Transcript Antibiotics

Antibiotics
I-Antimetabolites
Folate Antagonists
Folate-derived cofactors are essential for the synthesis
of purines and pyrimidines (precursors of RNA and
DNA) and other compounds necessary for cellular
growth and replication. Therefore, in the absence of
folate, cells cannot grow or divide. To synthesize the
critical folate derivative, tetrahydrofolic acid, humans
must first obtain preformed folate in the form of folic
acid as a vitamin from the diet. In contrast, many
bacteria are impermeable to folic acid and other folates
and, therefore, must rely on their ability to synthesize
folate de novo. The sulfonamides (sulfa drugs) are a
family of antibiotics that inhibit this de novo synthesis
of folate.
Cont; Sulfonamides
-One of the first groups of antibiotics
-Bacteriostatic in action
-Prevent synthesis of folic acid required for
synthesis of purines and pyrimidines.
-Does not affect human cells or certain bacteria
that can use preformed folic acid
-Examples:
Short acting: sulfadiazine, sulfamethazine
Intermediate acting : sulfamethoxazole
Long acting : sulfathiazole , sulfasalazine
F. Spectrum of Activity
-Broad range of Gm+ and Gm-They are also active against some protozoa as
toxoplasmosis and chloroquine-resistant malaria
when combined with pyrimethamine (which
interferes with folic acid synthesis by inhibiting the
enzyme dihydrofolate reductase).
G. Resistance
- common due to:
1) an altered dihydropteroate synthetase.
2)decreased cellular permeability to sulfa drugs
3) enhanced production of the natural substrate,
PABA.
H. Uses
1- Respiratory and urinary tract infection. 2-Ulcerative colitis
3-Skin wounds and skin burns.
4-Toxoplasmosis and malaria.
5-in burn units,they have been effective in reducing burn-associated
sepsis, because they prevent colonization of bacteria (silver
(sulfadiazine given topically).
6-Sulfonamides are as efficacious as oral penicillin in preventing
streptococcal infections and recurrences of rheumatic fever
among susceptible subjects
7-For some sexually transmitted infections (e.g. trachoma,
chlamydia)
I. Side effects
-Hypersensitivity reactions (e.g., rashes and drug fever) in a small
number of patients. Other cause allergic reactions include
photosensitivity. -Stevens-Johnson syndrome is also associated
with sulfonamide use; it is characterized by fever, malaise,
erythema ,and ulceration of the mucous membranes of the
mouth and genitalia.
-High concentration of sulfonamides with aqueous solubility which is
sufficiently low, the free drug or its metabolites may form crystals
and cause bleeding or complete obstruction of the kidneys.
i-Combinations of sulfa (for lowering the dosage of
individual agents)
ii- A lot of fluids intake
iii-Alkalinization of the urine (to increase excretion)
to reduce the chance of crystalluria
-Sulfonamides compete for sites on plasma proteins that are
responsible for the binding of bilirubin. As a result, less bilirubin is
bound, and in the newborn, the unbound bilirubin can be
deposited in the basal ganglia, causing kernicterus, a toxic
encephalopathy. For this reason, sulfonamides should not be
administered to newborns or to women during the last 2 months
of pregnancy or lactating females.
D.
Antibacterial spectrum
-The antibacterial spectrum of trimethoprim is
similar to that of sulfamethoxazole. It is active against most gram-
positive and gram negative organisms. There is little activity against
anaerobic bacteria.However, trimethoprim is 20-to 50-fold more
potent than the sulfonamide.
E. Uses
Trimethoprim may be used alone in the treatment of acute UTIs and in the
treatment of bacterial prostatitis and vaginitis is used in the treatment of
genitourinary, GI, and respiratory tract infections.
F. Resistance
Resistance in gram-negative bacteria is due to the presence of an altered
dihydrofolate reductase that has a lower affinity for trimethoprim.
Overproduction of the enzyme may also lead to resistance, because this
can decrease drug permeability.
G. Adverse effects
Trimethoprim can produce the effects of folic acid deficiency. These effects
include megaloblastic anemia, leukopenia, and granulocytopenia,
especially in pregnant patients and those having very poor diets. These
blood disorders can be reversed by the simultaneous administration of
folinic acid, which does not enter bacteria.
