Antibiotics

Definition
• Medications used to treat bacterial infections

• Ideally, before beginning antibiotic therapy,

the suspected areas of infection should be
cultured to identify the causative organism
and potential antibiotic susceptibilities.

03/09/21 Chapter 17-1

 Antibiotics

• Empiric therapy: treatment of an infection

before specific culture information has
been reported or obtained.
• Prophylactic therapy: treatment with
antibiotics to prevent an infection, as in
intra-abdominal surgery.

03/09/21 Chapter 17-2

 Antibiotics
• Bactericidal: kill bacteria

• Bacteriostatic: inhibit growth of susceptible

bacteria, rather than killing them
immediately; will eventually lead to
bacterial death

03/09/21 Chapter 17-3

 Anti-Bacterial Agents
• Sulfonamides

• Penicillins
• Cephalosporins
• Tetracyclines
• Aminoglycosides
• Quinolones
• Macrolides
03/09/21 Chapter 17-4
 2- Penicillins

• Natural penicillins

• Penicillinase-resistant penicillins

• Aminopenicillins

• Extended-spectrum penicillins

03/09/21 Chapter 17-5

 Cont….
A-Natural penicillins
• penicillin G, penicillin V potassium

B-Penicillinase-resistant penicillins
• cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin

03/09/21 Chapter 17-6

 Cont….
C-Aminopenicillins
• amoxicillin, ampicillin, bacampicillin

D-Extended-spectrum penicillins
• piperacillin, ticarcillin, carbenicillin, mezlocillin

03/09/21 Chapter 17-7

 Overview of Penicillins

• First introduced in the 1940s

• Bactericidal: inhibit cell wall synthesis

• Kill a wide variety of bacteria

• Also called “beta-lactams”

03/09/21 Chapter 17-8

 Cont…

• Bacteria produce enzymes capable of

destroying penicillins.

• These enzymes are known as

beta-lactamases.

• As a result, the medication is not effective.

03/09/21 Chapter 17-9
 Cont…
• Chemicals have been developed to inhibit
these enzymes:
– clavulanic acid
– tazobactam
– sulbactam
• These chemicals bind with beta-lactamase
and prevent the enzyme from breaking
down the penicillin

03/09/21 Chapter 17-10

 Cont…
• Penicillin-beta-lactamase inhibitor combination
drugs:

– ampicillin + sulbactam = Unasyn

– amoxicillin + clavulanic acid = Augmentin

– ticarcillin + clavulanic acid = Timentin

– piperacillin + tazobactam = Zosyn

03/09/21 Chapter 17-11

 Penicillins: Mechanism of Action

• Penicillins enter the bacteria via the cell wall.

• Inside the cell, they bind to penicillin-binding protein.

• Once bound, normal cell wall synthesis is disrupted.

• Result: bacteria cells die from cell lysis.

• Penicillins do not kill other cells in the body.

03/09/21 Chapter 17-12

 Penicillins: Therapeutic Uses

• Prevention and treatment of infections caused

by susceptible bacteria, such as:
– gram-positive bacteria

– Streptococcus, Enterococcus, Staphylococcus

species

03/09/21 Chapter 17-13

 Penicillins: Adverse Effects
• Allergic reactions occur in 0.7% – 8% of
treatments
– urticaria, pruritus, angioedema

• 10% of allergic reactions are life-threatening

and
• 10% of these are fatal

03/09/21 Chapter 17-14

 Penicillins: Side Effects
• Common side effects:

