Antimicrobials Ho

• Antibacterials
• Antifungals
• Antivirals
• Antiparasitics
There are Three in this Relationship

Drug
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Infection
Host Bacteria
Host defence
Targets: unique to prokaryote and fungal
microorganisms or much more important in
these organisms than in humans/animals.
E.g bacterial and fungal cell wall
synthesizing enzymes,
- the bacterial ribosome
- the enzymes required for nucleotide
synthesis and DNA replication , and
the machinery of viral replication .
 Figure 26.12

Cell wall synthesis DNA gyrase DNA-directed RNA polymerase

RNA elongation
Cycloserine Quinolones Nalidixic acid Actinomycin Rifampin
Vancomycin Ciprofloxacin Streptovaricins
Bacitracin Novobiocin
Penicillins
Cephalosporins Protein synthesis
Monobactams
Carbapenems
(50S inhibitors)
Erythromycin (macrolides)
DNA Chloramphenicol
Clindamycin
Folic acid metabolism Lincomycin
Trimethoprim THF mRNA
Sulfonamides
Protein synthesis
Ribosomes (30S inhibitors)
DHF
50 50 50
Tetracyclines
30 30 30 Spectinomycin
Streptomycin
Gentamicin
Cytoplasmic membrane Kanamycin
structure and function Amikacin
Polymyxins Nitrofurans
Lipid
Daptomycin biosynthesis
Protein synthesis
Platensimycin (tRNA)
PABA CytoplasmicCell wall
membrane Mupirocin
Puromycin

© 2012 Pearson Education, Inc.

 Eukaryotes Bacteria Obligately parasitic Bacteria Viruses

RNA DNA
Fungi Mycobacteria Gram-negativeGram-positive Chlamydia Rickettsia viruses viruses
Bacteria Bacteria

Tobramycin Penicillins
Nonnucleoside
Azoles reverse transcriptase
Allylamines Sulfonamides inhibitors
Cycloheximide Cephalosporins Protease inhibitors
Polyenes Streptomycin Quinolones Fusion inhibitors
Polyoxins Tetracycline
Nucleic acid Nucleoside analogs
analogs Vancomycin Interferon
Isoniazid Polymyxins
Echinocandins Daptomycin

Platensimycin

© 2012 Pearson Education, Inc.

 Bacteriostatic vs. bactericidal drugs:

 Antimicrobial drugs are classified as either bacteriostatic

or bactericidal.
 Bacteriostatic drugs arrest the growth and replication of bacteria
at serum levels achievable in the patient, thus limiting the spread
of infection while the body's immune system attacks,
immobilizes, and eliminates the pathogens.
 If the drug is removed before the immune system has scavenged
the organisms, enough viable organisms may remain to begin a
second cycle of infection.
 Bactericidal drugs kill bacteria at drug serum levels achievable in
the patient.

 Because of their more aggressive antimicrobial action, these

agents are often the drugs of choice in seriously ill patients.
 Minimum inhibitory concentration (MIC) is the
smallest amount of an agent needed to inhibit
growth of a microorganism
Varies with the organism used, inoculum size,
temp, pH, etc.
Disc diffusion assay
Antimicrobial agent added to filter paper disc
MIC is reached at some distance
 Zone of inhibition
 Area of no growth around disc

© 2012 Pearson Education, Inc.

 Figure 26.10

Minimum
inhibitory
concentration

© 2012 Pearson Education, Inc.

 Figure 26.11

Nutrient Inoculate plate

agar plate with a liquid
culture of a test
organism

Discs containing
antimicrobial
agents are placed
on surface

Incubate for 24–48 h

Test organism shows

susceptibility to some
agents, indicated by
inhibition of bacterial
growth around discs
(zones of inhibition)
© 2012 Pearson Education, Inc.
 Minimum inhibitory concentration:
 To determine the minimum inhibitory concentration
(MIC), tubes containing serial dilutions of an antibiotic
are inoculated with the organism whose susceptibility is
to be tested
 The tubes are incubated and later observed to determine
the MIC that is, the lowest concentration of antibiotic
that inhibits bacterial growth.

 To provide effective antimicrobial therapy, the clinically

obtainable antibiotic concentration in body fluids should
be greater than the MIC.
 Note: This assay is now done automatically using
microtiter plates.
Minimum bactericidal concentration:
This quantitative assay determines the
minimum concentration of antibiotic that
kills the bacteria under investigation.
The tubes that show no growth in the MIC
assay are subcultured into antibiotic-free
media. The minimum bactericidal
concentration is the lowest concentration of
antimicrobial agent that results in a 99.9
percent decline in colony count after
overnight broth dilution incubations
 Effect of the site of infection on therapy: The blood-brain
barrier
 Adequate levels of an antibiotic must reach the site of infection
for the invading microorganisms to be effectively eradicated.
 Lipid solubility of the drug: For example, lipid-soluble drugs,
such
as the quinolones and metronidazole, have significant
penetration into the CNS. In contrast, b-lactam antibiotics, such
as penicillin, are ionized at physiologic pH and have low solubility
in lipids.
-Meningeal inflamation may alter bbb permeability
 Molecular weight of the drug: A compound with a low
molecular weight has an enhanced ability to cross the
blood-brain barrier, whereas compounds with a high molecular
weight (for example, vancomycin) penetrate poorly, even in the
presence of meningeal inflammation.
 Protein binding of the drug:
Challenge
Antimicrobial resistance
Antibacterials
INHIBITORS OF CELL WALL SYNTHESIS

 Beta-lactams
 compounds of this family all contain the beta-lactam ring

 The different groups within this family are distinguished by

the structure of the ring attached to the beta-lactam ring

and by the side chains attached to these rings.
 Mechanism of action

 Beta-lactams inhibit cell wall synthesis

-by binding to enzymes known as 'penicillin binding

proteins'
(PBPs).
 These proteins are carboxypeptidases and transpeptidases

responsible for the final stages of cross-linking the bacterial

cell wall structure
The Penicillins
 • Penicillin G and penicillin V -have greatest
activity against Gram-positive organisms, Gram-
negative cocci, and non-β-lactamase-producing
anaerobes. However, they have little activity
against Gram-negative rods, and they are
susceptible to hydrolysis by β-lactamases.

