ANTIMICROBIAL AGENTS

AND CHEMOTHERAPY
MICROBIOLOGY
JOAN E. CERRADA, MD
Antimicrobial agents and chemotherapy

OBJECTIVES
• To review the principles of giving antimicrobial
therapy
• To give an overview of the antimicrobial
agents and their modes of action
• To be aware of the adverse effects of
antimicrobial agents
• To know the mechanism of resistance to
antimicrobial agents
 ANTIMICROBIAL AGENTS
ANTI-BACTERIAL
ANTI-TUBERCULOUS AGENTS
ANTI-FUNGAL
ANTI-VIRALS
(ANTI-PARASITIC DRUGS WILL BE DISCUSSED IN PARASITOLOGY)
 ANTIBACTERIAL AGENTS

CLASSIFICATION 1. Bactericidal vs Bacteriostatic

2. By target site
3. By chemical structure
 ANTIBACTERIAL AGENTS

CLASSIFICATION By target site:

1. cell wall synthesis
2. Protein synthesis
3. Nucleic acid synthesis
4. Cell membrane function
Pharmacokinetics and Pharmacodynamics
 Absorption

Distribution

Metabolism

Elimination

PHARMACOKINETICS AND PHARMACODYNAMICS

Pharmacokinetics

 describes the time course of drug levels

in body fluids as a result of absorption,
distribution, and elimination of a drug
after administration.
 Absorption is best described by the
drug's bioavailability, which is defined
as the percentage of a drug's dose that
reaches the systemic circulation.
Pharmacokinetics

 Distribution is the process by

which a drug diffuses from the
intravascular fluid space to
extravascular fluid spaces
Pharmacodynamics

 The biochemical and

physiologic effects of the
drugs and their mechanisms
of actions
Pharmacodynamics

 Antimicrobial drugs can be divided into

three main groups based on
pharmacodynamic characteristics that
affect bacterial clearance
 Time-dependent

 Concentration-dependent

 Drugs that are predominantly

bacteriostatic
Pharmacodynamics

 Time-dependent antibiotics
 relatively slow bactericidal action
 short PAEs for gram-positive cocci and no or
short PAEs for gram-negative bacilli
 the duration that drug levels exceed the MIC
relative to the dosing interval and the
frequency of drug administration are
important determinants of outcomes
 shorter dosing interval will increase the time
that concentrations remain greater than the
MIC of the infecting microorganism
Pharmacodynamics

 Concentration-dependent antibiotics
 Prolonged PAEs
 aminoglycosides, fluoroquinolones,
daptomycin, colistin, metronidazole,
possibly the azalide azithromycin, and the
ketolides
 the amount of drug (based on the Cmax
and AUC relative to the MIC) rather than
the dosing frequency determines the
efficacy for these drugs.
Pharmacodynamics

 Drugs that are predominantly

bacteriostatic and that produce moderate
to prolonged PAEs
 macrolides, clindamycin, the streptogramins
such as quinupristin/dalfopristin, the
tetracyclines, tigecycline, and linezolid.
 prolonged PAE
 efficacy is determined less by time and
more by the AUC that is greater than the
MIC.
 ANTIBACTERIAL AGENTS

RESISTANCE A resistant organism is one that

will not be inhibited or killed
by an antibacterial agent at
concentrations of the drug
achievable in the body after
normal dosage.
MECHANISMS OF
RESISTANCE
 ANTIBACTERIAL AGENTS

RESISTANCE  Inherent resistance

 Acquired resistance
Inherent resistance

RESISTANCE  Chromosomally-mediated resistance

 mutant selection
 occur at a frequency of 106-108/cell
division
 such mutations usually involve genes
encoding the target site, or cell structures
affecting access to the target site.
Acquired resistance: transposons