– nausea, vomiting, diarrhea, abdominal pain

• Other side effects are less common

03/09/21 Chapter 17-15

 cephalexin
Cephalosporins
-Iactam - closely related both structurally and
functionally to the penicillins.
Mostly semisynthetic !!- mode of action as penicillins
same resistance mechanisms - however, they tend to be
more resistant than the PNCs to -Iactamases.
Antibacterial spectrum
Classified as first, second, third, or fourth generation,
based largely on their bacterial susceptibility patterns and resistance
to -Iactamases.
ineffective against MRSA, (vancomycin)L. monocytogenes,
(ampicillin)Clostridium difficile,(metronidazole) and the
enterococci (E. faecalis). Use Amoxacillin.
 Pharmacodynamics
First generation:
• cephalexin, cephalotin, cefazolin
• Effective in G+ and few G- bacilli;
• activity against Proteus mirabilis (UTI) E. coli (UTI, diarhea) and
Klebsiella Pneumoniae (Pneumonia, UTI)
Second generation:
• Cefuroxime, cefoxitin, cefotetan
• Greater activity against three additional G- organisms: H.
influenzae (Meningitis) Enterobacter aerogenes (UTI) and some
Neisseria species.
• Activity against gram-positive organisms is weaker.
– effective against Bacteroides fragilis (Peritonitis) cefoxitin is the most
potent
– N.B. They are not first line for bacteriodes because of increasing resistance
 Pharmacodynamics
Third generation
Inferior to first-generation in activity against G+ cocci,
enhanced activity against gram-negative bacilli
+ most other enteric organisms (Salmonela, shigela) plus Pseudomonas
aeruginosa.
Ceftriaxone or cefotaxime
agents of choice in the treatment of meningitis. (cross BBB)
Ceftazidime - against Pseudomonas aeruginosa.
Fourth generation
Cefepime, Cefpirom
only parenteral
Wide spectrum, active against streptococci and staphylococci
Not MRSA
 Advanced generation : Ceftaroline is a broadspectrum active against
MRSA
 Major Differences between Cephalosporin
Generations
Activity against Resistance to Distribution to
Gram Negative Beta- CSF
Lactamase
Generation enzymes
1st (e.g., Low Low Poor
cephalothin)
2nd (e.g., Higher Higher Poor
cefamandole)
3rd (e.g. Higher Higher Good
ceftriaxone)
4th (e.g. Highest Highest Good
cefepime)
19
 Therapeutic Uses
 Skin and soft tissue infections due to S. aureus and S. pyogenes (1st
GCs)
 Colorectal surgery, where prophylaxis for intestinal anaerobes is
desired (2nd GCs)
 Generally 2nd GCs displaced by 3rd GCs
 Oral 2nd GCs can be used to treat RTI (pneumonia caused by susceptible speci)

 In situations where facultative Gm(-) and anaerobes are involved (intra-

abdominal infections, pelvic inflammatory disease)

20
 Therapeutic Uses (cont’d)
 3rd GCs (with or without aminoglycosides)
 Drugs of choice for serious infections caused by Klebsiella (Pneumonia, UTI)
Enterobacter(UTI) Proteus (UTI) Serratia (Pneumonia)and Haemophilus spp.
(Meningitis)
 Ceftriaxone is the therapy of choice for all forms of gonorrhea and for severe
forms of Lyme disease.
 Drugs of choice for the treatment of meningitis caused by H. influenzae,
sensitive S. pneumoniae, N. meningitidis, and gram-negative enteric bacteria

21
 Therapeutic Uses (cont’d)
 4th GCs
 Empirical treatment of nosocomial infections where
antibiotic resistance owing to extended-spectrum -
lactamases or chromosomally induced -lactamases
are anticipated

22
 4-Tetracyclines
• demeclocycline (Declomycin)
• oxytetracycline
• tetracycline
• doxycycline (Doryx, Doxy-Caps, Vibramycin)
• minocycline

03/09/21 Chapter 17-23

 Antibiotics: Tetracyclines
• Natural and semi-synthetic
• Bacteriostatic—inhibit bacterial growth
• Inhibit protein synthesis
• Stop many essential functions of the bacteria

03/09/21 Chapter 17-24

 Antibiotics: Tetracyclines

• Bind to Ca2+ and Mg2+ and Al3+ ions to

form insoluble complexes.
• Thus, dairy products, antacids, and iron
salts reduce absorption of tetracyclines.

03/09/21 Chapter 17-25

 Tetracyclines: Therapeutic Uses

• Wide spectrum:
– gram-negative, gram-positive, protozoa, Mycoplasma,
Rickettsia, Chlamydia, syphilis, Lyme disease

• Demeclocycline is also used to treat pleural and

pericardial effusions (fluid in body cavity or tissue)

03/09/21 Chapter 17-26

 Tetracyclines: Side Effects

Strong affinity for calcium

• Discoloration of permanent teeth

• May retard fetal skeletal development if taken

during pregnancy

03/09/21 Chapter 17-27

Tetracycline-Stained Teeth

http://www.wisconsinreconstructiveimplantdentist.com/images/tetracycline4.jpg

28
 Tetracyclines: Side Effects

Alteration in intestinal flora may result in:

• Superinfection (overgrowth of nonsusceptible organisms such
as Candida)
• Diarrhea

• Pseudomembranous colitis

03/09/21 Chapter 17-29

 Tetracyclines: Side Effects

May also cause:

• Gastric upset

• Enterocolitis

• Maculopapular rash (pigmented spot in skin)