Most streptococci are very susceptible.

- are readily hydrolyzed by penicillinase, -
ineffective against most strains of S. aureus.

23
 • The penicillinase-resistant penicillins
-methicillin, , cloxacillin and
flucloxacillin , nafcillin, oxacillin, and
dicloxacillin have less-potent antimicrobial
activity against microorganisms that are
sensitive to penicillin G, but they are
preferred agents for treatment of
penicillinase-producing S. aureus and
Staphylococcus epidermidis that are not
methicillin resistant

- not against enterococci, anaerobic

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bacteria, and Gram-negative cocci an rods ,
 Ampicillin, amoxicillin, and others such as
bacampicillin and pivampicillin are the
aminopenicillins, whose
antimicrobial activity is extended to include
some gram-negative microorganisms
-e.g., Haemophilus influenzae, Escherichia coli,
and
Proteus mirabilis
- available as co-formulations with a β-lactamase
inhibitor such as clavulanate or sulbactam to
prevent hydrolysis by β-lactamases.

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  ampicillin and amoxicillin -similar spectrums of activity, but amoxicillin is
better absorbed orally
 Amoxicillin is given orally to treat bacterial sinusitis, otitis, and lower
respiratory tract infections
 Ampicillin and amoxicillin – most active against pneumococci with
elevated
MICs to penicillin
 Ampicillin (but not amoxicillin) is effective for shigellosis.

 Ampicillin, at dosages of 4–12 g/d intravenously, is useful for treating

serious
infections caused by susceptible organisms, including anaerobes,
enterococci, L monocytogenes, and β-lactamase-negative strains of
Gram-negative cocci and bacilli such as E coli, and Salmonella sp. Non-β-
lactamase-producing strains of H influenzae are generally susceptible

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  Ampicillin is not active against Klebsiella sp,
Enterobacter sp, P aeruginosa,Citrobacter sp,
Serratia marcescens, indole-positive Proteus species

 Agents with extended antimicrobial activity against

Pseudomonas, Enterobacter, and Proteus spp.
include : azlocillin, carbenicillin, mezlocillin,
ticarcillin, ticarcillin/clavulanate , and carbenicillin
indanyl sodium.
-are inferior to ampicillin against gram-positive
cocci and Listeria monocytogenes and are less
active than piperacillin against Pseudomonas.

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 Piperacillin and piperacillin/tazobactam have
excellent antimicrobial activity against many
isolates of Pseudomonas, E. coli, Klebsiella,
and other gram-negative microorganisms.

 Piperacillin retains the activity of ampicillin

against gram-positive cocci and L.
monocytogenes.

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29
 General Common Properties

 penicillins are distributed widely throughout the body.

 Therapeutic concentrations : achieved readily in joint fluid,
pleural fluid, pericardial fluid, and bile.
 low concentrations of these drugs are found
in prostatic secretions, brain tissue, and intraocular fluid.
 Concentrations of penicillins in CSF are variable but are less
than 1% of those in plasma when the meninges are normal.
 When there is inflammation, concentrations in CSF may
increase to as much as 5% of the plasma value.
 eliminated rapidly by glomerular filtration and renal tubular
secretion, such that their half-lives in the body are short,
typically 30–90 min.
 As a consequence, concentrations of these drugs in urine are
high.

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31
 Penicillin-resistant pneumococci are especially
common in pediatric populations and are often
also resistant to third-generation
cephalosporins.
Greater than 90% of strains of S. aureus, most
strains of S. epidermidis, and many strains of
gonococci are now resistant to penicillin G.
 With rare exceptions, meningococci remain
quite sensitive to penicillin G.

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Cephalosporins
the most commonly used antibiotics
similar in structure to the penicillins, both
containing a four-member beta-lactam ring.
also bactericidal and inhibit cell wall
synthesis
 Mechanism of Action
 inhibit bacterial cell wall synthesis.

Classification
based on general features of antimicrobial activity
 The first-generation cephalosporins include cefazolin,
cefadroxil,cephalexin, cephalothin, cephapirin, and cephradine ;
have good activity against gram-positive bacteria and modest activity
against gram-negative microorganisms. Most gram-positive cocci (with
the exception of enterococci, MRSA, and S. epidermidis) are susceptible.

 Most oral cavity anaerobes are sensitive, but the B. fragilis group is
resistant.

 have modest activity against Moraxella catarrhalis, E. coli, Klebsiella

pneumoniae, and P. mirabilis.

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 Second-generation cephalosporins :
-include cefaclor, cefamandole, cefonicid,
cefuroxime, cefprozil, loracarbef, and ceforanide,
and the structurally related cephamycins cefoxitin and
cefotetan, which have activity against anaerobes.

- have somewhat increased activity against gram-

negative microorganisms (including activity against H.
influenzae) but are much less active than the third-
generation agents.
-A subset of second-generation agents (cefoxitin and
cefotetan) also has modest activity against B. fragilis.

35
  Third-generation cephalosporins: include cefoperazone, cefotaxime,
ceftazidime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime
proxetil, cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam.

 generally are less active than first-generation agents against gram-

positive cocci, although ceftriaxone and cefotaxime in particular have
excellent antistreptococcal activity.
 much more active than prior generations against the Enterobacteriaceae,
 Activity against Bacteroides spp. But inferior to that of cefoxitin and
cefotetan

 Antipseudomonal cephalosporins include ceftazidime and cefepime.

