Pharmacist Tahira Y.

Principles Of Antimicrobial Therapy

1. Antimicrobial therapy takes advantage of which thing--------------that
exist between microorganisms and human beings.
Biochemical Differences

2. Selection of the most appropriate antimicrobial agent requires

knowledge of which factors
 Identity of the organism
 The susceptibility of the organism to a particular agent
 The site of the infection
 Patient factors
 The safety and efficacy of the agent
 The cost of therapy

3. What is Empiric therapy

Immediate administration of drug(s) prior to bacterial identification and
susceptibility testing

4. Which factor is central to selection of appropriate therapy?

Characterizing the organism

5. Name some body fluids that are sterile

 Blood,
 Cerebrospinal fluid [CSF]
 Pleural fluid
 Synovial fluid
 Peritoneal fluid
 Urine

6. For which patients immediate empiric therapy is indicated?

 For critically ill patients,
 A neutropenic patient (one who is at risk for infections due to a
reduction in neutrophils)
 A patient with meningitis
Pharmacist Tahira Y.

7. What are bacteriostatic drugs?

These drugs were thought to only arrest the growth and replication of
bacteria at drug levels achievable in the patient.

8. What are bactericidal drugs?

Bactericidal drugs were able to effectively kill ≥99.9% (3-log reduction)
within 18 to 24 hours of incubation.

9. Newer techniques that are accurate,rapid and cost-effective for

microbial identification are,
 Polymerase chain reaction (PCR)
 Matrix-assisted laser desorption/ionization time-of-flight
(MALDI-TOF) mass spectrometry

10.What is Minimum Inhibitory Concentration (MIC)?

MIC is the lowest antimicrobial concentration that prevents visible growth
of an organism after 24 hours of incubation.

11. What is minimum bactericidal concentration (MBC)?

MBC is the lowest concentration of antimicrobial agent that results in a
99.9% decline in colony count after overnight broth dilution
incubations.MBC is rarely determined in clinical practice due to the time
and labor requirements.

12.The penetration and concentration of an antibacterial agent in the CSF

are influenced by which four factors
 Lipid Solubility(Major factor)
 Molecular weight
 Protein binding
 Efflux transporter proteins

13.Give examples of Lipid soluble drugs?

 Chloramphenicol
Pharmacist Tahira Y.

 Metronidazole

14.Give examples of drug swith low lipid solubility?

 B-lactam antibiotics
 Isoniazid

15.Which patient factors should be kept in mind while selecting

antimicrobial agent?
 Immune system
 Kidneys
 Liver
 Circulation
 Age
 Pregnancy and breast feeding in women

16.Rational dosing of antimicrobial agents depends on which factors?

It is based on pharmacodynamics (the relationship of drug concentrations to
antimicrobial effects) and pharmacokinetic properties (the absorption,
distribution, metabolism, and elimination of drugs).

17.Which factors have influence on Frequency of dosing?

Three important properties that have a significant influence on the frequency
of dosing are
 Concentrationdependent killing
 Time-dependent (concentration-independent) killing
 Postantibiotic effect (PAE)

18.Define concentration dependent killing?

Certain antimicrobial agents, including aminoglycosides and daptomycin,
show a significant increase in the rate of bacterial killing as the
concentration of antibiotic increases from 4- to 64-fold the MIC of the drug
for the infecting organism.This is known as concentration dependent killing.

19.Define time dependent killing of microbes?

Pharmacist Tahira Y.

The clinical efficacy of drugs like β-lactams, glycopeptides, macrolides,

clindamycin, and linezolid is best predicted by the percentage of time that
blood concentrations of these drugs remain above the MIC. This effect is
sometimes called time-dependent (or concentration-independent) killing.

20.Which two antibiotic classes show post-antibiotic effect?

 Aminoglycosides
 Fluoroquinolones

21.Name some clicinally important micro-organisms?

The clinically important bacteria have been organized into eight groups
based on Gram stain,morphology, and biochemical characteristics.
 Gram(+)cocci
 Gram(+)bacilli
 Gram(-)cocci
 Gram(-)rods
 Anaerobes
 Spirochetes
 Chlamydia

22.What are Narrow spectrum antibiotics?

Chemotherapeutic agents that act only on a single or a limited group of
microorganisms are said to have a narrow spectrum. For example, isoniazid
is active only against Mycobacterium tuberculosis.

23.What are Extended spectrum antibiotics?

Extended spectrum is the term applied to antibiotics that are modified to be
effective against gram-positive organisms and also against a significant
number of gram-negative bacteria. For example, ampicillin is considered to
have an extended spectrum because it acts against gram-positive and some
gram-negative bacterias.

24.What are Broad spectrum antibiotics?

Pharmacist Tahira Y.

Drugs such as tetracycline, fluoroquinolones and carbapenems affect a wide

variety of microbial species and are referred to as broad-spectrum antibiotics
.