RESISTANCE
Acquired resistance: plasmid-mediated

RESISTANCE
Mechanism of resistance
RESISTANCE TO ANTIBACTERIAL AGENTS
Mechanism of resistance
Antibacterial Altered target Altered uptake Drug inactivation
Beta-lactams - + ++
Glycopeptides -
Aminoglycosides - + ++
Tetracyclines - +
Chloramphenicol - +
Macrolides ++
Trimethoprim ++ -
Quinolones - +
Rifampicin ++
(-) rare; (+) common; (++) very common, in many species
Classes of antibacterial agents

ANTIBACTERIAL
AGENTS
 Inhibitors of Cell Wall Synthesis
 Inhibitors of Protein Synthesis
 Inhibitors of Nucleic Acid Synthesis
 Inhibitors of Cytoplasmic Membrane
Function
INHIBITORS OF CELL WALL SYNTHESIS
Inhibitors of Cell Wall Synthesis

 Beta-lactams
 PCNs,Cephalosporins, carbapenems,
monobactams
 Glycopeptides
 Vancomycin, Teicoplanin
 Cycloserine
 Bacitracin
Inhibitors of Cell Wall Synthesis

CYTOPLASM  Synthesis of cell wall precursors

 Cycloserine

CYTOPLASMIC  Synthesis of new cell wall sub-unit

MEMBRANE
attached to lipid carrier
 Bacitracin, Glycopeptides
 Attachment of new wall unit to growing
CELL WALL
peptidoglycan
 Beta-lactams
The Beta-Lactam drugs
The Beta-Lactam drugs

BETA-LACTAM
RING
The Beta-Lactam drugs

MECHANISM
OF ACTION
 Inhibit cell wall synthesis by
binding to enzymes known as
PBPs responsible for the final
stages of cross-linking of the
bacterial cell wall structure.
The Beta-Lactam drugs

GENERAL  Most achieve clinically useful

PROPERTIES concentrations in the CSF when the
meninges are inflammed
 In general, they are not effective
against intracellular organisms
 ALL Beta- Lactams are excreted in the
urine
The Beta-Lactam drugs

GENERAL  Bactericidal (except against

PROPERTIES enterococcus)
 Time-dependent
 Short elimination half-life
The Beta-Lactam drugs

MECHANISM  Production of Beta-lactamase enzymes

OF
RESISTANCE
 most common
 Trapping mechanism
 Modification of target PBPs
 Impaired penetration of drugs to
target PBPs
 Shortage of autolytic enzymes
 Presence of efflux pump
The Beta-Lactam drugs:

 Penicillin
 Other Penicillins Cloxacillin, Flucloxacillin,
Cephalexin, Cefaclor,
 Cephalosporins Ampicillin,
Cefadroxil,Amoxicillin,
Cefuroxime,
Carbenicillin,,
Cefamandole, Ticarcillin,
Cefotaxime,
 Cephamycins Azlocillin, Mezlocillin,
Ceftriaxone, Ceftazidime,
 Carbapenems Ertapenem
Cefazolin, Cefotaxime,
Cefoxitin
Piperacillin, Co-
Amoxyclav, Imipenem
Cefoperazone, Cefepime,
Sultamicillin,
 Monobactams Cefpirome
Meropenem
Piperacillin-Tazobactam,
Aztreonam
Doripenem
Ticarcillin-Clavulanate,
Ticarcillin-Clavulanate
 TRIVIA
Who discovered Penicillin?

ALEXANDER FLEMING

What year?
1928
The Beta-Lactam drugs

 Natural PCN
PENICILLIN
 prototype is Penicillin G
 pH-sensitive: not given orally
 Effective against gram (+) cells except
meningococci and gonococci
 High dose with anaerobic coverage
 Susceptible to penicillinase
 Semi-synthetic PCNs
 Acid-stable
 Extended-spectrum
 Penicillinase-resistant
The Beta-Lactam drugs