These agents expand on the gram-negative activity of the third generation
to provide useful activity against P. aeruginosa.
 Ceftazidime and ceftolozane have weaker gram-positive activity than
third-generation agents, while cefepime’s activity is similar to that of
ceftriaxone.

36
 Fourth generation
Cefepime parenterally.
Cefepime -wide antibacterial spectrum,
with activity against streptococci and
staphylococci (methicillin susceptible).
 effective on aerobic gram- neg .
organisms, such as Enterobacter species, E.
coli, K. pneumoniae, P. mirabilis, and P.
aeruginosa.

37
 advanced generation
Ceftaroline is a broad-spectrum
 against MRSA, and it is indicated for the treatment of
complicated skin and skin structure infections and
community-acquired pneumonia.
 In addition to its broad gram-positive activity, it also has
similar gram-negative activity to the third-generation
cephalosporin ceftriaxone.
 Important gaps in coverage include P. aeruginosa,
extended-spectrum β-lactamase (ESBL)-producing
Enterobacteriaceae, and Acinetobacter baumannii.
 twice-daily dosing regimen
 ceftobiprole

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  Administration
Many of the cephalosporins must be administered IV or IM because of their
poor oral absorption. (there are Exceptions )
Distribution
All cephalosporins distribute very well into body fluids. However, adequate
therapeutic levels in the CSF, regardless of inflammation, are achieved with
only a few cephalosporins.
 For example, ceftriaxone and cefotaxime are effective in the treatment of
neonatal and childhood meningitis caused by H. influenzae. Cefazolin is
commonly used for surgical prophylaxis due to its activity against
penicillinase-producing S. aureus, along with its good tissue and fluid
penetration.
Elimination
-through tubular secretion and/or glomerular filtration .
 doses must be adjusted in renal dysfunction

 One exception is ceftriaxone, which is excreted through the bile into the
feces and, therefore, is frequently employed in patients with renal
insufficiency.

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40
Glycopeptides

 Glycopeptides include vancomycin and

teicoplanin .
 Teicoplanin is a complex of five different, but
closely related, molecules.
 Mechanism of action
 Glycopeptides interfere with cell wall synthesis
by binding to terminal D-alaD-ala at the end of
pentapeptide chains that are part of the growing
bacterial cell wall structure.
 This binding inhibits the transglycosylation
reaction and prevents incorportation of new
subunits into the growing cell wall.
 Glycopeptides act at an earlier stage than beta-
 Indications
 Both vancomycin and teicoplanin are only active
against Gram-positive organisms.
 They are mainly used for the treatment of
infections caused by Gram positive cocci and
Gram-positive rods that are resistant to beta-
lactam drugs, or in patients who are allergic to
beta-lactams.
 Oral administration is used for the treatment of
Clostridium difficile in antibiotic-associated
colitis.
 Toxicity
 Vancomycin must be given by slow intravenous
infusion to avoid 'red man' syndrome (due to
histamine release)
 The glycopeptides are potentially ototoxic and
nephrotoxic
 Teicoplanin is less toxic than vancomycin.
 Resistance
 Acquired resistance has now been reported
among enterococci, where resistance is plasmid-
mediated and transmissible
3 INHIBITORS OF PROTEIN SYNTHESIS

 Aminoglycosides
 This is a family of related molecules containing either
streptomycin or 2- deoxystreptamine, e.g gentamicin
 Mechanism of action
 Aminoglycosides inhibit and kill organisms by interfering with
the binding of formylmethionyl-tRNA to the ribosome, and
thereby, preventing the formation of initiation complexes from
which protein synthesis proceeds.
 Indications
 Gentamicin, amikacin and netilmicin are used in combination
with other antibiotics for the treatment of serious Gram-
negative infections, including those caused by P. aeruginosa.
They are not active against streptococci, but are synergtsttc in
combination with ß-lactams. They are active against
staphylococci.
 Tobramycin is slightly more active than gentamicin
against P aeruginosa.
 Streptomycin is now reserved almost entirely for the
treatment of mycobacterial infections.
 Spectinomycin is used to treat beta-lactam resistant
Neisseria gonorrhoeae infections.
 Toxicity
 The aminoglycosides are potentially nephrotoxic and
ototoxic, and the therpeutic 'window' between serum
concentrations required for successful treatment and
those that are toxic, is small.
 Blood concentrations should be monitored regularly,
particularly in patients with renal impairment.
 Aminoglycosides given once a day are more active and less
nephro- and ototoxic than aminoglycosides given 8 or 12
hourly
 Resistance
 Production of aminoglycoside-modifying enzymes is the
most important mechanism of acquired resistance.
 The genes for these enzymes are often plasmid-mediated
and transferable from one bacterial species to another.
 The effect of the enzymes is to alter the structure of
aminoglycoside molecule which consequently changes
the uptake of drugs by the bacteria. Resistance may
also arise in Gram-negative rods through alterations
in cell wall permeability through the porins.
Tetracyclines

 Tetracyclines are a family of large cyclic structures which

have several sites for chemical substitutions. The members
of the family differ mainly in their pharmacological
properties, rather than in their antibacterial spectra
 Mechanism of action
 Tetracyclines inhibit protein synthesis by preventing
aminoacyl transfer RNA from entering the acceptor sites on
the ribosome.
 Indications
 Tetracyclines are used in the treatment of infections caused
by Mycoplasma, Chlamydiae and Rickettsiae. Tetracyclines
are active against a wide variety of different bacterial
species, but their use is now restricted by widespread
resistance
 Toxicity
 Suppression of normal gut flora causes
gastrointestinal upset and diarrhoea and leads to
overgrowth by resistant bacteria, (e.g
Staphylococcus aureus) and fungi, e.g Candida.
 Brown staining of teeth occurs in the fetus and in
children, and thus these drugs should be avoided in
pregnancy and in children under 8 years of age.
 Resistance
 The mechanism of resistance is associated with the
efflux mechanism which positively pumps out the
antibiotic of the cells
 Chloramphenicol