25.When bacteria are said to be drug resistant?

Bacteria are considered resistant to an antibiotic if the maximal level of that
antibiotic that can be tolerated by the host does not halt bacterial growth.
Some organisms are inherently resistant to an antibiotic. For example, most
gram-negative organisms are inherently resistant to vancomycin.

26.What are major contributors of antibiotic resistance?

 Genetic modification
 Protein modification

27.Examples of antibiotic-inactivating enzymes include,a way of antibiotic

resistance
 β-lactamases (“penicillinases”) that hydrolytically
inactivate the βlactam ring of penicillins,
cephalosporins, and related drugs
 Acetyltransferases that transfer an acetyl group to
the antibiotic, inactivating chloramphenicol or
aminoglycosides
 Esterases that hydrolyze the lactone ring of
macrolides

28.What are major complications of antibiotic therapy?

 Hypersensitivity
 Direct toxicity
 Superinfection

29.Define Superinfection?
Drug therapy, particularly with broad-spectrum antimicrobials or
combinations of agents, can lead to alterations of
Pharmacist Tahira Y.

the normal microbial flora of the upper respiratory, oral, intestinal, and
genitourinary tracts, permitting tovergrowth of opportunistic organisms,
especially fungi or resistant bacterias.

30.On what basics antimicrobials are classified?

 By their chemical structure(Beta-
lactams,aminoglycosides)
 Mechanism of action(Cell wall synthesis
inhibitors)
 Activity against particular type of
organisms(Bacteria,Fungi,Virus)

31.Give some examples of antibiotic resistance?

 Alteration in the target enzyme,DNA gyrase,has
resulted in resistance to Fluoroquinolones.
 Beta-lactams enter gram(-) cells through porin
channels.Enterococci is largely resistant to
Cephalosporins by producing beta-
lactamasees.However,resistant organisms may
also have alteted porin channels through whiuch
Carpapenems do not pass.
 Tetracycline was effective against gynecologic
infection due to Bacteroids,but now these
organisms are resistant due to presence of
plasmid-mediated protein that promotes efflux
of drug.
 Beta-lactamases(penicillinases) destroy
antibiotic with beta-lactam nucleus.Neisseria
gonorhoea is now largely resistant to penicillin
because of penicillinase activity.

Cell wall synthesis inhibitors

Pharmacist Tahira Y.

1. Give general classification of cell wall inhibitors?

Penicillins Cephalosporins Carbapenems Monobactam
Amoxicillin (Amoxil) Cefaclor Doripenem (Doribex) Aztreonam
Ampicillin Cefixime (Cebosh) Imipenem (Primaxin)
Penicillin G Ceftriaxone (Oxidil) Meropenem
Nafcillin Cefprozil Ertapenem

2. Give structure description of Penicillins?

The basic structure of penicillins consists of a core four-membered β-lactam
ring, which is attached to a thiazolidine ring and an R side chain. Members
of this family differ from one another in the R substituent attached to the 6-
aminopenicillanic acid residue.

Mechanism of action  Penicillins interfere with the last step

of bacterial cell wall synthesis, which
is the cross-linking of adjacent
peptidoglycan strands by a process
known as transpeptidation.
 Their target is Penicillin-binding
proteins.
Antibacterial spectrum  Pneumococcal
infections,Gonorroea,Syphilis,Respirat
ory infections
Resistance  β-Lactamase production(Major factor)
 Decreased permeability to the drug
 Altered PBPs
Pharmacokinetics  Route of administration determined by
stability of stomach acid and severity
of infection
 The acidic environment within the
intestinal tract is unfavorable for the
absorption of penicillins.
 All penicillins cross placental barrier
but are not teratogenic.
 Excretion through renal route
Pharmacist Tahira Y.

Adverse drug reactions  Penicillins are among the safest drugs

some ADRs are,
 Hypersensitivity
 Diarrhea
 Nephritis(Particularly methicillin)
 Neurotoxicity
 Hematologic toxicities

3. What are Cephalosporins and write their classification?

The cephalosporins are β-lactam antibiotics closely related both structurally and
functionally to penicillins. Most cephalosporins are produced semisynthetically by
the chemical attachment of side chains to 7-aminocephalosporanic acid. Structural
changes on the acyl side chain at the 7 position alter antibacterial activity and
variations at the 3-position modify the pharmacokinetic profile.

Antibacterial spectrum  Effective against enterobactor

species,E.coli,Klebsilla
pneumonia,H.influenza,Staphyloco
ccal species.

