1

Antibacterial Drugs

Ewa Grabowska

Department of Pharmacology

Medical University of Lodz

Bacteria

„-”

•

membrane-enclosed nucleus

•

mitochondria

•

endoplasmic reticulum

•

Golgi bodies

•

80S ribosomes

•

mitosis or meiosis

„+”

•

nucleoid

•

plasmids

•

cell wall

•

70S ribosomes

•

ability to form spores

2

Criteria for Bacteria Classification

• Shape

• Oxygen use

• Response to the Gram’s stain

• Ability to form spores

• Nutritional requirements

Model of Gram–Positive Bacteria

Cell Wall

3

Model of Gram–Negative Bacteria

Cell Wall

Physiological Role of the Microflora

•

protection against the outside and invading

pathogens

• modulation of the immune system response

• food breakdown and vitamin synthesis

4

Classification of Antibacterial

Drugs

• Antibiotics

• Chemotherapeutic or synthetic agents

• Semisynthetic agents

Antibiotics

• bacteriostatic

Minimum Inhibitory Concentration (MIC)

• bactericidal

Minimum Bactericidal Concentration (MBC)

• broad spectrum

• narrow spectrum

5

Antibiotic Resistance

• innate

(dependent on the specific properties of the given

group of bacteria and mechanism of the drug action)

• acquired

(dependent on the mutation(s) in the genome of

the bacterium that is not innately resistant to a given antibiotic)

Biochemical Mechanisms

of Acquired Antibiotic Resistance

• Reduced bacterial permeability

• Enzymatic alteration of antibiotics

• Alteration in the target site

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Antibiotics Inhibiting Bacterial Cell

Wall Synthesis

β-lactams

vancomycin

bacitracin

ββββ

-Lactam Antibiotics

Chemical Structures

penicillins

cephalosporins

carbapenems

monobactams

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Mechanisms of

ββββ

-Lactam

Resistance

• Production of

β

-lactamase

• Elaboration of altered PBPs

( = penicillin-binding proteins )

• Reduced permeability in Gram-negative outer

cell membranes

8

Clinical uses of the penicillins

• bacterial meningitis

(caused by Neisseria meningitidis,

Streptococcus pneumoniae):benzylpenicillin,
high doses intraveniously (i.v)

• bone and joint infections

(e.g with Staphylococcus aureus): flucloxacillin

• skin and soft tissue infections

(e.g with Streptococcus pyogenes or S.aureus):

benzylpenicillin, flucloxacillin.

• pharyngitis

(from S. pyogenes): phenoxylmethylpenicillin.

Clinical uses of the penicillins

• otitis media

(organism commonly include S. pyogenes, Haemophilus

influenze): amoxicillin.

• bronchitis

(mixed infections common): amoxicillin

• pneumonia : amoxicillin
• urinary tract infections

(e.g with E.coli): amoxicillin

• gonorrhea: amoxicillin (plus probenecid)
• serious infections with P. aeruginosa : piperacillin

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Clinical uses of the penicillins

Penicillins are given by mounth or, in
more severe infections, intravenously,
and often in combination with other
antibiotics.

Standard Penicillins

Structure of Side Chain R

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Standard Penicillins

Activity Spectrum

• Streptococcus pneumoniae

• Neisseria meningitidis

• Treponema pallidum

• Pasteurella multocida

• Listeria monocytogenes

Antistaphylococcal penicillins

Structure of Side Chain R

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Antistaphylococcal penicillins

Activity Spectrum

Penicillinase - producing staphylococci

Aminopenicillins

• Ampicillin

• Amoxicillin

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Aminopenicillins

Activity Spectrum

• Escherichia coli
• Proteus mirabilis
• Haemophilus influenzae
• Salmonella spp.
• Shigella spp.
• Enterococci
• Listeria monocytogenes
• Streptococcus pneumoniae
• Neisseria meningitidis

Antipseudomonal penicillins

Carboxypenicillins:

Carbenicillin,

Ticarcillin

Ureidopenicillins :

Piperacillin,

Azlocillin

Mezlocillin.