 Chloramphenicol contains a nitrobenzene nucleus

which is responsible for some of the toxic
problems associated with the drug
 Mechanism of action
 Chloramphenicol blocks the action of
peptidyltransferase thereby preventing peptide
bond synthesis and thus inhibits bacterial protein
synthesis.
 Indications
 Chloramphenicol is active against a wide variety
of bacterial species: Gram positive and Gram
negative, aerobes and anaerobes, including intra
cellular organisms such as Salmonella typhi,
Chlamydiae and Rickettsiae
 Toxicity
 Dose-dependent bone marrow suppression,
occurs when the drug is given for long periods
and is reversible when treatment is stopped.
 An idiosyncratic, not dose-dependent
reaction, causes aplastic anaemia.
 Chloramphenicol is also toxic to neonates
particularly premature babies whose liver
enzyme systems are incompletely
developed.
 This can result in the "grey baby syndrome''.
 Chloramphenicol serum concentrations
should be monitored in infants and children
 Resistance
 The most common mechanism involves inactivation of
the drug by plasmid mediated chloramphenicol acetyl
transferases produced by resistant bacteria.
 Acetylated chloramphenicol fails to bind to the
ribosomal target.
 Resistance is becoming increasingly common and
this, together with the potential toxicity, has
significantly reduced the use of the drug.
 Macrolides

 Macrolides, lincosamides, ketolides, and streptogramins

share overlapping binding sites on ribosomes, and have
similar antimicrobial activities, as well as similar
mechanisms of resistance
 The macrolides are a family of large cyclic molecules, all
containing a macrocyclic lactone ring.
 The macrolide class of antibiotic agents includes
compounds with 14-membered (erythromycin,
clarithromycin) 15-membered (azithromycin), and 16-
membered (rokitamycin, spiramycin and josamycin) ring
structures.
 Streptogramin antibiotics, such as pristinamycim or
dalfopristin-quinupristin, contain two active components,
type A and type B, which synergistically inhibit peptide
elongation.
 Streptogramin B agents include quinupristin and
pristinamycin lA
 Streptogramin A agents include dalfopristin and
pristinamycim IIA. .
 Mechanism of action
 Erythromycin binds to the 23S rRNA in the 50S subunit of the
ribosome and blocks the trans-location step in protein synthesis,
thereby preventing the release of tRNA after peptide bond formation.
 Indications
 Erythromycin is active against Gram-positive cocci and is an
important alternative treatment for infections caused by streptococci
in patients allergic to penicillin.
 It is active against Legionella pneumophila and Campylobacter jejuni.
 It is also active against Mycoplasma, Chlamydiae and Rickettsiae
and is therefore an important drug for treatment of atypical
pneumonia and chlamydia! infections of the urogenital tract.
 Spiramycin is used, almost exclusively, for the treatment of
cryptosporidiosis and in the prevention of congenital toxoplasmosis.
 Toxicity
 Erythromycin is a relatively non-toxic
drug, although it causes nausea and
vomiting after oral administration in a
significant number of patients.
 Resistance
 Two main mechanisms of resistance are
described. The first mechanism is due to
alteration in the 23S rRNA target
 The second mechanism involves the
presence of an efflux pump
 Lincosamides
 This group contains lincomycin and clindamycin
 Mechanism of action
 Lincosamides bind to the 50S ribosomal subunit
and inhibit protein synthesis by inhibiting peptide
bond formation.
 Indications
 Clindamycin has a spectrum of activity similar to
erythromycin, but it is much more active against
anaerobes, both Gram-positive, e.g. Clostridium
spp, and Gram-negative, e.g. Bacteroides.
 Cl. difficile is resistant and may overgrow in the
gut, causing pseudomembranous colitis.
 The activity of clindamycin against
Staphylococcus aureus and its penetration into
bone makes it a valuable drug in the treatment
of osteomyelitis .
 Toxicity
 The association between antibiotic
administration and pseudomembranous colitis
caused by C. difficile was first noted following
clindamycin treatment.
 Fusidic acid
 Fusidic acid is a compound which
inhibits protein synthesis by forming a
stable complex with elongation factor
EF-G, guanosine diphosphate and the
ribosome.
 Indications
 Fusidic acid is active against Gram-positive cocci and is used is
in the treatment of staphylococcal infections, which are
resistant to beta-lactams, or in patients who are allergic to
alternative staphylococcal agents.
 Fusidic acid should be given in combination with another anti
staphylococcal agent, e.g rifampicin or b-lactams, to prevent
the emergence of resistant mutants.
 Toxicity
 Fusidic acid may occasionally cause jaundice and
gastrointestinal upset
 Resistance
 Resistant mutants with altered EF-G emerge rapidly in
staphylococcal populations exposed to the drug in monotherapy
INHIBITORS OF NUCLEIC ACID SYNTHESIS