1st Generation  Cephalaxin

 Cefazolin
 Cefadroxil

2nd
Classification Generation  Cefuroxime
sodium
 Cefuroxime axetil

3rd  Ceftriaxone
Generation  Cefotaxime
 Ceftazidime

4th  Cefepime
Generation
Advanced  Ceftaroline
Generation
Pharmacokinetics  Many of the cephalosporins must
Pharmacist Tahira Y.

be administered IV or IM (Figure
29.12) because of their poor oral
absorption.
 Excretion is through renal route.
Resistance  Resistance to the cephalosporins is
either due to the hydrolysis of the
beta-lactam ring by β-lactamases or
reduced affinity for PBPs.
Adverse drug reactions  Allergic reactions are a concern.
 Current data suggest that the cross-
reactivity between penicillin and
cephalosporins is around
3% to 5% and is determined by the
similarity in the side chain, not the
β-lactam structure.
 The highest rate of
allergic cross-sensitivity is between
penicillin and first-generation
cephalosporins.

4. Other Beta-lactam Antibiotics

Properties Carbapenems Monobactams

Structure Carbapenems are The monobactams, which
synthetic β-lactam also disrupt bacterial cell
antibiotics that differ in wall synthesis, are unique
structure from the because the β-lactam ring is
penicillins in that the not fused
sulfur atom of the to another ring.
thiazolidine ring has  Aztreonam
been externalized and
replaced by a carbon
atom.
 Imipenem
 Meropenem
 Doripenem
 Ertapenem
Antibacterial spectrum Imipenem plays a role in Aztreonam antimicrobial
Pharmacist Tahira Y.

empiric therapy because activity directed primarily

it is active against β- against gram-negative
lactamase–producing pathogens, including the
 Gram-positive and  Enterobacteriaceae
gram-negative  P. aeruginosa.
organisms It lacks activity against
 Anaerobes gram-positive organisms
and anaerobes.
 P. aeruginosa
Pharmacokinetics Imipenem undergoes Aztreonam is
cleavage by a administered either IV or
dehydropeptidase found IM and can accumulate in
in the brush border of the patients with renal failure.
proximal renal tubule.
Compounding imipenem
with cilastatin protects
the parent drug from
renal dehydropeptidase
and, thus, prolongs its
activity in the body.
Doses of these agents
must be adjusted in
patients with renal
insufficiency.
Adverse drug reactions Imipenem/cilastatin can Some of ADRs are
cause  phlebitis,
 Nausea, vomiting,  skin rash,
and diarrhea  Occasionally,
 Eosinophilia and abnormal liver
neutropenia function tests.
 High levels of Aztreonam may offer a
imipenem may safe alternative for treating
provoke seizures; patients who are allergic to
 Carbapenems and other penicillins,
penicillin share a cephalosporins, or
common bicyclic carbapenems.
core. Structural
similarity may
confer cross-
reactivity between
Pharmacist Tahira Y.

classes.

5. What are Beta-lactamase inhibitors and explain their role?

Hydrolysis of the β-lactam ring, either by enzymatic cleavage with a β-
lactamase or by acid, destroys the antimicrobial activity of a β-lactam
antibiotic.They perform their function by inactivating β-lactamases,
thereby protecting the antibiotics that are normally substrates for these
enzymes.β-Lactamase inhibitors are Clavulanic acid,Sulbactam and
azobactam.

Combinations Antibacterial activity

Ceftolozane+Tazobactam Used is in the treatment of
resistant Enterobacteriaceae and
multidrug-resistant Pseudomonas
aeruginosa.This combination has
narrow gram-positive and very limited
anaerobic activity.
Ceftazidime+Avibactam (IV) This combination has
broad gram-negative activity including
Enterobacteriaceae and P. aeruginosa.
 This combination is indicated for
the treatment of intra-abdominal
infections (in combination with
metronidazole) and for the
management of complicated
urinary tract infections.
Meropenem+Vaborbactam It is approved for the
treatment of complicated urinary tract
infections including pyelonephritis.

Vancomycin Daptomycin Telavancin

Mechanism of Inhibits bacterial cell Causes rapid Inhibits bacterial
action wall synthesis depolarization cell wall
of cell synthesis,disrupts
membrane cell membrane
inhibits
Pharmacist Tahira Y.

intracellular
synthesis of
DNA,RNA, and
protein
Pharmacodyna Combination of Concentration Concentration
mic concentration dependent dependent dependent
and time dependent
Antibacterial Activity limited
spectrum togram(+) organisms:
 Staphylococcus
aureus(incluing
MRSA)
 Streptococcus
pyrogens
 S.agalactiae same same
 Vancomycin
resistant
Enterococcus
faecalis
ande.faecium
Route IV/PO IV IV
Adverse Effects  Infusion related  Elevated  Taste
due to histamine hepatic disturbance
release transami  Foamy
 Fever,chills,phlebit nases urine
is  Myalgia  QTc
 Red man syndrome and prolongatio
 Dose related rhabdom n
ototoxicity and yolysis  Interferenc
nephrotoxicity e with
coagulation
 Not
recommend
ed in
pregnancy
Key learning Drug of choice for Daptomycin is Use with caution
points seveere MRSA,oral form inactivated by with baseline
only used for C.difficil pulmonary renal function
surfactants and
should never be
Pharmacist Tahira Y.