PENICILLIN  Hypersensitivity – 5 to 20 %
ADVERSE  skin rashes, fever, eosinophilia,
EFFECTS angioedema, serum sickness
 Cross-reactivity exists among all
penicillins and even other b-lactams
 The most serious hypersensitivity
reaction is anaphylactic shock. (very
rare, the ratio is about 0.5 to 1 of
10000 patients )
The Beta-Lactam drugs

PENICILLIN  Gastrointestinal upset, ( orally

administered preparations)
ADVERSE
EFFECTS  Nephrotoxicity, is very rare.
 Superinfections: results from alterations
in intestinal flora.
The Beta-Lactam drugs

OTHER  Penicillinase-resistant PCNs

PENICILLINS
 Oxacillin, Cloxacillin, Flucloxacillin,
Dicloxacillin
 Drugs of choice for treatment of
Staphylococci
The Beta-Lactam drugs

OTHER  Broad-spectrum PCNs

PENICILLINS
 Ampicillin,Amoxicillin
 More satisfactory for the treatment of
Streptococcus viridans and enterococci
 With gram-negative coverage similar to
Chloramphenicol
 Acid-resistant

 NOT penicillinase-resistant
The Beta-Lactam drugs

OTHER  Anti-pseudomonal Penicillins

PENICILLINS
 Carbenicillin, Ticarcillin, Piperacillin
 Penicillinase-resistant

 Acid-sensitive

 Combined with aminoglycoside for

better action against Pseudomonas
aeruginosa
The Beta-Lactam drugs

OTHER  Beta-lactamase Inhibitor Combinations

PENICILLINS (BLICS)
 Co-Amoxylav, Ampicillin-Sulbactam,
Piperacillin-Tazobactam, Cefoperazone-
Sulbactam, Ticarcillin-Clavulanate
 With enhanced bactericidal actions

 Penicillinase-resistant
 The Beta-Lactam drugs

CEPHALOSPORINS  Closely related in structure to PCN

 Relatively stable in dilute acid and are
highly resistant to penicillinase
 All cephalosporins are active against
most G+cocci, including penicillinase-
producing staphylococci and many strains
of G- bacilli
 Ineffective against enterococci
 The Beta-Lactam drugs

CEPHALOSPORINS:  First generation:

GENERATIONS:  Cephalothin, Cefalexin, Cefazolin
Chronological  Stronger antimicrobial action on
development
G+bacteria than that of the other
Antimicrobial generations, but their action on G- bacteria
spectrum
is relatively poor
 No anti-pseudomonal action

 Do not penetrate the CNS so can not be

used to treat meningitis
 The Beta-Lactam drugs

CEPHALOSPORINS:  Second generation:

GENERATIONS:  Cefamandole, Cefoxitin, Cefaclor, Cefonicid,
Cefuroxime, Cefotetan, Cefprozil
Chronological
development  Action on G+ bacteria is the same or a little

Antimicrobial
bit less than that of the first generation
spectrum  Increased action on gram-negative bacteria
 Cefoxitin: with action against anaerobes
(B. fragilis)
 Ineffective against P. aeruginosa
 Cefuroxime: the only 2nd generation
Cephalosporin that crosses the BBB
 The Beta-Lactam drugs

CEPHALOSPORINS:  Third generation:

GENERATIONS:  Cefotaxime, Ceftizoxime, Ceftriaxone,
Chronological Cefoperazone, Ceftazidime, Cefixime,
development Cefpodoxime
Antimicrobial  Highest activity against G- bacteria, lowest
spectrum
against G+ bacteria
 Highest resistance to Beta-lactamase

 Best penetration into CSF

 Lowest to no nephrotoxicity
 The Beta-Lactam drugs

CEPHALOSPORINS:  Third generation:

GENERATIONS:  Ceftizoxime: good activity against B.fragilis
Chronological  Ceftazidime, Cefoperazone: with anti-
development
pseudomonal activity
Antimicrobial
spectrum  Ceftriaxone: longest half-life among
cephalosporins
 Cefixime: the only oral 3rd gen ceph