03/09/21 Chapter 17-30

 Aminoglycosides
amikacin, gentamicin, tobramycin and streptomycin (Commonly used
aminoglycosides).
 Other aminoglycosides neomycin, netilmicin, kanamycin
• For serious infections due to aerobic gram-negative bacilli Pseudomonas
aeruginosa (Pneumonia, UTI) Klebsiella pneumoniae (Pneumonia, UTI) and
Enterobacter sp)UTI
• Aminoglycosides + B-lactam for E. faecalis and E. faecium infective
endocarditis
 Use is limited by the occurrence of serious toxicities
 Partially replaced by safer ATB
 3rd generation cephalosporins, fluoroquinolones, carbapenems
 only against aerobic organisms
 anaerobes lack the oxygen-requiring transport system
 Streptomycin - used to treat tuberculosis
 (kanamycin also effective), tularemia caused by francisella tularensis.
Bactericidal - inhibit bacterial protein synthesis
 susceptible organisms have an oxygen-dependent system that transports the
ATB across the cell membrane.
 bind to the 30S ribosomal subunit
 Aminoglycosides
• Three most common (systemic): gentamicin,
tobramycin, amikacin, streptomycin

• Cause serious toxicities:

– Nephrotoxicity (renal failure)

– Ototoxicity (auditory impairment [eighth cranial nerve])

– Neuromuscular damage

• Must monitor drug levels to prevent toxicities

03/09/21 Chapter 17-32

 6-Flouroquinolones

• ciprofloxacin
• moxifloxacin
• lomefloxacin
• norfloxacin

03/09/21 Chapter 17-33

 Quinolones: Mechanism of Action
• Bactericidal

• Effective against gram-negative organisms and some

gram-positive organisms
• Inhibit DNA gayrase enzyme of the bacteria and thus
stop bacteria DNA synthesis, causing death
• Do not affect human DNA

03/09/21 Chapter 17-34

 Quinolones: Therapeutic Uses
• Lower respiratory tract infections

• Bone and joint infections

• Infectious diarrhea

• Urinary tract infections

• Skin infections

• Sexually transmitted diseases (e.g gonorrhea)

03/09/21 Chapter 17-35

 Quinolones: Side Effects

Body System Effects

CNS headache, dizziness, fatigue,
depression, restlessness

GI nausea, vomiting, diarrhea,

constipation, thrush,

Integumentary photosensitivity

03/09/21 Chapter 17-36

 7-Macrolides
• erythromycin
• azithromycin
• clarithromycin
– Proteing synthesis inhibitor
– bacteriostatic action

03/09/21 Chapter 17-37

 Macrolides: Therapeutic Uses
• Strep infections
– Streptococcus pyogenes
(group A beta-hemolytic streptococci)

• Mild to moderate URI

– Haemophilus influenzae

• Spirochetal infections
– Syphilis and Lyme disease

• Gonorrhea, Chlamydia, Mycoplasma

03/09/21 Chapter 17-38

Clinical uses summary
 Macrolides: Side Effects
GI effects, primarily with erythromycin:

• nausea, vomiting, diarrhea, hepatotoxicity,

flatulence, jaundice, anorexia

• Newer agents, azithromycin and clarithromycin: fewer

side effects, longer duration of action,
better efficacy, better tissue penetration

03/09/21 Chapter 17-40

 INHIBITORS OF METABOLISM

• Sulfonamides
• Trimethoprim and pyrimethamine
• Interfere with the production of folic acid coenzymes that are
required for purine and pyrimidine synthesis
 FOLATE
ANTAGONISTS
INHIBITORS OF
FOLATE SYNTHESIS
• Silver sulfadiazine
• Sulfacetamide
• Sulfadiazine
• Sulfamethoxazole
• Sulfasalazine
• Sulfisoxazole
INHIBITORS OF
FOLATE REDUCTION
• Pyrimethamine
• Trimethoprim
INHIBITORS OF FOLATE
SYNTHESIS AND REDUCTION

• Co-trimoxazole
SOLPHONAMIDES
 Sulfonamides
• Analogues of para-aminobenzoic acid

• Broad spectrum

• Competitive inhibitors of dihydropteroate synthase – needed

for folic acid synthesis
45
 Sulfonamides
Bacteriostatic
All sulfa drugs
Structurally related to p-aminobenzoic acid (PABA)
Spectrum G(+) and G(-) bacteria, nocardia,(an actinomyce that
causes pneumonia and brain abscess in HIV) Chlamydia
trachomatis, Some enteric bacteria (E coli, klebsiella, salmonella,
shigella, and enterobacter), and some protozoa. Poor activity in
anaerobes
Complete cross-resistance
 Overproduction of PABA!!
 Production of folate synthetase enzyme with low affinity for
sulphonamid
 Impaired permeability
 Adopt alternative pathway of folate metabolism
 Pharmacokinetics
 Divided into three major groups (on the basis of their half-lives)
1. Oral, absorbable
 Short-, sulfamethizole, sulfisoxazole
 medium-, sulfamethoxazole, sulfadiazine
 or long-acting , sulfadoxine, sulfamethopyrizine .
2. Oral, nonabsorbable, sulfazalasine
3. Topical, sulfacetamide, silver sulfadiazine, mafenide acetate

47
Sulfapyridine intermediate 17 h slow
 Clinical Uses
 Infrequently used as single agents!!.

 largely replaced by trimethoprim-sulfamethoxazole (Co-trimoxazole).