used in
treatment of
pneumoniae

Fosfomycin polymyxins
Structure Fosfomycin is a The polymyxins are
bactericidal synthetic cation polypeptides that
derivative of phosphonic bind to phospholipids on
acid the bacterial cell
membrane of gram-
negative
bacteria.
Mechanism of action It blocks cell wall They have a detergent-
synthesis by inhibiting like effect that disrupts
the enzyme Enolpyruvyl cell membrane integrity,
transferase, a key step in leading to leakage of
peptidoglycan synthesis cellular
components and cell
death.
Indications It is indicated for urinary They have activity
tract infections caused by against most
E. coli or E. faecalis and clinically important gram
is considered first-line -negative bacteria,
therapy for acute cystitis including P. aeruginosa,
E. coli, K. pneumoniae,
Acinetobacter spp.,
and Enterobacter spp.
Adverse drug reactions The most commonly Only two forms of
reported adverse effects polymyxin are in clinical
include diarrhea, use today polymyxin B
vaginitis, nausea, and and colistin (polymyxin
headache E).
Colistin is only
available as a prodrug.
The use of these drugs
has been limited due to
the increased risk of
nephrotoxicity and
neurotoxicity.
Pharmacist Tahira Y.

Protein Synthesis Inhibitors

1. Write down classification of protein synthesis inhibitors?

Tetracyclines  Demeclocycline
 Doxyclcline
 Minocycline
 Tetracycline
Glycylcyclines  Tigecycline
Macrolides/ketolides  Azithromycin
 Clarithromycin
 Erythromycin
 Telithromycin
Aminoglycosides  Amikacin
 Gentamicin
 Streptomycin
 Neomycin
 Tobramycin
Macrocyclic  Fidaxomicin
Lincosamides  Clindamycin
Oxazolidinones  Linezolid
 Tedizolid
others  Chloramphenicol
 Quinupristin/Dalfopristin

2. Tetracyclines and Glycylcyclines

Tetracycline Glycylcyclines
Mechanism of action Tetracyclines enter Tigecycline exhibits
susceptible organisms via bacteriostatic action by
passive diffusion and by reversibly binding to the
Pharmacist Tahira Y.

an energy-dependent 30S ribosomal subunit and

transport protein inhibiting bacterial protein
mechanism.They bind synthesis.
reversibly to the 30S
subunit of the bacterial
ribosome. This action
prevents binding of
tRNA to the
mRNA–ribosome
complex, thereby
inhibiting bacterial
protein synthesis.
Indications These are bacteriostatic It is indicated for the
used for treatment of complicated.
 Peptic ulcer  Skin and soft tissue
disease infections,
 Lyme disease  Complicated intra-
 Chlorea abdominal
 Rocky mountain infections
spotted fever  Community-
 Acne and acquired
Chlamydia pneumonia.
infection
resistance The most commonly Resistance to tigecycline
encountered resistance is has been observed and is
an efflux pump that primarily attributed to
expels drug overexpression of efflux
out of the cell. pumps.
Adverse drug  Gastric discomfort  Nausea,vomiting.
reactions  Hepatotoxicity  Acute pancreatitis
 Phototoxicity  Elevations in liver
 Vestibular enzymes and serum
dysfunction creatinine
 Pseudotumor  A boxed warning
cerebri states that
 The tetracyclines tigecycline should
should not be used be reserved for use
in pregnant or in situations when
breast-feeding alternative
Pharmacist Tahira Y.

women or in treatments are not

children less than 8 suitable
years of age.  Color
discoloration,fetal
harm

3. Aminoglycosides and Macrolides

Aminoglycosides Macrolides
Mechanism of action Aminoglycosides diffuse The macrolides and
through porin channels in the ketolides bind irreversibly
susceptible organisms. These to a site on the 50S
organisms subunit of the bacterial
also have an oxygen- ribosome, thus inhibiting
dependent system that translocation steps of
transports the drug across the protein synthesis.They
cytoplasmic membrane. may also interfere with
Inside the cell other steps, such as
they bind the 30S ribosomal transpeptidation.
subunit, where they interfere
with assembly of the
functional ribosomal
apparatus.
Indications  Tularemia,lymphoid  Corynebacterium
disease (Gentamicin is diphtheria
used)  Chlamydial
 Infections due to infections
Pseudomonas  Mycoplasma
aeruginosa pneumonia
 Mycobacterium
avium complex
Pharmacokinetics The highly polar,  The erythromycin
polycationic structure base is destroyed by
prevents adequate absorption gastric acid thus,
after oral either enteric-coated
administration; therefore, all tablets or esterified
aminoglycosides (except forms of the
neomycin) must be given antibiotic are
Pharmacist Tahira Y.