 This category comprises antibacterial agents which act as

inhibitors of nucleic acid synthesis.
 Sulphonamides
 This group of molecules are all structural analogues of
para-amino benzoic acid (PABA).
 Mechanism of action
 Sulphonamides act in competition with PABA for the active
site of dihydropteroate synthetase, an enzyme which
catalyses a step in the synthetic pathway of tetrahydrofolic
acid (THFA), required for the synthesis of purines and
pyrimidines and thus for nucleic acid synthesis.
 Indications
 The sulphonamides have a spectrum of activity primarily
against Gram-negative organisms (except Pseudomonas).
Thus, they are used in the treatment of urinary tract
infection. However, resistance is widespread.
 Toxicity
 Sulphonamides are relatively free of toxic side effects, but
rashes and bone marrow suppression may occur.
 Resistance
 Plasmid-mediated genes code for an altered
dihydropteroate synthetase, which has a greatly decreased
affinity for the sulphonamide, but is essentially unchanged
in its affinity for PABA.
 Trimethoprim (and cotrimoxazole)
 Trimethoprim is one of a group of pyrimidine-like
structures analogous to the aminohydroxypyrimidine
moiety of the folic acid molecule
 Mechanism of action
 Trimethoprim, like sulphonamides, also prevents the
synthesis of THFA, but at a later stage by inhibiting
dihydrofolate reductase.
 Trimethoprim is often given in combination with
sulphamethoxazole (cotrimoxazole).
 The advantages of this combination over either drug alone are :
 mutant bacteria which are resistant to one agent are unlikely to be
resistant to the other, i.e double mutation;
 the two agents act synergistically against some bacteria
 Indications
 Trimethoprim alone is active against Gram-negative rods with the
exception of Pseudomonas species and its main use is in the
treatment (and long-term prophylaxis) of urinary tract infection.
 Cotrimoxazole is active against a wide range of urinary tract
pathogens and S. typhi. When given intravenously in high doses, this
combination is valuable for the treatment of Pneumocystis carinii
pneumonia.
 Toxicity
 Trimethoprim alone and in combination with sulphamethoxazole can
cause neutropenia. Nausea and vomiting may occur.
 Resistance
 Plasmid-encoded dihydrofolate reductases with altered affinity for
trimethoprim, allow the synthesis of THFA to proceed unhindered by the
presence of trimethoprim.
Quinolones

 This is a large family of synthetic agents.

 Nalidixic acid is one of the earlier molecules, but the
synthesis of fluoroquinolones has led to a number of chemical
derivatives with improved antibacterial activity .
 Mechanism of action
 Quinolones act by inhititing the activity of DNA gyrase , the
bacterial cell can no longer 'pack' its DNA into the cell.
 lndications
 Nalidixic acid is only active against enterobacteria and its use
is limited to the treatment of urinary tract infection.
 Ciproftoxacin has a greater degree of activity than nalidixic
acid against Gram-negative rods and is particularly active
againstP. aeruginosa. Dosage may be adapted according to
pharmacokinetics
 moxiftoxacin is also active against Streptococcus pneumoniae.
 In addition to the treatment of urinary tract infection, the newer
quinolones are useful for systemic Gram-negative infections and may
find a role in the treatment of chlamydia! and rickettsial infections.
 They may also be useful in infections caused by other intracellular
organisms such as L. pneunwphila and S. typhi, and in combination
with other agents for 'atypical' mycobacteria.
 They are active against staphylococci, but less so against
streptococci. Enterococci are resistant.
 Ciprofloxacin, otloxacin and moxiftoxacin can all be administered
orally.
 Toxicity
 Gastro-intestinal disturbances are the most common side effects.
 Quinolones are usually avoided in children because of the risk of
arthropathy. Seizure threshold may be reduced by ciprofloxacin
Rifamycins

 Rifampicin is a large molecule with a

complex structure
 Mechanism of action
 Rifampicin binds to the 13-subunit of the
RNA polymerase and blocks the
synthesis of proteins.
 Indications
 Rifampicin is used in treatment of mycobacterial
infections. Rifampicin is the drug of choice for the
prophylaxis of close contacts of meningococcal and
Haemophilus meningitis. The drug is used in combination
in the treatment of staphylococci infections.
 Toxicity
 Rashes, hypersensitivity reactions and jaundice occur
with rifampicin treatment.
 Resistance
 Chromosomal mutations produce alterations in the RNA
polymerase target which induces lowered affinity for
rifampicin.
Metronidazole

 Metronidazole is a nitromidazole antibiotic used for the treatment of

anaerobic and protozoal infections.
 entering the cell through passive diffusion.
 Cause DNA destabilization and rupture with cell death.
 there is limited resistance to this drug.
 Like clindamycin, metronidazole has excellent oral bioavailability,
with more than 90% absorbed.
 Metronidazole is commonly used in preterm infants for anaerobic
infections, including Necrotizing enterocolitis( NEC), meningitis and
bacteremia
 The metabolism of metronidazole is primarily hepatic
 Nitrofurantoin

· Reduction inside the bacterial cell by nitrofuran reductase to

multiple reactive intermediates
· Attack ribosomal proteins, DNA, respiration, pyruvate
metabolism & other macromolecules within the cell
· Effect is bactericidal for many G- (+) & G- (-) bacteria
· Used to treat lower UTI’s (including E. coli)
Oral agent that exerts antibacterial activity in the urine,
but has little systemic antibacterial effect
· Excreted into the urine
· SEs: anorexia, N, V, Neuropathies & hemolytic anemia in
pts with G-6-dehydrogenase deficiency.
71
Mupirocin

· Kills staphylococci by inhibiting isoleucyl tRNA synthetase

· Topical Tx of minor skin infections, such as impetigo
· Intranasal application for elimination of MRSA carriage by
pts or health care workers
· Rapidly inactivated after absorption
 systemic levels are undetectable
· Mupirocin effectively eliminates S aureus nasal carriage
by pts or health care workers,
 But results are mixed with respect to its ability to
prevent subsequent staphylococcal infection

72
Fusidic acid

· Fusidic acid binds to elongation factor G (EF-G) on the

ribosome
 Inhibits release of EF-GDP, blocking further elongation
· Bacteriostatic
· Topical use against staph. infections
· Systemic use
 Tx of skin & soft tissue infections or osteomyelitis caused
by staph. Aureus
 Tx of pneumonia, septicemia, endocarditis
· Ophthalmic: Tx of superficial infection of the eye &
conjuctivites

73
Polymyxins

· Includes: polymyxin B & polymixin E (colistin)

· Active against G- (-)
· There use largely restricted to topical use
Mostly for skin & eye infections
· Neurotoxic & nephrotoxic
· Colistin (parentral)
A last resort antibiotic for multidrug resistant
Pseudomonas aeruginosa (e.g. Cystic fibrosis
pts) & Acinetobacter

