphorylated intracellularly & competes with the
natural substrate, deoxyguanosine triphosphate, for viral RT
Effective against 3TC-resistant strains of HBV & dosed QD
Primarily excreted unchanged in the urine
Dose adjustment required in renal dysfunction
148

Telbivudine
A thymidine analog, used in the treatment of HBV
 MOA: posphorylated intracellularly to the triphosphate, terminate
further elongation of the DNA chain
Administered orally, once a day
Eliminated renally as parent drug
Dose must be adjusted in renal failure
 AEs: fatigue, headache, diarrhea & ↑in liver enzymes & creatine
kinase 149

Ribavirin
A synthetic guanosine analog
Effectivea against RNA & DNA viruses: used in severe RSV,
chronic HCV infections (standard or pegylated interferon or
with DAAs)
 MOA:
Inhibits replication of RNA & DNA viruses:
By inhibiting GTP formation
Preventing viral mRNA capping &
Blocking RNA-dependent RNA polymerase
150

 Combination with other agents:
Improves viral clearance
Decreases relapse rates
Improves rates of sustained virologic response
✍The addition of ribavirin to DAA-based regimens is based on
HCV genotype/subtype, cirrhosis status, mutational status &
treatment history
151

Dose: always weight-based & administered in two daily divided
doses with food (fatty meal ↑es absorption)
Effective orally & by inhalation (Rx of RSV infection)
Excretion: via urine (parent drug & metabolites)
 AEs: anemia, elevated bilirubin
 Teratogenic: CI in pregnancy
152

In a nutshell
Chronic hepatitis B may be treated with peginterferon-α-2a: SC
injection once weekly
Oral therapy HBV: lamivudine, adefovir, entecavir & tenofovir
Preferred Rx for HCV is a combination of DAAs, the selection of
w/c is based on the HCV genotype
In certain cases, ribavirin is added to a DAA regimen to
enhance virologic response
With the introduction of new DAAs, pegylated interferon-α is no
longer commonly used in HCV & it is not recommended due to
inferior efficacy & poor tolerability
153

154

Life cycle of HIV
Binding of gp120 to CD4 & co-receptor on the cell surface
Fusion of the viral envelope with the cell membrane controlled
by gp41 domain of env
Entry: full-length viral RNA enters the cytoplasm, undergoes
replication to a short-lived RNA – DNA duplex
The original RNA is degraded by the RNase H activity of RT to
allow creation of a full-length double-stranded DNA
155

Since HIV reverse transcriptase is error prone & lacks a
proofreading function, mutation is frequent & occurs at about
three bases of every full-length (9300-base-pair) replication
Viral DNA moves into cell nucleus & integrated into a host
chromosome by the viral integrase in a random or quasi-
random location
Following integration, the virus may remain quiescent, not
producing RNA or protein but replicating as the cell divides
156

 HIV provirus DNA is transcribed back to both viral genomic
RNA & viral mRNA, which is translated to HIV polyproteins
 The RNA virus & polyproteins are assembled beneath the cell
membrane
 The assembled package becomes enveloped in the host cell
membrane as it buds off to form an HIV virion
 Further assembly & maturation occurs outside the cell by the
protease enzyme, rendering the HIV virion infectious
157

158

How HIV enters in to the cell?
gp120 env protein binds to CD4 molecule, found on T-cells
macrophages & microglial cells
Binding to CD4 is not sufficient for entry
V3 loop of gp120 env protein binds to co-receptor (CCR5 or
CXCR4)
159

 CCR5 receptor: used by macrophage-tropic HIV variants
Since it is present on macrophage lineage cells
Most infected individuals harbor predominantly the CCR5-tropic
virus
HIV with this tropism is responsible for nearly all naturally
acquired infections
 CXCR4 receptor: used by lymphocyte-tropic HIV variants
160

A shift from CCR5 to CXCR4 utilization is associated with
advancing disease &
The increased affinity of HIV-1 for CXCR4 allows infection of T-
lymphocyte lines
A phenotypic switch from CCR5 to CXCR4 heralds accelerated
loss of CD4+ helper T cells & ed risk of immunosuppression
Whether co-receptor switch is a cause or a consequence of
advancing disease is still unknown
But it is possible to develop clinical AIDS without this switch
161

Classes of Anti-retroviral drugs
 Reverse transcriptase inhibitors: NRTIs, NNRTIs
 Protease inhibitors (PIs)
 Integrase strand transfer inhibitors (INSTIs)
 Entry inhibitors: fusion inhibitor, a CCR5 antagonist & a CD4
post-attachment inhibitor (ibalizumab)
In addition, 2 drugs, ritonavir (RTV or r) & cobicistat (COBI or
c); used as PK enhancers or boosters to improve the PK
profiles of some ARV drugs (PIs & EVG)
162

163

164

Uses of Anti-retroviral drugs
For the treatment of HIV disease, PMTCT, PrEP, PEP
FTC, 3TC & TDF: active against hepatitis B virus (HBV) &
TDF also has activity against herpesviruses
165