III-Cotrimoxazole
The combination of trimethoprim with sulfamethoxazole, called cotrimoxazole shows
greater antimicrobial activity than equivalent quantities of either drug used alone .The
combination was selected because of the similarity in the half-lives of the two drugs.
Rationally, by blocking the first stepin folic acid synthesis, there is no real reason to
block further steps. However, there are some bacteria which can inhibits the initial
blockage, and so this may be the rationale for the use of such combination.
-There is synergy between the two drugs - the combined effect is greater that the
expected sum of their activities
-Individually the drugs are bacteriostatic; however, in combination they are
bactericidal
-The use of two drugs will delay the emergence of resistance.
Mechanism of action
Resistance
-The bacteria by gentic mutation they do not need to make folic acid they utilize
already formed folic acid.
--Overproduce the target e.g. To overcome trimethoprim, bacteria can
overproduce DHFR to overcome the inhibition of trimethoprim.
-Bacteria produce mutated DHFR
Side effects
TMP-SMX can cause the same adverse effects as those associated with
sulfonamide administration. Most of the adverse effects of this combination are
due to the sulfamethoxazole component.
Uses
TMP-SMX is used in the treatment of infection caused by ampicillin-resistant
Shigella and for antibiotic-resistant Salmonella.
-Successful in treatment of traveler’s diarrhea due to susceptible E. coli.
-Because trimethoprim accumulates in the prostate, TMP-SMX is used to treat
prostatitis caused by sensitive organisms.
- Used n Pneumocystis jiroveci pneumonia occur in HIV patients.
Uses of Cotrimoxazol
II-Protein Synthesis
Inhibitors
Reason For Selective Toxicity
A number of antibiotics exert their antimicrobial
effects by targeting the bacterial ribosome, which has
components that differ structurally from those of the
mammalian cytoplasmic ribosome. In general, the
bacterial ribosome is smaller (70S) than the
mammalian ribosome (80S) and is composed of 50S
and 30S subunits (as compared to 60S and
40S subunits in human).
Inhibitors of bacterial protein synthesis, Overview
 These agents are bacteriostatic, protein-synthesis inhibitors that target the
ribosome
 Examples: tetracyclines, aminoglycosides, macrolides, chloramephnicol
Chloramphenicol
Θ
Tetracyclines
Θ
(P-site)
(A-site)
Θ
Macrolides,
clindamycin
1-Aminoglycosides
They are highly polar with polycationic structure. These characters prevent
adequate absorption of these antibiotics after oral administration. Therefore,
all aminoglycosides (except neomycin )must be given parenterally to achieve
adequate serum levels.
Note: The severe nephrotoxicity associated with neomycin precludes
parenteral administration, and its current use is limited to topical application
for skin infections or oral administration to prepare the bowel prior to surgery.
The bactericidal effect of aminoglycosides is concentration and time
dependent; that is, the greater the concentration of drug, the
greater the rate at which the organisms die. They also have a postantibiotic
effect (residual bactericidal activity persisting after the serum concentration
has fallen below the MIC). Because of these properties once-daily dosing with
the aminoglycosides can be employed.
The aminoglycosides synergize with β-lactam antibiotics and vancomycin
because of the latter's action on cell wall synthesis, which enhances diffusion
of the aminoglycosides into the bacterium producing synergistic bactericidal
effect in vitro against enterococci, streptococci and staphylococci
1-Aminoglycosides
Mechanism of action
•
Aminoglycosides diffuse through aqueous channels formed by porin
proteins in the outer membrane of G-ve bacteria to enter the periplasmic
space. Their transport across the cytoplasmic membrane depends on
electron transport (membrane electrical potential is required to drive
permeation of these antibiotics)
•
This active transport is rate-limiting and can be inhibited by divalent
cations (e.g., Ca2+ & Mg2+), a reduction in pH and anaerobic conditions.
The last two conditions impair the ability of the bacteria to maintain the
membrane potential, which is the driving force necessary for transport.
Thus the antimicrobial activity of aminoglycosides is reduced markedly
in the anaerobic environment of an abscess for example.