74
Antimycobacterial agents
General considerations

· TB is caused by Mycobacterium tuberculosis

· Complicating factors
 Slow growing, dormant killed very slowly
 Mycolic acid, waxy impermeable to drugs
 Intracellular organisms
 inaccessible for most drugs
 Increased risk of resistance
· Combination therapy with 2 or more drugs

76
General considerations…

· The objective of therapy:

To eliminate & prevent relapse
• To accomplish this goal must kill actively
dividing & resting
• Since the response of mycobacterial
infection to chemotherapy is slow, Tx is
prolonged
Prevent the emergence of resistance
Drug resistance may be single or multiple

• Drug-resistant tuberculosis:
– When it is resistant to one first-line Anti TB
drug, either isoniazid or rifampin
• Multidrug-resistant tuberculosis :
– When it is resistant to isoniazid & rifampin, &
possibly additional agents
• Extensively drug-resistant tuberculosis:
– When it is resistant to isoniazid, rifampin,
fluoroquinolones, & either aminoglycosides or

• Combination of drugs are required

capreomycin or both

To limit drug adverse effects

77
Drug resistance may be single or multiple

· Drug-resistant tuberculosis:
When it is resistant to one first-line Anti TB
drug, either isoniazid or rifampin
· Multidrug-resistant tuberculosis :
When it is resistant to isoniazid & rifampin, &
possibly additional agents
· Extensively drug-resistant tuberculosis:
When it is resistant to isoniazid, rifampin,
fluoroquinolones, & either aminoglycosides or
capreomycin or both

78
 Antitubercular Agents
· First-Line Agents · Second-Line Agents
Isoniazid capreomycin
Ethambutol Cycloserine
pyrazinamide (PZA) Ethionamide
Rifampin Kanamycin
streptomycin para-aminosalicyclic
acid (PAS)
i cs Levofloxacin
n
o RESPI - as in TB is
em
n most commonly a
M ”RESPIratory” infection
79
a) Isoniazid (INH)

· Antimicrobial activity and therapeutic use

It blocks the synthesis of mycolic acids in the
mycobacterial cell wall
Bactericidal, but only in proliferating cells
It is indicated for:
• Tx of TB: used in combination with other drugs
• Chemoprophylaxis of TB: used alone for 6
months to a yr after exposure
· Pharmacokinetics
It is inactivated in the liver, primarily by acetylation

80
Isoniazid (INH)…

· Major adverse effects

Peripheral Neuropathy
Hepatotoxicity
· Other ADRs includes:
CNS effects: seizures, dizziness
GI distress
Allergy to isoniazid can produce fever, rashes, &
a syndrome resembling lupus erythematosus

81
b) Ethambutol

· Antimicrobial activity and therapeutic use

Inhibit cell wall biosynthesis
The drug is bacteriostatic, not bactericidal
It is employed for initial treatment of TB & for treating
pts who have received therapy previously
Like other drugs for TB, ethambutol is always
employed as part of a multidrug regimen
· Pharmacokinetics
Ethambutol undergoes little hepatic metabolism & is
excreted primarily in the urine.

82
Ethambutol…

· Adverse effects
Ethambutol is generally well tolerated
The only significant adverse effect is optic
neuritis
Other Adverse Effects
• Allergic reactions (dermatitis, pruritus), GI
upset, and confusion
• Asymptomatic hyperuricemia

83
c) Rifampin

· Antimicrobial activity and therapeutic use

It inhibits RNA synthesis by binding to the beta-
subunit of bacterial RNA-Polymerase
It is a bactericidal drug
Useful against G-(+) & G-(-) cocci, & chlamydia, as
well as mycobacteria
 Other common uses:
• In combination with dapsone, for Leprosy
• For prophylaxis in kids exposed to H. Influenzae
type b
• To treat chronic Meningococcal carriers

84
Rifampin…

· Pharmacokinetics
It is well absorbed if taken on an empty
stomach
It is eliminated primarily by hepatic metabolism
It induces hepatic drug-metabolizing enzymes

85
Rifampin…

· Adverse effects & Interactions

 Major adverse effects
• Hepatotoxicity
• Discoloration of Body Fluids
 Other Adverse Effects
• GI disturbances (anorexia, nausea, abdominal
discomfort)
• Cutaneous reactions (flushing, itching, rash)
 Drug Interactions
• Accelerated Metabolism of Other Drugs

86
 d) Pyrazinamide
· Antimicrobial activity and therapeutic use
Pyrazinamide is bactericidal to M. tuberculosis
as a "sterilizing" agent active against residual intracellular
organisms that may cause relapse.
· Pharmacokinetics
Metabolisms is in the liver & excretion is renal, primarily
as inactive metabolites
· Adverse effects
 Major Adverse effects:
• Hepatotoxicity in 5% of pts
Other Adverse Effects
• Hyperuricemia
• GI disturbances (NVD), rashes, & photosensitivity 87
e) Streptomycin

· Used only in severe TB infections, due to its high

incidence of adverse effects
· It is still considered a first-line drug
· Acts mainly on extracellular tubercle bacilli

88
Second-line antituberculosis drugs

· In general, these drugs are less effective, more

toxic, and more expensive than the first-line drugs
As a result, their principal indication is TB
caused by organisms that have proved
resistant to first-line agents
In addition, second-line drugs are used to treat
severe pulmonary TB as well as disseminated
(extrapulmonary) infection
· The second-line drugs are always employed in
conjunction with a major anti-TB drug

89
3. Antifungal Drugs
Antifungal Agents

· Antifungal Agents
Systemic
• Example: Amphotericin B, fluconazole,
ketoconazole, itraconazole