parenterally to administered.
achieve adequate serum  Erythromycin is one
concentrations. of the few antibiotics
that diffuse into
All aminoglycosides cross the
prostatic fluid and it
placental barrier and may also accumulate in
accumulate in fetal plasma macrophages.
and amniotic fluid.
Resistance  Efflux pumps  Inability of the
 Decreased uptake organism to take up
 Modification and the antibiotic
inactivation by plasmid  Presence of efflux
-associated synthesis of pump
enzymes. [Note:  Decreased affinity
Amikacin is less of the 50S
vulnerable to these ribosomal subunit
enzymes
 Cross-resistance not
possible
Adverse drug  Ototoxicity  Gastric distress and
reactions  Nephrotoxicity motility
 Paralysis  Cholestatic jaundice
 Skin rashes  Ototoxicity
 QTc prolongation

4. Which tetracycline appears in tears?

Minocycline achieves high concentrations in saliva and tears.

5. Which tetracycline is preferred in patiets with renal dysfunction?

Doxycycline is preferred in patients with renal dysfunction as it is
primarily eliminated via the bile into the feces.

6. Antibacterial mode of Protein synthesis inhibitors?

Antibacterial mode
Tetracyclines Bacteriostatic
Glycylcyclines Bacteriostatic
Aminoglycosides Bacteriocidal
Macrolides Bacteriostatic may be Bactericidal at
Pharmacist Tahira Y.

higher doses.
Fidaxomicin Bactericidal

7. Classification of Fidaxomicin,Clindamicin?
Fidaxomicin Clindamicin
Mechanism of Fidaxomicin acts on the Clindamycin has a
action sigma subunit of RNA mechanism of action that
polymerase, thereby is similar to that of the
disrupting macrolides.
bacterial transcription,
terminating protein synthesis
and resulting in cell death.
Fidaxomicin has a very
narrow spectrum limited to
gram-positive aerobes and
anaerobes.
Antibacterial  Clostridium difficile Clindamycin is
spectrum  Coss-resistance with used primarily in the
other antibiotic not treatment of infections
documented. caused by gram-positive
organisms, including
MRSA and
streptococcus and
anaerobic bacteria
Pharmacokinetic Following oral Clindamycin undergoes
s administration, fidaxomicin extensive oxidative
has minimal systemic metabolism to active and
absorption and primarily inactive products and is
remains excreted into bile and
within the gastrointestinal urine. Low urinary
tract. excretion of active drug
limits its clinical utility
for urinary tract
infections.
Adverse drug  Nausea,  Rash, the most
reactions vomiting,abdominal common adverse
pain. effect is
 Anemia,neutropenia  Diarrhea,caused
 Hypersensitivity by overgrowth of
Pharmacist Tahira Y.

reactions angioedema, C. difficile.

dyspnea, and pruritus
have occurred.

8. Anticaterial spectrum of chloramphenicol?

The use of chloramphenicol a broad-spectrum antibiotic, is restricted to life-
threatening infections for which no alternatives exist.

Chloramphenicol
Mechanism of action Chloramphenicol binds reversibly to
the bacterial 50S ribosomal subunit
and inhibits protein synthesis at the
peptidyl transferase reaction Because
of some similarity of mammalian
mitochondrial ribosomes to
those of bacteria, protein and ATP
synthesis in these organelles may be
inhibited at high circulating
chloramphenicol concentrations,
producing bone marrow toxicity.
[Note: The oral formulation of
chloramphenicol
was removed from the US market
due to this toxicity.]
Antibacterial spectrum  Chlamydiae
 Rickettsiae
 Spirochetesand
anaerobes. The drug is
primarily bacteriostatic, but it
may exert bactericidal activity
depending on the dose and
organism.
Resistance  Enzymes that inactivate
chloramphenicol.
 Decreased ability to penetrate
the organism
 Ribosomal binding site
alterations
Pharmacist Tahira Y.

Pharmacokinetics Chloramphenicol is administered

intravenously and is widely
distributed throughout the
body.Chloramphenicol is also
secreted into breast milk and
should be avoided in breastfeeding
mothers.
Adverse drug reactions  Anemias
 Gray baby syndrome

9. Explain Oxazolidinones and quinopristin/Dalfopristin?

Quinupristin/Dalfopristin Oxazolidinones
Mechnaism of Each component of this Linezolid and tedizolid
action combination drug binds to a bind to the bacterial 23S
separate site on the 50S ribosomal RNA of the
bacterial ribosomes. 50S subunit, thereby
 The combination drug inhibiting the formation
has bactericidal activity of the 70S initiation
against most complex and translation
susceptible organisms of bacterial proteins
and has a long PAE. .Bacteriostatic
Antibacterial  Quinupristin/dalfopristi  Gram-positive
spectrum n is active primarily organisms such as
against gram-positive staphylococci,
cocci streptococci, and
 Its primary use is for enterococci,
the treatment of E.  Corynebacterium
faecium infections, species and
including VRE strains  Listeria
monocytogenes
Resistance  Enzymatic processes Resistance primarily
commonly account for occurs via .
resistance  Reduced binding
 An active efflux pump at the target site.
can also decrease levels  Cross-resistance
of the antibiotics with other protein
synthesis inhibitors
does not occur.
Pharmacokinet  Quinupristin/dalfopristi  Linezolid and
Pharmacist Tahira Y.