Reverse Transcriptase Inhibitors (RTIs)
 The original inhibitors of reverse transcriptases of HIV are
nucleoside antimetabolites (AZT, the prototype) that are
converted to active forms via phosphorylation reactions
 Nuceoside/tide RTIs:
Components of most combination drug regimens
Used together with an INSTI/PI
HAART viral RNA, reverse CD4 cells & decrease OIs
166

Other NRTIs
MOA: identical to that of zidovudine
Each requires metabolic activation to nucleotide forms that
inhibit reverse transcriptase
Used as starter regimen for all RVI patients
Resistance mechanisms are similar
Not complete cross-resistance between NRTIs
Toxicity: less bone-marrow suppressing than AZT
167

Intracellular activation of NRTIs 168

 ADRs:
Myalgia: due to mitochondrial toxicity caused by the inhibition
of DNA polymerase
Headache
Diarrhea: with ddI, likely as a result of the buffers used in oral
formulations, some of which contain magnesium, a known
laxative
169

Lactic acidosis: impairment of mitochondrial function leads to
a reliance on anaerobic metabolism, which produces excessive
amounts of lactate
Lipodystrophy: with d4T
Peripheral neuropathy: with ddI, d4T, ddC; caused by
mitochondrial toxicity
Pancreatitis: ddI, d4T, ddC; caused by mitochondrial toxicity
Hepatotoxicity: ddI, ZDV
170

Bone marrow suppression (anemia): ZDV
Hypersensitivity: ABC, characterized by fever, GI problems
(abdominal pain, rash, malaise, and fatigue)
Acute renal failure: TDF
Stomatitis & oral ulcers: ddC
171

NNRTIs
Do not require metabolic activation
 MOA:
Inhibit reverse transcriptase at a site different from NRTIs
Additive or synergistic: combination with NRTIs &/or Pls
Are not myelosuppressant
172

 ADRs:
Rash: macular or papular rash to Stevens-Johnson syndrome
Hepatitis
CNS: EFV; dizziness, impaired concentration, psychiatric
(dysphoria, vivid dreams, psychosis, insomnia)
173

Protease Inhibitors: PIs
MOA: aspartate protease (pol gene encoded) cleaves precursor
polypeptides in HIV buds to form the proteins of the mature virus
core
The enzyme contains a dipeptide structure not seen in mammalian
proteins
Protease inhibitors bind to this dipeptide, inhibiting the enzyme
Resistance occurs via specific point mutations in the pol gene (e.g.
T889C in DNA polymerase beta (POLB) gene), such that there is not
complete cross-resistance b/n d/t PIs
Ritonavir: induces CYP – 1A2 & inhibits 3A4 & 2D6
174

 ADRs:
GI (NVD)
Hyperlipidemia: PIs stimulate lipogenesis in hepatocytes; less
with Atazanavir
Lipodystrophy: fat redistribution
Hyperglycemia, insulin resistance: PIs inhibit the activity of
GLUT-4, inhibiting insulin-stimulated glucose uptake by cells;
less with Atazanavir
175

Rash: with amprenavir
Crystalluria, nephrolithiasis (indinavir): Indinavir has poor
solubility and precipitates easily. Patients are advised to
increase fluid intake while on Indinavir
Hyperbilirubinemia (atazanavir) is not considered to be a
serious side effect or sign of hepatotoxicity
176

Integrase Inhibitors: INSTIs
 MOA:
Bind to HIV integrase while it is in a specific complex with viral
DNA then viral DNA can’t become incorporated into the human
genome & cellular enzymes degrade unincorporated viral DNA
177

CCR5 antagonist
 MVC: blocks CCR5 protein on macrophage surface to prevent
viral entry
Take without regard to meals
 AEs: constipation, dizziness, infection, rash, orthostatic
hypotension
178

Fusion inhibitor: FI
 T-20: binds gp41 and inhibits fusion of HlV-1 to CD4+ cells
Approved only for ART-experienced pts with drug resistance
Adult dose: 90 mg SC BID
 AEs: injection-site rxns: pain, erythema, induration, nodules
179

CD4 post-attachment inhibitor: Ibalizumab
Approved only for ART-experienced pts with drug resistance
Adult dose: 2000 mg LD infused (IV) over ≥30’, followed by
800 mg MD infused (IV) over at least 15-30’ every 14 days
 AEs: ND, dizziness, rash (5-8%); immune reconstitution
syndrome (1 case)
180

ART-regimens
Should be initiated in all living with HIV, regardless of WHO
clinical stage & at any CD4+ cell count
1st –line ART for treatment-naïve patients (adults) are INSTI-
based; INSTI + NNRTI + NRTI
Two NRTIs + a NNRTI or INSTI or PI; with a PK enhancer
A pregnancy test prior to the initiation of ART
181

 Examples:
TAF + FTC + BIC (Bictegravir)
ABC + 3TC + DTG: only for HLA-B*5701 negative patients
TAF/TDF + FTC + DTG
TAF/TDF + FTC + RAL
TDF + FTC + EVG/c: EVG also has a lower barrier to
resistance than DTG & BIC
182

Summary
183