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Antipseudomonal penicillins

Activity Spectrum

• Pseudomonas aeruginosa

• Escherichia coli
• Proteus mirabilis
• Haemophilus influenzae
• Salmonella spp.
• Shigella spp.
• Enterococci
• Listeria monocytogenes
• Streptococcus pneumoniae
• Neisseria meningitidis

Penicillins



The first choice for many infections.



Benzylpenicillin:

• given by injection, short half-life and destroyed

by

β

-lactamases

• spectrum: Gram-positive and Gram-negative

cocci and some Gram-negative bacteria

• many staphylococci are now resistant.

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Penicillins



Beta-lactamase-resistant penicillins, e.g
flucloxacillin

• Given orally
• Spectrum as for benzylpenicillin
• Many staphylococci are now resistant



Broad-spectrum penicillins, e.g amoxicillin

• Given orally; they are destroyed by

β

- lactamases

• Spectrum: as for benzylpenicillin (though less potent);

they are also active against Gram-negative bacteria

Penicillins



Extended - spectrum penicillins, e.g ticarcilin

• given orally; they are susceptible to

β

-

lactamases

• spectrum : as for broad-spectrum penicillins;

they are also active against pseudomonas.

• a combination of clavulanic acid plus amoxicillin

is effective against many

β

-lactamase-producing

organisms.

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Penicillins

Adverse Effects

• Hypersensitivity reaction
• Skin rashes and fever
• Acute anaphylactic shock (which may, in some

cases, be fatal but is fortunately very rare)

• Diarrhoea
• Nephritis
• Neurotoxicity
• Platelet dysfunction

Classification of Cephalosporins

Ceftazidime

Third generation

with P.aeruginosa

activity

Fourth generation

Third generation

Second generation

with B. fragilis

activity

Second generation

with H. influenzae

activity

First generation

Cefepime, cefpirome

Cefdinir, cefixime, ceftibuten, cefotaxime,
ceftriaxone, ceftizoxime, cefoperazone,
moxalactam

Cefmetazole, cefotetan, cefoxitin

Cefaclor (p.o.), cefamandole, cefonicid,
ceforanide, cefprozil (p.o.), cefuroxime,
cefuroxime axetil (p.o.)

Cefadroxil (p.o.), cefazolin, cephalexin
(p.o.), cephalothin, cephapirin, cephradine
(i.v./p.o.), cephaloridine

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Cephalosporins - pharmacokinetics

• First - generation oral cephalosporins are usually

well absorbed.

• Second- and third – genertion drugs

(e.g cefuroxime and cefotaxime), are acid labile and

must be given by a parenteral route.

• Cefuroxime has been formulated as a prodrug

( cefuroxime axetil ) for oral use, which has good

absorption and is hydrolysed at first pass metabolism
through the liver to cefuroxime.

• Most cephalosporins are primarily excreted by the

kidney and have short half-lives.

Clinical uses of the

cephalosporins

• Septicaemia (e.g cefuroxime, cefotaxime)

• Pneumonia caused by susceptible organisms

• Meningitis (e.g ceftriaxone, cefotaxime)

• Biliary tract infection ( acute cholecistis or

cholangitis caused by E.coli ).

• Urinary tract infection (especially in pregnancy,

or in patients unresponsive to other drugs)

• Sinusitis ( e.g cefadroxile )

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First-Generation Cephalosporins

Activity Spectrum

• Streptococci (S. pyogenes)

• Staphylococci (S. aureus)

• Escherichia coli

• Proteus mirabilis

• Klebsiella pneumoniae

Second-Generation Cephalosporins

Activity Spectrum

• Haemophilus influanzae

• Bacteroides fragilis

• Streptococci (S. pneumoniae)

• Staphylococci (S. aureus)

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Third-Generation Cephalosporins

Activity Spectrum

• Enterobacteriaceae

• Haemophilus influenzae

• Neisseria (N. meningitidis, N. gonorrhoeae)