ic n is available tedizolid are well

intravenously. absorbed after oral
 Both compounds administration. IV
undergo hepatic formulations are
metabolism, with also available.
excretion mainly in the Although the metabolic
feces. pathway of linezolid has
not been fully
determined, it is known
that it is metabolized via
oxidation to two inactive
metabolites.
Adverse drug  Venous irritation  Gastrointestinal
reactions commonly occurs when upset, nausea,
quinupristin/dalfopristin diarrhea, headache,
is administered through and rash.
a peripheral rather than  Thrombocytopenia
a central line. has been reported,
 Hyperbilirubinemia usually in patients
occurs in about 25% of taking the drug for
patients longer than 10
days.
 Serotonin
syndrome if given
concomitantly with
large quantities of
tyramine-
containing foods,
selective serotonin
reuptake
inhibitors.

10.Which two Protein synthesis inhibitors have Post Antibiotic Effect?

Aminoglycosides,Quinupristin/Dalfopristin show PAE.

Quinolones, Folic Acid Antagonists, and Urinary Tract

Antiseptics
Pharmacist Tahira Y.

1. General classification

Fluoroquinolon  Ciprofloxacin
es  Delafloxacin
 Gemifloxacin
 Levofloxacin
 Moxifloxacin
 Ofloxacin
Inhibitors of  Mafenide
Folate synthesis  Silver sulfadiazine
 Sulphadiazine
 sulfasalazine
Inhibitors of  Pyrimethamine
Folate  Trimethoprim
reduction
Comination of  Cotrimoxazole(Trimethprim+sulphamethoxazol
both inhibitors e)
Urinary tract  Nitrofurantoin
antiseptics  Methenamine

2. Mechanism of action of Fluoroquinolones?

DNA gyrase is responsible for reducing torsional stress ahead of
replicating forks by breaking double-strand DNA and introducing
negative supercoils. Topoisomerase IV assists in separating daughter
chromosomes once replication is completed. Following cell wall entry
through porin channels,fluoroquinolones bind to these enzymes and
interfere with DNA ligation.

3. What are Fluoroquinole targets in Gram(+) and Gram(-) bacterias?

In general, fluoroquinolones have different targets for gram negative
(DNA gyrase) and gram-positive organisms (topoisomerase IV) resulting
in rapid cell death.

4. Name some intracellular organisms?

 Chlamydia
 Legionella
 Mycoplasma spp.
Pharmacist Tahira Y.

5. Which is the main source of Fluoroquinolone resistanc?

Main source of fluoroquinolone chromosomal mutations within
topoisomerases, although decreased entry, efflux systems, and modifying
enzymes play a role.
6. Name the enzyme responsible for Fluoroquinolone degradation?
An aminoglycoside acetyltransferase variant can acetylate
fluoroquinolones, rendering them inactive.

7. Name some agents that can interfere wit Fluoroquinolone

absorption?
Ingestion of fluoroquinolones with sucralfate, aluminum- or
magnesium-containing antacids, or dietary supplements containing iron
or zinc can reduce the absorption. Calcium and other divalent cations also
interfere with the absorption of these agents.

8. Write some common adverse drug reactions of Fluoroquinolone?

 Common adverse effects leading to discontinuation are
nausea, vomiting, headache, and dizziness.
 Boxed warnings for tendinitis, tendon rupture,
peripheral neuropathyand CNS effects (hallucinations,anxiety)
 Use in the pediatric population should be limited
to distinct clinical scenarios (Cystic fibrosis exacerbation)
 Fluoroquinolones may prolong the QTc interval

9. Give some clinical uses of Fluoroquinolones?

Drug name Clinical uses
Ciprofloxacin  Anthrax,Intra-abdominal
infections(2nd choice)
 Traveler’s diarrhea
 Urinary tract infections
Delafloxacin  It is an option for managing acute
bacterial skin and skin structure
infections. It is available as an
intravenous and oral formulation
Levofloxacin  Urinary tract infections
Pharmacist Tahira Y.

 Respiratory infections due to

activity against S.pneumoniae
 Levofloxacin has enhanced activity
against S. pneumoniae
and is first-line therapy for
community-acquired pneumonia
(CAP).
Gemifloxacin  Gemifloxacin is indicated for
management of community-
acquired respiratory infections.
Unlike the other compounds, it is only
available as an oral formulation.
Moxifloxacin  Anaerobic infections
 Respiratory infections due to
activity against S.pneumoniae
 Moxifloxacin may be considered as
a second-line agent for management
of drug-susceptible tuberculosis.