 Cefoperazone: 70% eliminated in the bile

 The Beta-Lactam drugs

CEPHALOSPORINS:  Relatively few and low

 Allergy/hypersensitivity reactions:
ADVERSE
-

EFFECTS
most common, 5-10%
 anaphylaxis,
fever, skin rashes, nephritis,
granulocytopenia, and hemolytic
anemia.
 Superinfection
 The Beta-Lactam drugs

MONOBACTAMS
-  Aztreonam
 Highly resistant to Beta-lactamases

 Highly active against aerobic G-

bacteria including P. aeruginosa

 Poor activity against G+ bacteria
and anaerobes
 Antimicrobial spectrum similar to

aminoglycosides
 The Beta-Lactam drugs

MONOBACTAMS
-

ADVERSE
-

EFFECTS
 The Beta-Lactam drugs

CARBAPENEMS
-  Ertapenem, Imipenem, Meropenem,
Doripenem
 Broadest spectrum of activity of all

antibiotics (except Ertapenem)

 Imipenem: easily hydrolyzed by
dehydropeptidase in the body
 Ertapenem: No activity against
pseudomonas and acinetobacter
 The Glycopeptides

VANCOMYCIN
TEICOPLANIN
Glycopeptides

VANCOMYCIN  Bind to terminal D-ala-D-ala at the end

TEICOPLANIN of pentapeptide chains that are part of
the growing bacterial cell wall structure

 Inhibits transglycosylation reaction and

prevents incorporation of new sub-units
into the growing cell wall
Glycopeptides

VANCOMYCIN  Properties:
TEICOPLANIN  Not absorbed from the GIT
 Excreted via the kidneys
 Penetrates CNS if with inflammation
 Indications:
 G+ infections resistant to Beta-lactams
 Beta-lactam allergy
 Teicoplanin less toxic than Vancomycin
 Resistance is plasmid-mediated
Glycopeptide: Vancomycin

VANCOMYCIN  Bactericidal for G+ bacteria

 Oral: for C. difficile infection
 IV: for resistant G+ bacteria to Beta-
lactam agents
Glycopeptide: Vancomycin

VANCOMYCIN  Phlebitis
ADVERSE  Ototoxicity, Nephrotoxicity
EFFECTS
 Red man or Red neck syndrome
INHIBITORS OF PROTEIN SYNTHESIS
Inhibitors of Protein Synthesis
Aminoglycosides
Tetracyclines
Chloramphenicol
Lincosamides
Macrolides
Fusidic acid
Inhibition of Protein Synthesis
 Inhibitors of Protein Synthesis

AMINOGLYCOSIDES  Mechanism of action:

 Preventsformation of initiation complex
from which protein synthesis proceeds
 Misreading of mRNA codons

Inhibitors of the
30S sub-unit
 Inhibitors of Protein Synthesis

AMINOGLYCOSIDES  Properties:
 Not absorbed from the GIT
 Do not penetrate well into tissues and
bones
 Do not cross the BBB

 Renally excreted

Inhibitors of the
30S sub-unit
TRIVIA
What is the oldest aminoglycoside?

STREPTOMYCIN
 Inhibitors of Protein Synthesis

AMINOGLYCISIDES  Gentamycin and the newer

aminoglycosides can be used to
treat G- infections including
P. aeruginosa
 Not active against streptococci but

with some activity against

Inhibitors of the
staphylococci
 Not absorbed from the GIT
30S sub-unit
 Inhibitors of Protein Synthesis

AMINOGLYCISIDES
 No anaerobic activity
 Tobramycin with higher activity

towards P. aeruginosa
 Streptomycin is reserved for
mycobacterial infection
Inhibitors of the
30S sub-unit
 Inhibitors of Protein Synthesis