Topical
• Examples: clotrimazole, miconazole,
nystatin

91
92
A. Polyenes: Amphotericin-B

· Bind to sterols in cell membrane lining

· Result: fungal cell death
· Do not bind to human cell membranes or kill
human cells
· Agent of choice for the treatment of many
severe systemic fungal infections
· Given by PO for fungal overgrowth
superinfections
· Intrathecal administration is required for Tx of
fungal meningitis

93
Amphotericin-B…

· Adverse reactions: Most Common

Nephrotoxicity, electrolyte wasting (primarily
K+ & Mg2+ , infusion reactions (fever, chills, N,
flushing, tachycardia, hypotension)
· Adverse reactions: Rare/Severe/Important
Bronchospasm, hypoxia, arrhythmias,
anemia, hypersensitivity

94
Polyenes… Nystatin

· Only used topically

B/c the adverse effects are too severe
Oral administration for the topical Tx of fungal
GI infections
· Adverse reactions: Most common
Mild nausea, vomiting (tablet)

· Counseling Point
Do not apply in large quantity to open wound
Cover medicated area with a gauze/bandage

95
B. Azole antifungals

· Includes: ketoconazole, miconazole, clotrimazole,

fluconazole, itraconazole
· Inhibit an enzyme, resulting in cell membrane
leaking
· Lead to altered cell membrane
· Result: fungal cell death

96
Azole antifungals…

· Adverse reactions for the drug class:

Most common
• V, abdominal pain, N, D, rash
Rare/Severe/Important
• Elevated liver function tests (rare severe
hepatic toxicity), hypersensitivity

· Major drug interactions for the drug class

Azoles inhibit the CYP450 system & ↑ conc of
drugs metabolized via this pathway

97
C. Other antifungal drugs

· Flucytosine
 Also known as 5-fluorocytosine (antimetabolite)
 Taken up by fungal cells & interferes with DNA synthesis
 Result: fungal cell death
 Side effects: N, V, anorexia, headache, dizziness, others

· Griseofulvin
 Disrupts cell division
 Result: inhibited fungal mitosis (reproduction)
 Side effects: rash, urticaria, headache, nausea, vomiting,
anorexia, others

98
4. Antiviral Drugs
Introduction: Characteristics of Viruses

· Use host cell to replicate → host targets cause toxicity

· Intracellular pathogens → drug must enter infected
cells
· Few unique viral functions → few selective viral
targets
· Establish latency → difficult to eliminate if not
replicating
· Differ in their coded functions → difficult to make
selective wide spectrum agents
· Higher mutation rate → resistance emergence
· Limited coded targets → cross resistance
100
Steps Viral replication

Attachment of the virus to receptors on the host cell

surface
Entry of the virus through the host cell membrane
Uncoating of viral nucleic acid
Synthesis of early regulatory proteins, eg. NA-
polymerases
Synthesis of new viral RNA or DNA
Synthesis of late, structural proteins
Assembly (maturation) of viral particles
Release from the cell
Antiviral agents can potentially target any of these steps
101
A. Antiviral drugs other than
ARV drugs
Antiviral drugs other than ARV drugs

a) Amantadine (inhibit uncoating)

Indications: Influenza A, Rubella
• Used prophylactically for Influenza-A infection
Adverse effects:
• CNS effects, including insomnia, restlessness,
nervousness, depression
b) Rimantadine
Alternative to Amantadine
 Adverse effects:
• May have lower adverse CNS effects than
Amantadine

103
Antiviral drugs other than ARV drugs…

c) Acyclovir: Acycloguanosine
Safest & most widely used agent to combat
Herpes viruses
Adverse effects: May involve kidney, skin,
soft tissues, CNS
d) Others: Ganciclovir, RIBAVIRIN, VIdarabine

104
105
B. ANTIRETROVIRAL
DRUGS
Antiretroviral drugs

· Classification of ARV drugs

Agents w/c inhibit enzymes required for HIV
replication
• Reverse transcriptase inhibitors (NRTIs &
NNRTIs), Integrase inhibitors, protease
inhibitors (PIs)
Agents w/c block viral entry into cells
• Fusion inhibitors & CCR5 antagonists

107
Classes of ARV drugs
I. NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS (NRTIs)
CLASS EFFECTS:
• MOA: require intracellular phosphorylation to
the 5’-triphosphate moiety to be active
• The 5’-triphosphate competes with endogenous
deoxynucleotides for reverse transcriptase (RT)
enzyme & prematurely terminates DNA
elongation due to the modified 3’-hydroxyl group

108
NRTI Mechanism of Action cont…

109
Classes of ARV drugs: NRTIs…

· Specific for HIV RT, but ADRs may in part be

owing to some inhibition of human DNA
polymerases, particularly mit DNA polymerase 
• Lactic acidosis, Pancreatitis,
lipodystrophy/lipoatrophy
(ddC>d4T>ddI>AZT>ABC=3TC=FTC=TDF)
· All drugs are renally eliminated

110
 Drug Adverse effects Other comments

Zidovudine • Bone marrow suppression • Do not use w/d4T

(AZT, ZDV) • GI
• Headache
• Myopathies • Used in pregnancy
• Metabolic abnormalities
(lipoatrophy, lipids, insulin
resistance)
• Mitochondrial toxicity
Lamivudine • Has activity against
(3TC) •Has minimal side effects Hepatitis B

Emtricitabine • Very well tolerated; however there • Similar to 3TC (do

(FTC) have been reports of skin not use in
hyperpigmentation combination)
• Has activity against
Hepatitis B

111
 Drug Adverse effects Other comments

Stavudine - Pancreatitis •Do not use

(d4T) - peripheral neuropathy w/AZT (both are
- N/V/D thymidine
- Metabolic abnormalities analogues)
(lipoatrophy, lipids, insulin Facial Lipoatrophy

resistance)
- Mitochondrial toxicity
1

- Myopathies
Didanosine - Pancreatitis - Do not use w/d4T
(ddI) - Peripheral neuropathy (similar toxicity)
- N/V/D
- Metabolic abnormalities
(lipoatrophy, lipids, insulin
resistance)
- Mitochondrial toxicity