 Many strains of formerly susceptible species are now resistant.

 Can be useful for treatment of urinary tract infections due to

susceptible organisms (Co-trimoxazole).
 Toxoplasmosis (combination of pyrimethamine and sulfadiazine is the
treatment of choice)

 Malaria (500 mg sulfadoxine plus 25 mg pyrimethamine as FANSIDAR) for

the prophylaxis and treatment of malaria caused by mefloquine -resistant
strains of Plasmodium falciparum
48
 Ulcerative colitis (sulfazalasine)

 Bacterial corneal infection (sulfacetamide)

(good penetration cornea)

 Malaria (500mgsulfadoxine + 25mg pyrimethamin )

FANSIDAR
 Sulfonamides - AE
• Nephrotoxicity
– a result of crystalluria
• sulfisoxazole and sulfamethoxazole – more soluble at urinary pH
than the older SA.
– Adequate hydration and alkalization of urine is necessary
• Note: It is contraindicated to use acidic drugs (salicylates) or food
(oranges etc.) which may lead to acidic pH of urine during therapy
with sulfonamides !!!
• Use sodium bicarbonate? Or take adequate fluid (water)
• Hypersensitivity – common (all sulfonamides, antimicrobial
sulfas, diuretics and sulfonylurea are partially cross allergenic)
– rashes, fever, angioedema, anaphylactoid reactions,
– Stevens-Johnson syndrome
• more frequently with the longer-acting agents
– Hepatitis
 co-trimoxazole
• Trimethoprim compounded with sulfamethoxazole (bactericidal)
– Selected because of similar PK profiles
• Sequential blockade in the synthesis of tetrahydrofolic acid
– doses of both drugs are 1/10 of those needed if drug were used alone.
– Fixed dose combition of 1:5 (TMP-SMZ) respectively.
– 80mg + 400mg tab, iv 160mg + 800mg tab, im 20mg + 100mg susp
• Broader spectrum than SA
– UTls and respiratory tract infections, Pneumocystis jirovecii
pneumonia(PJP) toxoplasmosis and ampicillin- or chloramphenicol-
resistant systemic salmonella infections. Also effective MRSA
• It is the drug of choice for infections caused by susceptible Nocardia species
(an actinomycetes that causes pneumonia and brain abcess in AIDs pts)
– Oral most commonly – i.v. exists in severe infections
• Resistance Iess frequent for the combination!!
– than to either of the drugs alone
– Reported in E.coli and MRSA
Cont..
Clinical uses of cotrimoxazole
ANTI-TUBERCULOSIS
 Introduction
 Mycobacteria are rod-shaped aerobic bacilli that multiple slowly
Their cell walls contain mycolic acids, which give the genus its name.
 Often neutral on gram staining
Once stained, the bacilli are not decolorized easily by acidified organic solvents
 hence called acid-fast bacilli (AFB)
 acid fastness due mainly to the organism’s high content of mycolic acids
 Mycobacterial infections result in the formation of slow growing,
Granulomatous lesions.
 Mycobacterium tuberculosis can cause latent tuberculosis
infection (LTBI)
N.B. In LTBI, the patient is infected with M. tuberculosis but does not have any
signs or symptoms of active TB disease.
 M. tuberculosis is transmitted by inhalation of infective droplets
coughed or sneezed into the air by a patient with tuberculosis 55
 Introduction…
 Mycobacteria
xctics of mycobacteria that makes the dx chronic and necessitate
prolonged trt.
 Are intracellular pathogens
 Organisms residing within macrophages are inaccessible to drugs that
penetrate these cells poorly
 Grow slowly
 Resistant to most antibiotics
 Can also be dormant
 Cell wall rich in lipids
 The cell wall is impermeable to many agents
 Consequence  effective therapy requires a prolonged course of
multiple drugs
 Patient compliance, drug toxicity, drug interactions, concurrence of other
diseases
Drugs used for Tuberculosis

57
 DRUGS USED IN TUBERCULOSIS
DRUGS USED TO TREAT
TUBERCULOSIS
• Ethambutol
• Isoniazid First line
• Pyrazinamide drugs
• Rifampin