AMINOGLYCISIDES  Pharmacokinetics:
 Exhibit post-antibiotic effect: there is no or
very little drug level detectable in blood,
but there still seems to be inhibition of
bacterial re-growth. This is due to strong,
irreversible binding to the ribosome, and
remains intracellular long after plasma
levels drop. This allows a prolonged
Inhibitors of the dosage interval.
30S sub-unit
 Inhibitors of Protein Synthesis

AMINOGLYCISIDES
 Toxicity:
 Nephrotoxic
 Ototoxic
 Small therapeutic window
 Netilmycin reportedly with lower
toxicity among AG
Inhibitors of the
30S sub-unit
 Inhibitors of Protein Synthesis

AMINOGLYCISIDES
 Resistance:
 Alteration in the ribosomal target
site
 Alteration in cell Wall
permeability
 Plasmid-mediated
Inhibitors of the
30S sub-unit
 Inhibitors of Protein Synthesis

AMINOGLYCISIDES  Indications for aminoglycoside therapy:

 Basic rule: use only in severe, life-
threatening infections:
 G- sepsis (including pseudomonas), usually
combined with Beta-lactams
 Bacterial endocarditis (synergy with PCN)
 S. aureus sepsis, combined with Beta-lactam
 Pyelonephritis, for difficult cases
Inhibitors of the  Post-surgical abdominal sepsis
30S sub-unit
 Inhibitors of Protein Synthesis

TETRACYCLINES
 Properties:
 Inhibits protein synthesis by
preventing aminoacyl transfer
RNA from entering the acceptor
site on the ribosome
 Good GI absorption
Inhibitors of  Inhibits intracellular bacteria
the 30S
sub-unit
 Excretion: renal
 Inhibitors of Protein Synthesis

TETRACYCLINES  Toxicity:
 GI upset and diarrhea
 Interferes with bone development
 Brown staining of teeth in fetus
and children

Inhibitors of the
30S sub-unit
 Inhibitors of Protein Synthesis

TETRACYCLINES  Resistance:
 Transposon facilitated
 Efflux pump

Inhibitors of the
30S sub-unit
 Inhibitors of Protein Synthesis

CHLORAMPHENICOL  Blocks the action of peptidyl

transferase in the 50S sub-unit
>>> prevents peptide bond
synthesis
 Inhibitors of Protein Synthesis

CHLORAMPHENICOL
 Properties:
 Well absorbed orally
 Well distributed in the body

 Metabolized in the liver

 Excretion: renal

Inhibitors of the 50S

sub-unit
 Inhibitors of Protein Synthesis

CHLORAMPHENICOL  Indications:
 Active against G+ and G- bacteria
including aerobes and anaerobes
 Active against intracellular
organisms: S.typhi, Chlamydia,
Rickettsiae
 Good concentration in the CSF

Inhibitors of the 50S

sub-unit
 Inhibitors of Protein Synthesis

CHLORAMPHENICOL  Toxicity:
 Bone marrow suppression:
 dose-dependent
 Idiosyncratic:
irreversible, causes
aplastic anemia (1:30,000 patients)
 Gray baby syndrome in prematures,
due to immature liver enzymes
Inhibitors of the 50S
sub-unit
 Inhibitors of Protein Synthesis

CHLORAMPHENICOL  Resistance:
 Drug inactivation (plasmid-
mediated)

Inhibitors of the 50S

sub-unit
 Inhibitors of Protein Synthesis

MACROLIDES  Mechanism of action:

 Binds to the 23S rRNA in the 50S sub-
unit of the ribosome and blocks the
translocation step in protein synthesis

Inhibitors of the 50S

sub-unit
 Inhibitors of Protein Synthesis

MACROLIDES  Properties:
 Usually administered as oral but can
be given via IV
 Can inhibit intracellular organisms

 Well distributed in the body

 Concentrated in the liver and

Inhibitors of the 50S

excreted in bile
sub-unit
 Inhibitors of Protein Synthesis

MACROLIDES  Properties:
 Active against G+ cocci
 Active against: L. pneumophila,
C. jejuni, mycoplasma, chlamydia
and rickettsia