• Streptococci (S. pneumoniae, S. pyogenes, S. faecalis)

• Staphylococci (S. aureus, S. epidermidis)

Fourth-Generation Cephalosporins

Activity Spectrum

• Enterobacteriaceae

• Pseudomonas aeruginosa

• Haemophilus influenzae

• N. gonorrhoeae

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Cephalosporins

Adverse Effects

• Allergic reactions (individuals allergic to penicillins)

• Disulfiram-like effect (when cefamandole or cefoperazone

ingested with alcohol)

• Unusual bleeding or bruising (more common for

cefamandole, cefoperazone, cefotetan, cefuroxime)*

* Simultaneous administration of vitamin K corrects the

problem

Cephalosporins

Adverse Effects

• black, tarry stools,
• nausea, vomiting
• headache
• diarrhoea
• painful or difficult urination
• shortness of breath
• oral and vaginal candidiasis
• vaginal itching or discharge
• hives or welts
• Itching, redness of skin or skin rash
• seizures

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Carbapenems

Activity Spectrum

• Streptococci

• Staphylococci

• Enterobacteriaceae

• Pseudomonas aeruginosa

• Haemophilus spp.

• Anaerobic bacteria

Carbapenems

Adverse Effects

• Nausea, vomiting, diarrhoea

• Eosinophilia, neutropenia

• Seizures (high levels of imipenem)

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Monobactams

The main monobactam is aztreonam.

Aztreonam is a

β

– lactam antibacterial

related to penicillin but with a single ring
structure ( ‘monocyclic

β

– lactam’).

Aztreonam is given intramuscularly (i.m)
or intravenously (i.v) and is

β

– lactamase

resistant.

It is excreted via renal tubular excretion
and can accumulate in patients with renal
failure. It has short half-life.

Monobactams

Activity Spectrum

Gram-negative aerobic bacteria:

• Pseudomonas aeruginosa
• Proteus mirabilis
• Providencia spp.
• E. coli
• Salmonella spp.
• Shigella spp.
• Klebsiella pneumoniae
• Haemophilus influenzae
• Neisseria meningitidis and Neisseria gonorrhoeae.

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Monobactams

Adverse Effects

• Phlebitis

• Skin rash

• Abnormal liver function

Mechanisms of Bacterial

Resistance to Vancomycin

Resistance to vancomycin is due to the

production of a new cell wall component
that prevents the drug from binding to the

wall.

Resistance to vancomycin is reported for

Enterococcus faecalis.

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Vancomycin

Activity Spectrum

Gram-positive bacteria, such as :

• Streptococci ( S. pyogenes, S.pneumoniae )

• Staphylococci ( S. aureus, S. epidermidis )

• Enterococci

• Corynebacterium ssp.

• Clostridium difficile

Vancomycin

Pharmacokinetics.

Vancomycin is :

• not absorbed from GI tract ,

• irritating if given by i. m injection ,

• administered by i. v

• not metabolized,

• eliminated by glomerular filtration and its

dosage is reduced in patients with
impaired renal function.

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Vancomycin

Adverse Effects

•

Red neck syndrome ,

•

Fever ,

•

Chills ,

•

Phlebitis at the infusion site.

Bacitracin

Chemical Structure, Activity Spectrum

and Adverse Effects

Gram-Positive bacteria

(e.g. staphylococci and streptococci)

potential nephrotoxicity that’s why it is

used only for topical application !!!!

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Antibiotics Inhibiting Bacterial Cell

Membrane Functioning

Polymyxin B

Polymyxin E (Colistin)

Polymyxin

Chemical Structure

DAB = alpha, gamma diamino butyric acid

R-CO: C7 – C9 Fatty acyl

For example, in polymyxin B1, R = (+)-6-methyloctanoyl

in polymyxin B2, R = 6-methylheptanoyl

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Polymyxin

Activity Spectrum

Gram-Negative bacteria:

• Pseudomonas aeruginosa

• Enterobacter aerogenes

• Eschericha coli

• Haemophilus influenzae

• Salmonella spp.