112
 Drug Adverse effects Other comments

Abacavir • HLA*B5701 test: should be

(ABC) •Hypersensitivity performed prior to starting
reaction (2-9%) ABC
•Never use the drug if HLA
is positive
• No renal adjustment b/c it is
metabolized to inactive
metabolites. (this is the only
one)
Tenofovir • N/V/D • Nucleotide analogue
(TDF) • Rare reports of (monophosphorylated)
renal dysfxn •Has activity against Hepatitis
• Generally very B
well tolerated

113
human leukocyte antigen HLA-B*57:01 allele
Classes of ARV drugs: NNRTIs

II. NONNUCLEOSIDE REVERSE TRANSCRIPTASE

INHIBITORS (NNRTIS)
CLASS EFFECTS:
• MOA: bind noncompetitively to RT & cause a
conformational change; do not require IC phosphorylation
& do not compete w/endogenous deoxynucleotides
• All are metabolized by CYP-450  multiple drug
interactions!!
• Very long half-lives
• Rash & LFT ↑ are associated with all the agents
• They are all metabolized in the liver, no renal adjustment
needed

114
 Drug Adverse effects Other Comments

Efavirenz •CNS effects: drowsiness,

(EFV) dizziness, vivid/strange dreams; •P-450 substrate & inducer
•RASH (up to 10% of people) •ATRIPLA® = EFV+FTC+TDF
•Teratogenic in monkeys
(Pregnancy category D)
Nevirapine •Rash (up to 25%) Nevirapine-Induced Rash

(NVP) •SJS has been reported 1

Courtesy of HIV Web Study,
www.hivwebstudy.org
1

• P-450 autoinducer & inducer of

•Drug induced hepatitis; ↑LFTs other drugs
•Black box warning: DON NOT
in women with >250 CD4s or men
with > 400 CD4s due to
hepatotoxicity
• Multiple drug interactions
Etravirine • Rash, including SJS • Substrate for P-450 3A4, 2C9,
(ETV) • Nausea 2C19
• Inducer of 3A4
• Inhibitor of 2C9 and 2C19
• Currently approved for ARV Ds
experienced Pts only

115
Classes of ARV drugs: Protease Inhibitors

III. PROTEASE INHIBITORS (PIS)

CLASS EFFECTS:
• MOA: block the maturation process, thereby
resulting in the production of immature,
noninfectious virions
• All are metabolized by CYP-450  multiple
drug interactions!!
• GI side effects, lipodystrophy, hyperlipidemia,
hyperglycemia, pancreatitis, LFT ↑ are common

116
 Generic Adverse Effects Other Comments

•Most potent CYP-450

Ritonavir (RTV) •GI inhibitor; now only used for
‘boosting’
•No documented lipid
Atazanavir (ATV) •GI abnormalities when used
•Hyperbilirubinemia ‘unboosted’; a.k.a the lipid
•Nephrolithiasis friendly protease inhibitor

•Acid-dependent absorption
C/I with high dose PPIs
Darunavir (DNV) •GI
•Sulfa moiety
(rash)

Lopinavir/ritonavir •GI • Mainly used in pregnancy

(LPV/r)

117
 Generic Adverse Effects Other Comments

Fosamprenavir •GI
(FPV) •Sulfa moiety

Indinavir (IDV) -
•GI, dry skin, Rarely used in clinical practice
alopecia, ingrown toe - Do NOT use w/ atv due to
nails, nephrolithiasis hyperbilirubinemia

Nelfinavir (NFV) •Diarrhea Rarely used in clinical practice

Saquinavir (SQV) • GI Rarely used in clinical practice

Tipranavir (TPV) • GI, LFTs, sulfa Only approved for ARVDs

moiety experienced pts

Dorsocervical Fat Pad

Source: Dominic C. Chow, MD, University of Hawaii; Larry J. Day, MD, 1

1 University of Michigan; Cecilia M. Shikuma, MD, University of Hawaii

118
 Classes of ARV drugs: Entry Inhibitors

· MOA: inhibits the fusion of HIV with the CD4 cells

MZM Drug Adverse Effects Other Comments

Fusion Enfurvitide •Injection site •BID SQ injection; no known

inhibition (T-20) reactions drug-drug interactions
(binds gp41, •ARVDs experienced pts
a protein on only
the viral
membrane)
CCR5 Maraviroc •Hepatotoxicity • Only approved for
receptor +/- systemic • ARVDs experienced pts
antagonist allergic reaction • Pts who have CCR5 tropic
(pruritic rash, virus
eosinophilia or • P-450 3A4 substrate
elevated IgE) • Dose depends on
coadministered agents
119
Classes of ARV drugs: INTEGRASE
INHIBITORS

V. INTEGRASE INHIBITORS
 MOA: Prevent covalent bonds from forming b/n integrase & host
DNA  HIV integrase unable to incorporate the viral DNA into the
CD4 cell chromosome  prevention of strand transfer & viral
replication

Drug Adverse Effects Other Comments

Raltegravir •No significant side effects •No P-450

in clinical trials metabolism;
•It is glucuronidated
by UGT 1A1

120
Antiretroviral Drugs…

· General Use
The goal of antiretroviral therapy in the
management of HIV infection:
• To improve CD4 cell counts & ↓ viral load
• If accomplished, this generally results in
slowed progression of the disease,
improved quality of life, & ↓ed opportunistic
infections
Prevention of Mother to Child Transmissions
(PMTCT)
Post-exposure prophylaxis (PEP)
121
ART or HAART

· Combination of at least 3 drugs, usually:

2 NRTIs
&
1 NNRTI or 1-2 PIs
Rarely Triple NRTIs

· Therapy with only one or 2 agents allows HIV to

overcome therapy through resistance mutations

122