10.Explain Sulphonamides and Folate antagonists?

Suphonamides Trimethoprim
Mechanism Microorganisms use the It is a potent inhibitor of
of action enzyme dihydropteroate bacterial dihydrofolate
synthetase to create reductas. Inhibition of this
dihydrofolic acid from the enzyme
precursor molecule prevents the formation of
p-aminobenzoic acid the metabolically active
(PABA). Sulfonamides are form of folic acid,
synthetic analogs of PABA. tetrahydrofolicacid.
Because of their structural Trimethoprim binds to
similarity, bacterial dihydrofolate
sulfonamides compete with reductase more readily than
PABA to inhibit it does to huma enzyme
dihydropteroate synthetase which accounts for the
and the genesis of bacterial selective toxicity of the
dihydrofolic drug.
acid. These agents
including cotrimoxazole,
are bacteriostatic.
Pharmacist Tahira Y.

Antibacteria  Enterobacteriaceae  Trimethoprim is 20-

l spectrum  Haemophilus to 50-fold more
influenzae, potent than the
 Streptococcus spp. sulfonamides.
 Staphylococcus  Urinary tract
spp.and Nocardia. infections (UTIs)
Resistance  Bacteria that obtain  Altered
folate from their dihydrofolate
environment are reductase
naturally resistant to  Efflux pumps and
sulfa drugs. decreased
 Altered permeability to the
dihydropteroate drug may play a role
synthetase
 Decreased cellular
permeability to sulfa
drugs
 Enhanced production
of the natural
substrate, PABA.
 Organisms resistant
to one member of
this drug family are
resistant to all.
Adverse  Crystalluria  Folic acid
drug  Hypersensitivity deficiency,Megalobl
reactions  Hematopoietic astic
disturbances anemia,leukopenia,
 Kernicterus and
granulocytopenia,
especially in
pregnant patients.
 Trimethoprim has a
potassium-sparing
effect and may cause
hyperkalemia

11.What are contraindications of Sulphonamides?

Pharmacist Tahira Y.

Due to the danger of kernicterus, sulfa drugs should be avoided in

newborns and infants less than 2 months of age,as well as in pregnant
women at term. Sulfonamides should not be given to patients receiving
methenamine, since they can crystallize in the presence of formaldehyde
produced by this agent.

12.For which conditions Cotrimoxazole is used?

It is effective in treating UTIs and respiratory tract infections, as well as
Pneumocystis jirovecii, toxoplasmosis, Listeria monocytogenes, and
Salmonella infections. It has activity against methicillin-resistant S.
aureus and can be particularly useful for skin and soft tissue infections
caused by this organism. It is the drug of choice for infections caused
by susceptible Nocardia spp. and Stenotrophomonas maltophilia.

13.Explain all about Methenamine?

Mechanism of action Methenamine salts are hydrolyzed

to ammonia and formaldehyde in
acidic urine(pH≤5.5).Formaldehyde
denatures proteins and nucleic
acids, resulting in bacterial cell
death. Methenamine is combined
with a weak acid(For example
hipuric acid) to maintain urine
acidity and promote production of
formaldehyde.
Antibacterial spectrum  Chronic suppressive therapy
to reduce the frequency of
UTIs.
Averse drug reactions  Gastrointestinal distress.

14.Write some contraindications to Methenamine?

Methenamine mandelate is contraindicated in patients with renal
insufficiency,because mandelic acid may precipitate. The methenamine
hippurate formulation should be used instead.
Sulfonamides, such as cotrimoxazole, react with formaldehyde and must
not be used concomitantly with methenamine.The combination increases
Pharmacist Tahira Y.

the risk of crystalluria and mutual antagonism.

Anti-mycobacterial Drugs
1. Name some non tuberculosis mycobacterias?
Non-tuberculous mycobacteria (NTM) include M. avium-intracellulare,
M. chelonae, M. abscessus, M. kansasii, and M. fortuitum.

2. Give classification of antimycobacterial drugs?

Drugs used to treat TB  Ethambutol

 Isoniazid
 Pyrazinamide
 Rifbutin
 Rifampin
 rifapentine
Drugs used to treat TB (2nd line)  Aminoglycosides
 Aminosalicylic acid
 Bedaquiline
 Capreomycin
 Cycloserine
 Ethionamide
 Fluoroquonoles
 Macrolides
Drugs used to treat leprosy  Clofazimine
 Dapsone
 Rifampin

3. Give treatment plan for LTBI?

LTBI can be treated for 9 months with isoniazid (INH) monotherapy or
with 12 once-weekly higher doses of INH and rifapentine. In contrast,
active TB disease must be treated with several drugs. Treatment for drug-
susceptible TB lasts for at least 6 months, while treatment of multidrug-
resistant TB (MDR-TB) typically lasts for about 2 years.
Pharmacist Tahira Y.