•
Once inside the cell, aminoglycoside binds irreversibly to the 30S
ribosomal subunit and interferes with initiation of protein synthesis by
fixing the 30S-50S ribosomal complex at the start codon (AUG) of
mRNA, leading to accumulation of abnormal initiation complexes, socalled streptomycin monosomes, blocking further translation of the
message
 Aminoglycoside binding to the 30S subunit also causes
misreading of mRNA, leading to:
 premature termination of translation with detachment of the
ribosomal complex and incompletely synthesized protein
(B) = nonsense
 incorporation of incorrect amino acids (indicated by the X),
resulting in the production of abnormal or nonfunctional
proteins (C) =misense
 The resulting aberrant proteins may be inserted into the cell
membrane, leading to altered permeability and further
stimulation of aminoglycoside transport. This leads to leakage
of small ions, followed by larger molecules and, eventually, by
proteins from the bacterial cell. This progressive disruption of
the cell envelope, as well as other vital cell processes, may help
to explain the lethal action of aminoglycosides
Resistance
1-Resistance can occur by altering the 30s
ribosome binding site of the drug / low
affinity of the drug.
2- Impaired intracellular transport: Decrease
the transport of the AB.
3- Inactivation by microbial
enzymes :Bacteria can produce
deactivating enzymes as
phosphotransferases, adenyltransferases
and acetyltransferases Each of these
enzymes has its own aminoglycoside
specificity; therefore, cross-resistance is
not an invariable rule.
Note:
1- Amikacin is less vulnerable to these
enzymes than are the other antibiotics of
this group
2-Any organism resistant to one
aminoglycoside is
not resistant to all
Pharmacokinetics
 They are highly polar cations and therefore are
very poorly absorbed from the GIT
 All aminoglycosides are absorbed rapidly from
intramuscular sites of injection
 Because of their polar nature, they do not
penetrate into most cells, the CNS and the eye
 The elimination of aminoglycosides depends
almost entirely on the kidney
 The half-lives of aminoglycosides in plasma are
similar (2-3 h in patients with normal renal
function)
 The half-life for tissue-bound aminoglycoside
has been estimated to range from 30 to 700 h
Spectrum and Uses
Aminoglycosides act bactericidal on
dividing and non dividing microorganisms.They are in general active
against aerobic Gram-negative
including Pseudomonas
aeruginosa.
The exact mechanism of their lethality
is unknown because other antibiotics
that affect protein synthesis are
generally bacteriostatic
They have little activity against
anaerobic microorganisms
Their action against most G+ve
bacteria is limited, and they should
not be used as single agents to treat
infections caused by such bacteria
Therapeutic Uses:
 Aminoglycosides are used in combination with a
penicillin or a cephalosporin for the therapy of
serious G-ve microbial infections (e.g., P. aeruginosa,
Enterobacter, urinary tract infections, bacteremia,
infected burns, pneumonia)
• Because of their toxicity with prolonged administration,
aminoglycosides should not be used for more than a
few days unless deemed essential for a successful or
improved outcome
• Once the microorganism is isolated and its sensitivities
to antibiotics are determined, the aminoglycoside
should be discontinued if the infecting microorganism is
sensitive to less toxic antibiotics
 Streptomycin (or gentamicin) is the drug of choice
for the treatment of tularemia
 Streptomycin and gentamicin are effective agents for
the treatment of all forms of plague
 Treatment of tuberculosis, streptomycin always
should be used in combination with at least one or
two other drugs to which the causative strain is
susceptible
 Neomycin and framycetin, whilst too toxic for
systemic use, are effective for topical treatment of
the conjunctiva or external ear.
 Respiratory tract infections.
 GIT infections as amebiasis (mostly neomycin).
Adverse effects
All aminoglycosides are ototoxic and nephrotoxic.
-Ototoxicity and nephrotoxicity are more likely to be encountered
when therapy is continued for more than 5 days, at higher doses,
in the elderly, and in the setting of renal insufficiency.
-Concurrent use with loop diuretics (eg, furosemide, ethacrynic
acid) or other nephrotoxic antimicrobial agents (vancomycin,
amphotericin) can potentiate nephrotoxicity and should be avoided.