• Shigella spp.

Polymyxins

Pharmacokinetics :



Colistin is very poorly absorbed from the gut and is
usually given by inhalation or topically to the skin.



It is excreted unchanged in the kidney, with
intermidiate half-life.



It is sometimes given by mouth for bowel sterilisation.

Unwanted effects :



Nephrotoxicity.



Neurotoxicity : dizziness, circumoral parasthaesiae
and convulsion. Rarely, neuromuscular blockade can
produce respiratory paralysis.

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Antibiotics Inhibiting Bacterial

Protein Synthesis

Aminoglycosides

Macrolides

Lincosamides

Streptogramins

Tetracyclines

Amphenicols

Oxazolidinones

Aminoglycosides

Chemical structure

Streptomycin

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Aminoglycosides

Activity Spectrum

• Aerobic Gram-negative bacilli,

• Staphylococci,

• Mycobacteria.

Aminoglicosides – Gentamycin:

• is still important in the treatment of many serious gram -

negative bacillary infections (caused by E.coli, P.mirabilis,
Klebsiella, Enterobacter, Serratia and P. aeruginosa).

• can be considered for the treatment of bacteremia, respiratory

and urinary tract infections, infected wounds, and bone, and
soft tissues infections including peritonitis and burns
complicated by sepsis.

• is also applied topically for use in the treatment of primary and

secondary infection caused by sensitive strains of
streptococcus, S.aureus, P. aeruginosa, E.coli, P. vulgaris.

• may also be used for ocular infections caused by

S. aureus, P. aeruginosa, P. vulgaris.

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Aminoglicosides – Tobramycin:

• has similar spectrum to that of gentamycin,

• may be indicated for the treatment of the

following infections when caused by susceptible
organisms : septicemia, urinary tract infections,
lower respiratory tract infections, serious skin,
soft – tissues infections, CNS infections.

• can be used topically for ocular infections

caused by S. aureus, P. aeruginosa, P. vulgaris
or K. pneumoniae.

Aminoglicosides – Amikacin:

• is indicated for the short – term treatment of

serious infections due to amikacin-susceptible
strains of e.g P. aeruginosa, E. coli and S.
aureus as well as Proteus, Klebsiella, Serratia,
Enterobacter and Citrobacter sp.

• is often considered to be the drug of choice for

the initial treatment of serious gram-negative
bacillary infections in hospitals, where
gentamicin resistance is a problem.

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Aminoglicosides – Netilmicin:

• has a similar spectrum of activity to that of

gentamicin and amikacin and tobramycin.

• is effective against some gentamycin-

resistant and tobramamycin-resistant
strains of Enterobacteriaceae.

• Is indicated for the treatment of infections

caused by susceptible strains of E. coli,
Proteus, Klebsiella, Enterobacter and
Staphylococcus sp.

Aminoglycosides

Adverse Effects

• Ototoxicity leading to deafness, tinnitus,

dizziness, vertigo, loss of balance

• Kidney damage (from mild renal impairment

to severe acute tubular necrosis)

• Neuromuscular paralysis
• Contact dermatitis (topically-applied

neomycin)

• The diuretics ethacrinic acid and furosemide

potentiate aminoglicosides ototoxicity.

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Macrolides

Erythromycin

Clarithromycin

Azithromycin

Macrolides

Chemical Structure

Erythromycin

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Mechanisms of Bacterial

Resistance to Macrolides

Altered target - the bacterial ribosomal RNA

of the 50 S ribosomal subunit

Macrolides

Activity Spectrum

• Streptococci
• Staphylococci
• Bordetella pertussis
• Corynebacterium diphtheriae
• Campylobacter jejuni
• Mycoplasma pneumoniae
• Ureaplasma urealyticum
• Legionella spp.
• Chlamydia spp.
• Haemophilus influenzae
• and some others

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Macrolides

Pharmacokinetics

Erythromycin :

is not stable in the stomach, it must be
protected from gastric juice,

diffuses well throughout the body,

enters most tissue compartments, with the
exception of the CSF.

is concentrated in the liver and excreted in
the bile.