• Aminoglycosides
• Aminosalicylic acid
• Capreomycin Second line
• Cycloserine drugs
• Ethionamide
• Flouroquinolone
• macrolides
Standard code for TB treatment regimens
DRUG ABBREVIATION

ISONIAZIDE H

RIFAMPIN R

ETHAMBUTOL E

PYRAZINAMIDE Z

STREPTOMYCIN S
 An example of treatment regimen with initial intensive 4 drug
combination treatment followed by continuation treatment with 2 drug
 Principles of anti-TB therapy
 Combination treatment is mandatory

 Single drug may suffice for prophylaxis

 INH + Rif is most effective

 Fast response at the start

 Symptomatic relief occurs with in 2-4 weeks

 Rate of bacteriological, radiological and clinical

improvement decline after 4 weeks
 Phases of treatment
 Initial phase: with quadruple therapy
• Objective: to kill the viable bacilli
• Drugs: INH + rifampin + pyrazinamide + ethambutol
• Duration of Rx: 2-3 months
 Continuation phase: with double therapy
• Objective: to suppress bacilli reproduction (only dormants b/c
viable bacilli is already killed plus cost and ADR)
• Drugs: INH + rifampin
• Duration of Rx: 4-6 months
 Antitubercular Agents:
Mechanism of Action
Three Groups
• Protein synthesis inhibitors streptomycin, kanamycin,
capreomycin, rifampin, rifabutin
• Cell wall synthesis inhibitors cycloserine, ethionamide,
isoniazid
• Other mechanisms of action

03/09/21 Chapter 17-63

 Antitubercular Agents:
Mechanism of Action isoniazid (INH)
• Drug of choice for TB

• Resistant strains of mycobacterium emerging

• Metabolized in the liver through acetylation—watch for “slow

acetylators”

03/09/21 Chapter 17-64

 Antitubercular Agents:
Therapeutic Uses
Used for the prophylaxis
or treatment of TB

03/09/21 Chapter 17-65

 Clinical uses…
 As a single agent also indicated for treatment of latent
tuberculosis.
 ‘chemoprophylaxis’(for exposed individuals to TB, e.g doctors, nurses..)
 INH for at least 3months after leaving exposure if –ve tuberculin test
 INH for one year if +ve tuberculin test
 The dosage is 300mg/d or 900mg twice weekly for 3months or 9months
respectively
Adverse effects
 Hepatitis, (check LFTs)
 Peripheral neuropathy (due to lack of pyrodixine, supplement Vitamin 6 )
 CNS, (may evoke seizure)
 Hypersensitivity reactions
 Drug interactions: inhibits the metabolism of carbamazepine and
phenytoin
 Antitubercular Agents: Side Effects
INH
peripheral neuritis, hepatotoxicity
Ethambutol
retrobulbar neuritis, blindness
Rifampin
hepatitis, discoloration of urine, stools

03/09/21 Chapter 17-67

SUMMARY OF FIRST-LINE ANTI-TB
DRUGS
 Antifungal Agents

03/09/21 Chapter 17-69

 Antifungal Agents

Drugs used to treat infections caused by fungi

• Systemic and topical

03/09/21 Chapter 17-70

 Mycotic Infections
Four General Types
• Cutaneous
• Subcutaneous
• Superficial
• Systemic*
*Can be life-threatening
*Usually occur in immunocompromised host

03/09/21 Chapter 17-71

 Mycotic Infections

Candida albicans
• Due to antibiotic therapy, antineoplastics,
or immunosuppressants
• May result in overgrowth and systemic
infections

03/09/21 Chapter 17-72

 Mycotic Infections
In the mouth:
• Oral candidiasis or thrush

• Newborn infants and immunocompromised patients

03/09/21 Chapter 17-73

 Mycotic Infections

Vaginal candidiasis:
• “Yeast infection”

• Pregnancy, diabetes mellitus, oral contraceptives

03/09/21 Chapter 17-74

 Antifungal Agents

Systemic
• Examples: amphotericin B, fluconazole,
ketoconazole, itraconazole

Topical
• Examples: clotrimazole, miconazole, nystatin

03/09/21 Chapter 17-75

 Antifungal Agents
• Broken down into four major groups based
on their chemical structure
– Polyenes: amphotericin B and nystatin

– Flucytosine

– Imidazoles: ketoconazole, miconazole, clotrimazole,

fluconazole
– Griseofulvin

03/09/21 Chapter 17-76

 Antifungal Agents:
Mechanism of Action
Polyenes: amphotericin B and nystatin
– Bind to sterols in cell membrane lining