-Ototoxicity can manifest itself either as auditory damage,
resulting in tinnitus and high-frequency hearing loss initially,
or as vestibular damage, evident by vertigo, ataxia, and loss of
balance.
Copnt.: Adverse effects
-Also they produce a curare-like effect with neuromuscular blocking
effect that results in respiratory paralysis. The mechanism
responsible is a decrease in both the release of acetylcholine from
prejunctional nerve endings and the sensitivity of the
postsynaptic site. Patients with myasthenia gravis are particularly
at risk.This paralysis is usually reversible by calcium gluconate or
neostigmine.
-Hypersensitivity occurs infrequently.
2- TETRACYCLINES
They are safe, inexpensive ,broad-spectrum, bacteriostatic
. antibiotics, that are effective against aerobic and anaerobic grampositive and gram-negative bacteria as well as against organisms
other than bacteria (ex. Protozoa).
7
6
5
4
The basic tetracycline structure consists
of four benzene rings with various
substituent on each ring.
-
Cont. Tetracyclines
 Oxytetracycline is a natural product
produced by Streptomyces rimosus.
 Tetracycline is a semisynthetic
derivative of chlortetracycline,
produced by Streptomyces
aureofaciens
 Demeclocycline is the product of a
mutant strain of Strep. Aureofaciens
 Methacycline, doxycycline and
minocycline all are semisynthetic
derivatives
Tetracyclines are classified as:
(1) short-acting :chlortetracycline, tetracycline,
oxytetracycline
(2) intermediate acting :demeclocycline and
methacycline
(3) long-acting :doxycycline and minocycline
The almost complete absorption and slow
excretion of doxycycline and minocycline
allow for once-daily dosing.
A newly approved tetracycline analog, tigecycline, Is a
semisynthetic derivative of minocycline.
Many tetracycline-resistant strains are susceptible to tigecycline.
It has broad spectrum. Tigecycline was developed to overcome
the recent emergence of tetracycline “resistant organisms that
utilize efflux and ribosomal protection to infer resistance
WHY???.
Mechanism of action
-Tetracyclines enter microorganisms in part by passive
diffusion (through cell wall) and in part by an energydependent process (active transport through cell
membrane). Susceptible cells concentrate the
drug intracellularly.
-Once inside the cell, tetracyclines bind reversibly to
the 30S subunit of the bacterial ribosome, blocking the
binding of aminoacyl-tRNA to the acceptor site on the
mRNA-ribosome complex. This prevents addition of
amino acids to the growing peptide.
-Tetracyclines are broad-spectrum bacteriostatic
antibiotics that inhibit protein synthesis.
Mechanisms of resistance
1. Decreased intracellular accumulation due to either
decreased influx or increased efflux by an active
transport protein pump … (the most important)
2. Ribosome protection due to production of proteins
that interfere with tetracycline binding to the
ribosome
3. Resistance is primarily plasmid-mediated and often
is inducible
Any organism resistant to one tetracycline
is resistant to all.
Antimicrobial actions:
 Tetracyclines are active against many G+ve & G-ve
bacteria, including anaerobes, rickettsiae,
chlamydiae, mycoplasmas
 They are also active against some protozoa, e.g.,
amebas
 The antibacterial activities of most tetracyclines are
similar except that tetracycline-resistant strains
may remain susceptible to doxycycline or
minocycline, which are less rapidly effluxed by the
pump that is responsible for resistance
Pharmacokinetics
Substitutions on these rings are responsible for variation in
thedrugs'individual pharmacokinetics, which cause small differences in
their clinical efficacy.
•Absorption after oral administration is approximately 30% for
chlortetracycline ,60–70% for tetracycline, oxytetracycline, and
methacycline; and 95–100% for doxycycline and minocycline.
•Absorption occurs mainly in the upper small intestine and is impaired
by food (except doxycycline and minocycline); by divalent cations (Ca2+,
Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain
multivalent cations. The decreased absorption results from chelation
with divalent and trivalent cations.