Inhibitors of the 50S

sub-unit
 Inhibitors of Protein Synthesis

MACROLIDES  Toxicity:
 Nausea and vomiting
 Phlebitis

Inhibitors of the 50S

sub-unit
 Inhibitors of Protein Synthesis

MACROLIDES  Resistance:
 Plasmid-mediated alteration in the 23S
rRna target

Inhibitors of the 50S

sub-unit
 Inhibitors of Protein Synthesis

LINCOSAMIDES  Mechanism of action:

(LINCOMYCIN AND
 Binds to the 50S ribosomal sub-unit,
CLINDAMYCIN)
inhibits protein synthesis by inhibiting
peptide bond formation

Inhibitors of the 50S

sub-unit
 Inhibitors of Protein Synthesis

LINCOSAMIDES  Properties:
(LINCOMYCIN AND
 Can be given oral, IV, IM
CLINDAMYCIN)
 Penetrates well into bones but NOT
into CSF even when meninges are
inflammed
 Metabolized in the liver

 Activity against G+ bacteria,

Inhibitors of the 50S
sub-unit
anaerobes
 C. difficile is usually resistant
 Inhibitors of Protein Synthesis

LINCOSAMIDES  Toxicity:
(LINCOMYCIN AND  Selection: CDAD
CLINDAMYCIN)

Inhibitors of the 50S

sub-unit
INHIBITORS OF NUCLEIC ACID SYNTHESIS
INHIBITORS OF NUCLEIC ACID
QUINOLONES
RIFAMPICIN
TRIMETHOPRIM
SULFONAMIDES
Inhibitors of Nucleic Acid Synthesis

Inhibitors of Sulphonamides
synthesis Trimethoprim
precursors
Inhibitors of DNA Quinolones
replication
Inhibitors of RNA Rifampicin
polymerase
TRIMETHROPRIM & SULFONAMIDES
Inhibitors of Nucleic Acid Synthesis

TRIMETHOPRIM
AND
 Trimethoprim is often given in
COTRIMOXAZOLE combination with sulfamethoxazole as
COTRIMOXAZOLE:
 Preventsdevelopment of resistance
 Synergism against some bacteria
Inhibitors of Nucleic Acid Synthesis

TRIMETHOPRIM
AND
COTRIMOXAZOLE
Inhibitors of Nucleic Acid Synthesis

TRIMETHOPRIM
AND
 Active against G+ and G- bacteria
COTRIMOXAZOLE
 No action against Pseudomonas
 Drug of choice for Pneumocystosis
 Renally excreted
 Given oral or IV
Inhibitors of Nucleic Acid Synthesis

TRIMETHOPRIM
AND
 Adverse effects and toxicity:
COTRIMOXAZOLE
 Neutropenia

 Nausea and vomiting

 Sulfonamides may cause BM suppression
and rashes
 SJS due to Sulfonamide component
Inhibitors of Nucleic Acid Synthesis

TRIMETHOPRIM
AND
 Resistance:
COTRIMOXAZOLE
 Plasmid-encoded dihydrofolate
reductases with altered affinity to
trimethoprim
QUINOLONES
 PREVENTS
SUPERCOILING OF THE
BACTERIAL
CHROMOSOME
Inhibitors of Nucleic Acid Synthesis

QUINOLONES  Properties:
 Well-absorbed from the GIT
 Excretion: mostly renal

 Activity: G-, G+, atypicals, MTb

QUINOLONES

OLDER GENERATION NEWER GENERATION

 Nalidixic acid  Moxifloxacin

 Norfloxacin  Levofloxacin
 Ofloxacin  Gatifloxacin
 Ciprofloxacin

G- > G+ G+ > G-
RESISTANCE TO FLUOROQUINOLONES

EFFLUX PUMP

MUTATIONS

CHANGES IN CELL WALL

PERMEABILITY MUTATIONS
Inhibitors of Nucleic Acid Synthesis

QUINOLONES  Adverse Effects:

 Most common: GI : 3–17% of patients with
mild nausea, vomiting, and/or abdominal
discomfort.
 CNS: headache and dizziness: 1–10% of
patients. Rarely, hallucinations, delirium, and
seizures have occurred, predominantly in
patients who also were receiving theophylline
or a nonsteroidal anti-inflammatory drug.
 Rashes
 Leukopenia, eosinophilia, and mild elevations
in serum transaminases occur rarely.
Inhibitors of Nucleic Acid Synthesis

QUINOLONES  Adverse Effects:

 Prolongation of the QTc interval
 hypoglycemia and hyperglycemia. Risk
factors for this adverse effect include
older age, renal insufficiency, and
concomitant therapy with glucose-altering
medications.
 Achilles tendon rupture or tendinitis: rare.
Renal disease, hemodialysis, and
glucocorticoid use may be predisposing
factors.
RIFAMYCINS
Inhibitors of Nucleic Acid Synthesis

RIFAMYCINS  Rifampicin is the most important

member
 Well-absorbed orally
 Evenly distributed
 Able to cross BBB
 Metabolized in the liver, excreted in
bile
Inhibitors of Nucleic Acid Synthesis

RIFAMYCINS  Mechanism of action

BLOCKS
NO PROTEIN
BIND TO… SYNTHESIS OF SYNTHESIS
mRNA
Inhibitors of Nucleic Acid Synthesis

RIFAMYCINS  Resistance:
CHROMOSOMAL
MUTATION IN
TARGET SITE
Inhibitors of Nucleic Acid Synthesis

RIFAMYCINS  First line drug for the treatment of

mycobacterial infections
 Has good anti-staphylococcal activity
Inhibitors of Nucleic Acid Synthesis

RIFAMYCINS  Adverse effects/Toxicity:

 Rashes

 Jaundice

 Reddish-orange urine, sweat, saliva (not

harmful but may be disturbing to patients;
need to inform prior to giving the drug)
OTHER AGENTS THAT AFFECT DNA
NITROIMIDAZOLES (METRONIDAZOLE)
 OTHER AGENTS THAT AFFECT DNA

NITROIMIDAZOLES  Metronidazole is the most important

agent in the group:
 Antibacterial,anti-parasitic
 Active againts anaerobes

MECHANISM OF ACTION
 OTHER AGENTS THAT AFFECT DNA

NITROIMIDAZOLES  Metronidazole:
 Given orally, IV, or per rectum
 Well- absorbed, well distributed into
tissues and the CSF
 Excreted in urine
 OTHER AGENTS THAT AFFECT DNA

NITROIMIDAZOLES  Adverse effects/toxicity:

 CNS
 Peripheral neuropathy
INHIBITORS OF CYTOPLASMIC MEMBRANE
FUNCTION
INHIBITORS OF CYTOPLASMIC MEMBRANE
FUNCTION

POLYMIXINS
INHIBITORS OF CYTOPLASMIC MEMBRANE
FUNCTION

POLYMIXINS
INHIBITORS OF CYTOPLASMIC MEMBRANE
FUNCTION

POLYMIXINS  Cyclic polypeptide

 Disrupts the phospholipid structure of
the cell membrane
 Colistin is the most common member
 Not absorbed orally
 Active against G- bacteria except
Proteus spp.
 Nephrotoxic
INHIBITORS OF CYTOPLASMIC MEMBRANE
FUNCTION

POLYMIXINS  Resistance:
 Chromosomally-mediated alterations in
membrane structure or antibiotic uptake
ANTI-TUBERCULOUS AGENTS
 FIRST LINE DRUGS SECOND LINE DRUGS