– Allow K+ & Mg++ to leak out, altering fungal cell

metabolism
– Result: fungal cell death

03/09/21 Chapter 17-77

 Antifungal Agents:
Mechanism of Action

flucytosine
• Also known as 5-fluorocytosine

• Taken up by fungal cells and interferes with

DNA synthesis
• Result: fungal cell death

03/09/21 Chapter 17-78

 Antifungal Agents:
Mechanism of Action
Imidazoles : ketoconazole, miconazole, clotrimazole,
fluconazole
– Inhibit an enzyme important for ergosterol biosynthesis,
resulting in cell membrane leaking
– Lead to altered cell membrane
– Result: fungal cell death

Griseofulvin
– Disrupts cell division
– Result: inhibited fungal mitosis (reproduction)

03/09/21 Chapter 17-79

 Adverse effect (Amphotericin B)
 Renal impairment (nephrotoxicity)
• sodium loading with infusions of normal saline and the lipid-based
amphotericin B products minimize toxicity.
 Hypotension
• due to hypersensitivity-anaphylaxis accompanied by hypokalemia
requiring KCl and monitoring of digoxin
 Thrombophlebitis
• adding heparin to the infusion can alleviate this problem.
 Hemolytic anemia (b/c highly protein bound)
 Hepatic damage
 Intrathecal inj. Can cause neurotoxicity & topical causes skin rash
 Drug interaction: AGs, cyclosporin,pentamidine, vancomyc& digoxin
 Antifungal Agents: Side Effects
fluconazole
• Nausea, vomiting, diarrhea, abdominal pain,
• Increased liver function test

flucytosine
• nausea, vomiting, anorexia

griseofulvin
• rash, urticaria, headache, nausea, vomiting, anorexia

03/09/21 Chapter 17-81

 Antimalarial, Antiprotozoal, and
Antihelmintic Agents

03/09/21 Chapter 17-82

 Protozoal Infections

Parasitic protozoa: live in or on humans

• malaria

• leishmaniasis

• amebiasis

• giardiasis

• trichomoniasis

03/09/21 Chapter 17-83

 Malaria
• Caused by the plasmodium protozoa.

• Four different plasmodium species.

• Cause: the bite of an infected adult mosquito.

• Can also be transmitted by infected individuals via blood

transfusion, congenitally, or via infected needles by drug
abusers.

03/09/21 Chapter 17-84

 Malarial Parasite (plasmodium)
Two Interdependent Life Cycles
• Sexual cycle: in the mosquito
• Asexual cycle: in the human

– Knowledge of the life cycles is essential in

understanding antimalarial drug treatment.
– Drugs are only effective during the asexual cycle.

03/09/21 Chapter 17-85

 Plasmodium Life Cycle
Asexual cycle: two phases
• Exoerythrocytic phase: occurs “outside”
the erythrocyte
• Erythrocytic phase: occurs “inside”
the erythrocyte

03/09/21 Chapter 17-86

 Antimalarial Agents
Attack the parasite during the asexual phase,
when it is vulnerable
• Erythrocytic phase drugs: chloroquine,
hydroxychloroquine, quinine, mefloquine
• Exoerythrocytic phase drug: primaquine
May be used together for synergistic or additive killing
power.

03/09/21 Chapter 17-87

 Antimalarials:
Mechanism of Action
4-aminoquinoline derivatives chloroquine
and hydroxychloroquine
• Bind to parasite nucleoproteins and interfere with protein
synthesis.????
• Prevent vital parasite-sustaining substances from being
formed.
• Alter pH within the parasite.
• Interfere with parasite’s ability to metabolize and
use erythrocyte hemoglobin.
• Effective only during the erythrocytic phase

03/09/21 Chapter 17-88

 Antimalarials: Mechanism of Action
Diaminopyrimidines : pyrimethamine and
trimethoprim
• Inhibit dihydrofolate reductase in the parasite.

• This enzyme is needed by the parasite to make essential

substances.
• Also blocks the synthesis of tetrahydrofolate.
These agents may be used with sulfadoxine or dapsone
for synergistic effects.

Sulfadoxine + pyrimethamine (Fansidar)

03/09/21 Chapter 17-89
 Antimalarials: Mechanism of Action
primaquine
• Only exoerythrocytic drug.
• Binds and alters DNA.

sulfonamides, tetracyclines, clindamycin

• Used in combination with antimalarials to increase
protozoacidal effects

03/09/21 Chapter 17-90

 Antimalarials: Drug Effects

• Kill parasitic organisms.

• Chloroquine and hydroxychloroquine also have

antiinflammatory effects.

03/09/21 Chapter 17-91

 Antimalarials: Therapeutic Uses

• Used to kill plasmodium organisms, the parasites that

cause malaria.
• The drugs have varying effectiveness on
the different malaria organisms.
• Some agents are used for prophylaxis against malaria.