Macrolides

Pharmacokinetics

Clarythromycin :

is well absorbed from the GI tract, with or
without food.

is metabolized in the liver and 30%-40% of
the administered dose can be recovered in
the urine.

is 60% to 70% bound to plasma proteins.

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Macrolides

Pharmacokinetics

Azithromycin :

is well and rapidly absorbed and widely
distributed throughout the body,

is eliminated slowly from the body,

is metabolised in the liver,

is eliminated in the bile.

Its half-life is 68 hours.

Macrolides

Pharmacological uses

Erythromycin :



tonsilitis, erysipelas, and scarlet fever (scarlatina).



chemoprophylaxis of streptococcal infections.



pneumococcal infections



diphteria and both early and late syphilis



treatment of Mycoplasma pneumoniae, Legionella
pneumophila.



treatment of Chlamydia trachomatis



treatment of Acne vulgaris

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Macrolides

Pharmacological uses

Clarythromycin :



Pneumonia caused by Mycoplasma pneumoniae
or Streptococcus pneumoniae,



Acute bacterial exacerbations of chronic
bronchitis due to H. influenzae, Moraxella
catarrhalis or S.pneumoniae,



Pharyngitis, tonsilitis due to Streptococcus
pyogenes,



Uncomplicated skin, skin-structure infection due
to S.aureus or S.pyogenes

Macrolides

Pharmacological uses

Azithromycin :



As an alternative antibiotic for the treatment of mild to
moderate pharyngitis/tonsilitis due to streptococcal
species,



To treat mild to moderate acute bacterial exacerbation of
chronic bronchitis due to H. influenzae, Moraxella
catarrhalis, S.pneumoniae



To treat uncomplicated skin and skin-structure infections
due to S.aureus, S.pyogenes or Streptococcus
agalactiae.



In the treatment of urethritis and cervictis

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Macrolides

Adverse Effects

• Gastrointestinal problems

• Cholestatic jaundice

• Transient deafness

Lincosamides

Lincomycin and Clindamycin

Chemical Structures

37

Clindamycin

Activity Spectrum

• Streptococci

• Staphylococci

• Anaerobic bacteria

• Mycoplasma hominis

Clindamycin

Adverse Effects

• Skin rashes

• Pseudomembranous colitis (due to overgrowth

of Clostridium difficile)

• Impaired liver function

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Tetracyclines

Chemical Structure

Tetracyclines

Demeclocycline

Doxycycline

Minocycline

Tetracycline

39

Mechanisms of Bacterial

Resistance to Tetracyclines

Changes in the transport mechanism, resulting

in a lack of tetracycline accumulation within

the bacterial cell

Tetracyclines

Activity Spectrum

• Chlamydiae

• Mycoplasmas

• Spirochetes

• Rickettsiae

• Legionella spp.

• Brucella spp.

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Tetracyclines

Adverse Effects

• Gastric discomfort

• Deposition in the bone and primary dentition

(growing children)

• Fatal hepatotoxicity (high doses in pregnant women)

• Phototoxicity

• Vestibular problems (dizziness, nausea, vomiting)

• Headache and blurred vision (adults)

• Superinfections (Candida, resistant staphylococci)

Amphenicols

Chloramphenicol

Chemical Structure

41

Mechanisms of Bacterial

Resistance to Chloramphenicol

• Reduced bacterial permeability

• Production of the chloramphenicol-modifying

enzyme, chloramphenicol acetyltransferase

Chloramphenicol

Activity Spectrum

Gram - positive and Gram - negative bacteria:

• Streptococcus pneumoniae

• Neisseria meningitidis

• Haemophilus influenzae

• Salmonella typhi

• Salmonella paratyphi

• Rickettsiae

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Chloramphenicol

Adverse Effects

• Anemias

• Gray baby syndrome (poor feeding, depressed

breathing, cardiovascular collapse, cyanosis,
death)

Oxazolidinones

Linezolid

Chemical Structure

43

Linezolid

Activity Spectrum

• Staphylococci

(including methicillin-resistant staphylococci)