 Isoniazid (1952)  Streptomycin

 Rifampin (1966)
 kanamycin, amikacin, and
capreomycin
 Pyrazinamide (1952)
 Ethionamide
 Ethambutol (1961)  Cycloserine
 PAS
 Ofloxacin, ciprofloxacin
levofloxacin and
moxifloxacin
 amithiozone
 ANTI-TUBERCULOUS AGENTS

ISONIAZID  Isonicotinic acid hydrazide

 Inhibits the synthesis of mycolic acid,
required for the mycobacterial cell wall
 Bactericidal for rapidly-growing
mycobacteria
 Well absorbed orally, crosses BBB
 Main toxic effects are hepatitis and
neurological complications
 ANTI-TUBERCULOUS AGENTS

ETHAMBUTOL  Inhibits but does not kill mycobacteria

 It disrupts arabinogalactan synthesis by
inhibiting the enzyme arabinosyl
transferase = increased CW permeability
 Well absorbed orally
 Well distributed including CSF
 Excreted unchanged in urine
 Important Toxic effect:
 Optic neuritis
 ANTI-TUBERCULOUS AGENTS

PYRAZINAMIDE  Bacteriostatic
 Well absorbed orally
 Metabolized in the liver, excreted in the
kidneys
 Side effects:
 Hepatotoxicity

 Arthralgia
ANTI-FUNGAL AGENTS
 ANTI-FUNGAL AGENTS
TARGET CHEMICAL GRP EXAMPLES MECH OF ACTION

Cell
Membrane Inhibit Lanosterol C14-
Synthesis Azoles Miconazole demethylase by binding to
Ketoconazole cytochrome P-450,
Fluconazole resulting in inhibition of
Voriconazole ergosterol synthesis

Bind to sterols
(ergosterol>>cholesterol)
Function Polyenes Amphotericin B in cell membrane, causing
Nystatin leakage of cellular
components and cell death
 ANTI-FUNGAL AGENTS
TARGET CHEMICAL GRP EXAMPLES MECH OF ACTION

Cell Wall
Synthesis
Echinocandins Mycafungin Inhibits 1,3 Beta D-
Caspofungin Glucan synthase
Anidulafungin leading to cell wall
disruption
 ANTI-FUNGAL AGENTS
TARGET CHEMICAL GRP EXAMPLES MECH OF ACTION

Nucleic Acid
Synthesis Pyrimidins Flucytosine Deaminated in cell to 5-
fluorouracil which
ultimately inhibits DNA
synthesis and causes
disturbance of protein
synthesis

Benzofurans Griseofulvin Inhibit nucleic acid synthesis

and microtubule assembly,
and chitin synthesis
ANTI-FUNGAL AGENTS
 ANTI-FUNGAL AGENTS
SYSTEMIC INFECTIONS SUPERFICIAL
Asp Cryp Histo Candi Dermatoph Candi
DRUG Cocc ytes
Blas
Amphotericin B + + + +
Nystatin +
Flucytosine + +
Griseofulvin +
Echinocandins + +/- +
Azoles
Miconazole + +
Ketoconazole + + + +
Itraconazole + + +
Fluconazole + +/- + +
 ANTI-FUNGAL AGENTS

DRUG IMPORTANT SIDE EFFECTS

Amphotericin B Nephrotoxicity, fever and chills, hypotension,
hypoK
Nystatin Hepatotoxicity
Flucytosine Jaundice, Neutropenia
Griseofulvin
Echinocandins GI side effects, hypotension, rashes (all are less
in anidulafungin)
Azoles
Miconazole Hepatotoxicity
Gynecomastia (ketoconazole)
Ketoconazole
Itraconazole
Fluconazole
ANTI-VIRAL AGENTS
ANTI-VIRAL AGENTS
ANTI-VIRAL AGENTS
ANTI-VIRAL AGENTS
ANTI-VIRAL AGENTS
ANTI-VIRAL AGENTS: HIV
Reference: Medical Microbiology by Mims, Playfair, et al