4. What is Directly Observation Therpy?

One successful strategy for achieving better treatment completion rates is
Directly observed therapy (DOT). Patients take the medications under
observation of a member of the health care team. DOT decreases drug
resistance and improves cure rates. Most public health departments offer
DOT services.

5. What is the most common adverse effect of Isoniazid?

Hepatitis is the most serious adverse effect associated with isoniazid.

6. What is the most important ADR of ethambutol?

The most important adverse effect is optic neuritis, which results in
diminished visual acuity and loss of ability to discriminate between red
and green. The risk of optic neuritis increases with higher doses and in
patients with renal impairment.

7. Name drugs that are reserved for multi-drug resistant TB?

Capreomycin is primarily reserved for the treatment of MDR-TB. Also
fluoroquinolones specifically moxifloxacin and levofloxacin, have an
important place in the treatment of multidrug-resistant tuberculosis.

8. Name one drug that is approved for the treatment of MDR-TB?

Bedaquiline is approved for the treatment of MDR-TB.Bedaquiline is
administered orally, and it is active against many types of mycobacteria.

9. Boxed warning of Bedaquiline?

Bedaquiline has boxed warning for QT prolongation, and monitoring of
the electrocardiogram is recommended. Elevations in liver enzymes have
also been reported and liver function should be monitored during therapy.

Antifungal Drugs
32.What is Mycoses and what are its types?
Pharmacist Tahira Y.

Infectious diseases caused by fungi are called mycoses, and they are often
chronic in nature. Mycotic infections may involve only the skin (cutaneous
mycoses extending into the epidermis), or may cause subcutaneous or
systemic infections.
33.Structural differences between Fungi and other organisms?

Unlike bacteria, fungi are eukaryotic, with rigid cell walls composed largely
of chitin rather than peptidoglycan (a characteristic component of most
bacterial cell walls). In addition, the fungal cell membrane contains
ergosterol rather than the cholesterol found in mammalian membranes.
These structural characteristics are useful targets for chemotherapeutic
agents against mycoses.

34.Major reason for rise in Mycoses cases?

The incidence of mycoses such as candidemia has been on the rise for the
last few decades. This is attributed to an increased number of patients with
chronic immune suppression due to organ transplantation, cancer
chemotherapy, or human immunodeficiency virus (HIV) infection.
35.Write Classification of Anti-fungal drgs?

Subcutaneous Infections Cutaneous Infections

Amphotericin B Butenafine
Anidulafungin Butoconazole
Micafungin Clotrimazole
Caspofungin Ciclopirox
Fluconazole Econazole
Flucytosine Griseofulvin
Isavuconazole Miconazole
Itraconazole Naftifine
Ketoconazole Nystatia
Posaconazole Oxyconazole
Voriconazole Sertaconazole
Sulconazole
Tavaborole
Terbinafine
Terconazole
Tioconazole
Pharmacist Tahira Y.

Tolnaftate

A.Drugs for Subcutaneous and Systemic Mycotic Infections

36.Write about Amphotericin B?
Amphotericin B Amphotericin B is a naturally occurring polyene antifungal
produced by Streptomyces nodosus. In spite of its toxic potential,
amphotericin B remains the drug of choice for the treatment of several life-
threatening mycoses.

Amphotericin B Natural Polyene

Source Streptomyces Nodosus
Amphotericin B binds to ergosterol in the
plasma membranes of fungal cells. There, it
forms pores (channels) that require
hydrophobic interactions between the
lipophilic segment of the polyene
Mechanism of action
antifungal and the sterol. The pores disrupt
membrane function, allowing electrolytes
(particularly potassium) and small
molecules to leak from the cell, resulting in
cell death.
Anti-fungal spectrum Effective against
 Candida albicans
 Histoplasma capsulatum
 Cryptococcus neoformans
 Coccidioides immitis
 Blastomyces dermatitidis, and many
strains of Aspergillus. [Note:
Amphotericin B is also used in the
treatment of the protozoal infection
leishmaniasis.]
Resistance Fungal resistance to amphotericin B, although
infrequent, is associated with decreased
ergosterol content of the fungal membrane.
Pharmacokinetics  Amphotericin B is administered by
slow intravenous (IV) infusion .
 Amphotericin B is insoluble in water
and must be coformulated with
sodium deoxycholate (conventional) or
artificial lipids to form liposomes.
 The liposomal preparations are
Pharmacist Tahira Y.

associated with reduced renal and

infusion toxicity but are more costly.
 Amphotericin B is extensively bound to
plasma proteins and is distributed
throughout the body. Inflammation
favors penetration into various body
fluids, but little of the drug is found in
the cerebral spinal fluid (CSF), vitreous
humor, peritoneal fluid
 Low levels of the drug and its
metabolites are excreted primarily in
the urine over a long period of time.
Adverse Effects Amphotericin B has a low therapeutic index.
 Fever and chills
 Renal impairment
 Hypotension
 Thrombophlebitis

37.