This document discusses the pharmacology of antimicrobial agents. It begins by defining antimicrobials as chemical agents that destroy or inhibit the growth of infective agents. It then discusses the different classes of antimicrobials including antibacterials, antifungals, antivirals, and antineoplastics. The remainder of the document focuses on various classes of antibacterial agents including beta-lactams such as penicillins and cephalosporins, carbapenems, monobactams, and other cell wall synthesis inhibitors. It covers their mechanisms of action, spectra of activity, pharmacokinetics, uses, and adverse effects.

1. Pharmacology of Antimicrobials
1

2. 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

3. Chemotherapy
Antimicrobials
Antibacterials
Antifungals
Antivirals
Antiprotozoals
Anthelmintics
Antineoplastics
3

4. 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

5.  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

6. 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

7. 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. 8

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

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

11. ✍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

12. 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. 13

14. Mechanisms of Resistance to Antimicrobial Agents
14

15. 15

16. BETA-LACTAM ANTIBIOTICS
16

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

18.  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

19.  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

20. 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

21. 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

22.  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

23.  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

24.  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

25.  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

26. 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

27. 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

28. 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

29.  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

30.  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

31.  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

32.  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

33. 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

34.  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

35. 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

36.  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

37. 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

38. 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

39. 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

40.  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

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

42.  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

43. 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

44. ✍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

45.  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

46. 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

47. 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

48.  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

49.  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

50.  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

51. Summary
51

52. Protein Synthesis
Simplified schematic of mRNA translation 52

53. 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

54. 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. 55

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

57. Summary of MOA of Protein Synthesis Inhibition
57

58. 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

59.  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

60.  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

61. 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

62. 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

63.  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

64. 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

65. Pharmacokinetics…
65

66.  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

67. 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

68. 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

69.  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

70.  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

71. 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

72.  PKs:
Inhibit CYP450s, except azithromycin
72

73.  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

74. 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

75. 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

76.  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

77. 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

78.  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

79. Summary
79

80. 80

81.  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

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

83. 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

84.  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

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

86. 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

87.  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

88.  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

89. 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

90. 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

91. 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. 92

93. 93

94. 94
Antifungal Drugs & Their Targets
Naftifine
Terbinafine

95. 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

96.  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

97.  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

98. 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

99. 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

100.  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

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

102.  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

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

104.  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. 105
(uracil
phosphoribosyltransferase)

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

107.  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

108.  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

109. 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

110. 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

111. 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

112. 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

113.  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

114. 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

115. 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

116. Site of action of Antiviral drugs
116

117. MOA of Antiviral Drugs
117

118. 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

119. 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

120. Common Mechanism for “ovirs” and NRTIs
120

121.  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

122.  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

123.  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

124.  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

125.  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

126. 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

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

128. 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

129. 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

130. 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. 131

132. 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

133. 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

134. 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

135. 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

136. 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

137. 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

138. 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

139. 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

140.  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

141. 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

142. 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

143.  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

144.  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

145. 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

146.  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

147. 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

148. 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

149. 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

150. 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

151.  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

152. 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

153. 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. 154

155. 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

156. 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

157.  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. 158

159. 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

160.  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

161. 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

162. 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. 163

164. 164

165. 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

166. 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

167. 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

168. Intracellular activation of NRTIs 168

169.  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

170. 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

171. 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

172. 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

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

174. 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

175.  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

176. 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

177. 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

178. 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

179. 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

180. 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

181. 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

182.  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

183. Summary
183