• Streptococci

(including penicillin-resistant pneumococci)

• E. faecium and E. faecalis

(including vancomycin-resistant enterococci)

Agents Inhibiting Bacterial DNA

Synthesis

Quinolones

Nitroimidazoles

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Mechanisms of Bacterial

Resistance to Quinolones

• Reduced bacterial permeability

• Altered target – DNA gyrase

Quinolones

Adverse Effects

• Nausea, vomiting, abdominal pain

• Photosensitivity

• Urticaria

• Fever

• CNS problems (headache, visual disturbance)

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Fluoroquinolones

Activity Spectrum

• Enterobacteriaceae
• Haemophilus spp.
• Moraxella catarrhalis
• Pseudomonas aeruginosa
• Legionella spp.
• Chlamydia spp.
• Mycoplasma spp.
• Some Mycobacteria

Fluoroquinolones

• Ciprofloxacin – acute bronchitis and acute

pneumonia, urinary tract infections, skin and
softtissues infections, bone and joint infections,
infectiuos diarrhoea.

• Norfloxacin – upper and lower tract infections,

pyelitis and pyelonephritis.

• Ofloxacin – lower respiratory tract infections (

pneumonia), acute exacerbations of chronic
bronchitis, uncomplicated cistis and complicated
urinary tract infections ( caused by e.g E. coli)

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Fluoroquinolones

Adverse Effects

• Diarrhoea

• CNS problems (nausea, headache, dizziness)

• Nephrotoxicity

• Phototoxicity

Nitroimidazoles

Metronidazole

Chemical Structure

47

Mechanisms of Bacterial

Resistance to Nitroimidazoles

• Decreased uptake of the drug

• Decreased nitroreductase production

Metronidazole

Activity Spectrum and Adverse Effect

Gram - negative anaerobes

including

Bacteroides fragilis

Possibly mutagenic (should be avoided in

pregnant women in the first trimester)

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Antibiotics Inhibiting Bacterial

RNA Synthesis

Rifamycins:

Rifampin

Rifabutin

Rifapentine

Rifampin

Activity Spectrum

• Mycobacterium spp.

• Staphylococci

• Neisseria meningitidis

• Haemophilus influenzae

• Legionella pneumophila

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Rifampin

Adverse Effects

• Hepatotoxicity

• Flu-like syndrome

• Fever

Agents Inhibiting Folate

Metabolism

Sulfonamides

Sulfons

Trimethoprim

Co-trimoxazole

50

Sulfonamides

Sulphamethoxazole

Chemical Structure

Mechanisms of Bacterial

Resistance to Sulfonamides

• Decreased permeability

• Increased PABA production

• Altered target - DHPS

51

Sulfonamides

Activity Spectrum

• Enterobacteriaceae

• Chlamydia spp.

Sulfonamides

Adverse Effects

• Nephrotoxicity as a result of crystalluria
• Hypersensitivity reactions as rashes, angioedema

and Stevens-Johnson syndrome

• Hemolytic anemia (patients with glucose 6-

phosphate dehydrogenase deficiency),
granulocytopenia, thrombocytopenia

• Kernicterus (newborns, infants less than 2

months, pregnant women)

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Trimethoprim

Chemical Structure

Trimethoprim

Adverse effects

• Megaloblastic anemia
• Leucopenia
• Thrombocytopenia

53

Trimethoprim

+

Sulphamethoxazole

=

Co-trimoxazole

Co-trimoxazole

Activity Spectrum

• Escherichia coli

• Proteus spp.

• Salmonella spp.

• Shigella spp.

• Neisseria spp.

• Streptococcus pneumoniae

• Haemophilus influenzae

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Co-trimoxazole

Adverse effects

• Skin reactions

• Nausea, vomiting, glossitis, stomatitis

• Megaloblastic anemia, leukopenia,

thrombocytopenia

• Fever, rashes, diarrhoea and/or pancytopenia

(HIV patients)

THE END

THE END