• Chloroquine is also used for rheumatoid arthritis and

lupus.

03/09/21 Chapter 17-92

 Antimalarials: Side Effects

• Many side effects for the various agents

• Primarily gastrointestinal: nausea, vomiting,

diarrhea, anorexia, and abdominal pain

03/09/21 Chapter 17-93

 Antiprotozoals
• atovaquone (Mepron)
• metronidazole (Flagyl)
• pentamidine (Pentam)
• iodoquinol (Yodoxin, Di-Quinol)
• paromomycin (Humatin)

03/09/21 Chapter 17-94

 Protozoal Infections
• amebiasis
• giardiasis
• pneumocystosis
• toxoplasmosis
• trichomoniasis

03/09/21 Chapter 17-95

 Protozoal Infections
Transmission
• Person-to-person
• Ingestion of contaminated water or food
• Direct contact with the parasite
• Insect bite (mosquito or tick)

03/09/21 Chapter 17-96

 Antiprotozoals: Mechanism of Action
and Uses atovaquone (Mepron)
• Protozoal energy comes from the mitochondria

• Atovaquone: selective inhibition of mitochondrial

electron transport

• Result: no energy, leading to cellular death

• Used to treat mild to moderate P. carinii

03/09/21 Chapter 17-97

 Antiprotozoals: Mechanism of Action
and Uses metronidazole
• Disruption of DNA synthesis as well as nucleic acid synthesis

• Bactericidal, amebicidal, trichomonacidal

• Used for treatment of trichomoniasis, amebiasis, giardiasis,

anaerobic infections, and antibiotic-associated

pseudomembranous colitis

03/09/21 Chapter 17-98

 Antiprotozoals: Mechanism of Action and
Uses pentamidine
• Inhibits DNA and RNA

• Binds to and aggregates ribosomes

• Directly lethal to Pneumocystis carinii

• Inhibits glucose metabolism, protein and RNA synthesis, and

intracellular amino acid transport

• Mainly used to treat P. carinii pneumonia and other protozoal

infections

03/09/21 Chapter 17-99

 Antiprotozoals: iodoquinol

• “Luminal” or “contact” amebicide

• Acts primarily in the intestinal lumen of the infected host

• Directly kills the protozoa

• Used to treat intestinal amebiasis

03/09/21 Chapter 17-100

 Antiprotozoals: paromomycin

• “Luminal” or “contact” amebicide

• Kills by inhibiting protein synthesis

• Used to treat amebiasis and intestinal protozoal infections,

and also adjunct therapy in management of hepatic coma

03/09/21 Chapter 17-101

 Antiprotozoals: Side Effects
atovaquone
• nausea, vomiting, diarrhea, anorexia

metronidazole
• metallic taste, nausea, vomiting, diarrhea,
abdominal cramps

iodoquinol
• nausea, vomiting, diarrhea, anorexia, agranulocytosis

03/09/21 Chapter 17-102

 Antiprotozoals: Side Effects

pentamidine
• bronchospasms, leukopenia, thrombocytopenia, acute
pancreatitis, acute renal failure, increased liver function
studies

paromomycin
• nausea, vomiting, diarrhea, stomach cramps

03/09/21 Chapter 17-103

 Antihelmintics
• Diethylcarbamazine
• Mebendazole
• Niclosamide
• Oxamniquine
• Piperazine
• Praziquantel
• Pyrantel
• Thiabendazole

03/09/21 Chapter 17-104

 Antihelmintics

• Drugs used to treat parasitic worm infections: helmintic

infections

• Unlike protozoa, helminths are large and have complex

cellular structures

• Drug treatment is very specific

03/09/21 Chapter 17-105

 Antihelmintics
• It is VERY IMPORTANT to identify the causative worm

• Done by finding the parasite ova or larvae in feces, urine,

blood, sputum, or tissue
– cestodes (tapeworms)

– nematodes (roundworms)

– trematodes (flukes)

03/09/21 Chapter 17-106

 Antihelmintics: Mechanism of
Action and Uses
diethylcarbamazine (Hetrazan)
• Inhibits rate of embryogenesis

thiabendazole (Mintezol)
• Inhibits the helminth-specific enzyme, fumarate reductase
– Both used for nematodes
(tissue and some roundworms)

03/09/21 Chapter 17-107

 Antihelmintics: Mechanism of Action

Piperazine and pyrantel

• Blocks acetylcholine at the neuromuscular junction, resulting

in paralysis of the worms, which are then expelled through

the GI tract

• Used to treat nematodes (giant worm and pinworm)

03/09/21 Chapter 17-108

 Antihelmintics: Mechanism of Action

mebendazole
• Inhibits uptake of glucose and other nutrients, leading to
autolysis and death of the parasitic worm
• Used to treat cestodes and nematodes

03/09/21 Chapter 17-109

 Antihelmintics: Mechanism of Action

Niclosamide
• Causes the worm to become dislodged
from the GI wall
• They are then digested in the intestines and expelled

• Used to treat cestodes

03/09/21 Chapter 17-110

 Antihelmintics: Mechanism of Action
Oxamniquine and praziquantel

• Cause paralysis of worms’ musculature and

immobilization of their suckers

• Cause worms to dislodge from mesenteric veins

to the liver, then killed by host tissue reactions

• Used to treat trematodes, cestodes

(praziquantel only)

03/09/21 Chapter 17-111

 Antihelmintics: Side Effects

• niclosamide, oxamniquine, praziquantel, thiabendazole,

piperazine, pyrantel

– nausea, vomiting, diarrhea, dizziness, headache

• mebendazole

– diarrhea, abdominal pain, tissue necrosis

03/09/21 Chapter 17-112

 Antiviral Agents

03/09/21 Chapter 17-113

 Understanding Viruses
Viral Replication
• A virus cannot replicate on its own.

• It must attach to and enter a host cell.

• It then uses the host cell’s energy to synthesize protein, DNA,

and RNA.

03/09/21 Chapter 17-114

 Understanding Viruses

• Viruses are difficult to kill because they live

inside our cells.
• Any drug that kills a virus may also kill our
cells.

03/09/21 Chapter 17-115

 Viral Infections
 Competent immune system:
• Best response to viral infections
• A well-functioning immune system will eliminate
or effectively destroy virus replication.

 Immunocompromised patients have

frequent viral infections
• Cancer patients, especially leukemia or lymphoma
• Transplant patients, due to pharmacological therapy
• AIDS patients, disease attacks immune system

03/09/21 Chapter 17-116

 Antivirals
Key characteristics of antiviral drugs:
• Able to enter the cells infected with virus.

• Interfere with viral nucleic acid synthesis and/or

regulation.

• Some agents interfere with ability of virus

to bind to cells.

• Some agents stimulate the body’s immune system.

03/09/21 Chapter 17-117

 Antivirals
Viruses killed by current antiviral therapy:
• Cytomegalovirus (CMV)

• Herpes simplex virus (HSV)

• Human immunodeficiency virus (HIV)

• Influenza A (the “flu”)

• Respiratory syncytial virus (RSV)

03/09/21 Chapter 17-118

 Antivirals: Mechanism of Action

Inhibit viral replication

• Inhibit viral attachment

• Prevent genetic copying of virus

• Prevent viral protein production

03/09/21 Chapter 17-119

 Antivirals
Synthetic Purine Nucleoside Analogues

Two types of nucleosides:

Purine nucleosides
• guanine
• adenosine

Pyrimidine nucleosides
• thymine
• cytosine

03/09/21 Chapter 17-120

 Antivirals: Purine Nucleosides
Agent Antiviral Activity
guanines
acyclovir HSV 1 & 2, VZV
ganciclovir (DHPG) CMV retinitis and systemic
CMV infection
ribavirin (RTCD) Influenza types A and B,
RSV, LV, HV
adenosines
didanosine (ddl) HIV
vidarabine (Ara-A) HSV, herpes zoster
03/09/21 Chapter 17-121
 Antivirals: Pyrimidine Nucleosides
Agent Antiviral Activity
cytosines
lamivudine (3TC) HIV
zalcitabine (ddC) HIV

thymine
idoxuridine (IDU) HSV
stavudine (d4T) HIV
trifluridine HSV
zidovudine (AZT) HIV

03/09/21 Chapter 17-122

 Other Antivirals
• amantadine and rimantadine

– influenza A

• foscarnet (Foscavir)

– CMV (retinitis and systemic)

• Neuraminidase Inhibitors: oseltamivir and zanamivir

– influenza types A and B

03/09/21 Chapter 17-123

 Antivirals: Side Effects
acyclovir
• Burning when topically applied, nausea, vomiting,
diarrhea, headache

amantadine and rimantadine

• Anticholinergic effects, insomnia, lightheadedness,
anorexia, nausea

didanosine (ddl)
• Pancreatitis, peripheral neuropathies, seizures

03/09/21 Chapter 17-124

 Antivirals: Side Effects
zidovudine (AZT)
• Bone marrow suppression, nausea, headache

foscarnet (Foscavir)
• Headache, seizures, acute renal failure, nausea,
vomiting, diarrhea

ganciclovir (Cytovene)
• Bone marrow toxicity, nausea, anorexia, vomiting

03/09/21 Chapter 17-125