•Tetracyclines are 40–80% bound by plasma proteins.Tetracyclines are
distributed widely to tissues and body fluids except for CSF, where
concentrations are 10–25% of those in serum.
(Minocycline reaches very high concentrations in tears and saliva, which
makes it useful for eradication of the meningococcalcarrier state).
-Tetracyclines cross the placenta to reachthe fetus and are also excreted
in milk. As a result of chelation with calcium, tetracyclines are bound to
and damage growing bones and teeth.
-Tetracyclines are excreted mainly in bile and urine. Some of the drug
excreted in bile is reabsorbed from the intestine (enterohepatic circulation)
and may contribute to maintenance of serum levels .
Excretion into the urine, mainly by glomerular Filtration . Small % of the
these drugs are excreted in feces.
-Doxycycline, in contrast to other tetracyclines, is eliminated mainly
nonrenaly , do not require dosage adjustment in renal failure. Thus it is
one of the safest TET for the treatment of extrarenal infections, making it
the tetracycline of choice for use in the setting of renal insufficiency.
Minocycline is recovered from urine and feces in significantly lower
amounts than are the other tetracyclines, and it appears to be metabolized
to a considerable extent. Its renal clearance is low. The drug persists in the
body long after its administration is stopped, possibly due to retention in
fatty tissues. Nonetheless, its half-life is not prolonged in patients with
hepatic failure
Spectrum & Clinical Uses
-Tetracyclines are active against many Gram-positive and Gram-negative bacteria,
including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and against some protozoa,
as amebas.
-Tetracyclines are sometimes employed in the treatment of protozoal infections, e.g., those
due to Entamoeba histolytica or Plasmodium falciparum.
-Tetracyclines remain effective in most chlamydial infections, including sexually
transmitted diseases.
-Tetracyclines are effective in treatment of Rocky Mountain spotted fever by rickettsia
rickettsii.
-Other uses include treatment of acne, They may act by inhibiting propionibacteria, which
reside in sebaceous follicles and metabolize lipids into irritating free fatty acids. The
relatively low doses of tetracycline used for acne are associated with few side effects
-They are used in combination regimens to treat gastric and duodenal ulcer disease
caused by H. pylori.
- Although all tetracyclines enter the (CSF), their levels are insufficient for therapeutic
efficacy, except for minocycline enters the brain in the absence of inflammation and also
appears in tears and saliva so it is useful in eradicating the meningococcal carrier state,
but not effective for CNS infections.
Adverse Reactions
TET can produce a variety of adverse effects ranging from minor
inconvenience to life-threatening.
-Hypersensitivity reactions (drug fever, skin rashes) to
tetracyclines are not very common.
-Nausea, vomiting, and diarrhea are the most common
reasons for discontinuing tetracycline medication.
These effects are attributable to direct local irritation of
the intestinal tract. These effects can usually be controlled by administering the drug with carboxymethylcellulose, reducing drug dosage, or discontinuing the drug.
-TET like other antimicrobial agents administered orally may
lead to development superinfections, as Tetracyclines
modify the normal flora, with suppression of susceptible
organisms and overgrowth of pseudomonas, proteus,
staphylococci, , clostridia (causing Pseudo membranous
colitis ), and candida. This can result in intestinal functional
disturbances, anal pruritus, vaginal or oral candidiasis
Diarrhea must be distinguished either:
A. Normal -loose stools do not contain blood or leukocytes
B. Pseudo membranous colitis -severe diarrhea, fever, stools
containing shreds of mucous membrane and large number of
neutrophils. As CI. difficile produces a toxin which is
cytotoxic to mucosal cells.
--Tetracyclines are readily bound to calcium deposited
in newly formed bone or teeth in young children.
When a tetracycline is given during pregnancy, it can
be deposited in the fetal teeth, leading to fluorescence,
discoloration, and enamel dysplasia; it can also be
deposited in bone, where it may cause deformity or
growth inhibition. If the drug is given for long periods to
children under 8 years of age, similar changes can result.
Tetracyclines can probably impair hepatic function,
especially during pregnancy, in patients with preexisting
hepatic insufficiency and when high doses are given
intravenously
Tetracyclines other than doxycycline may accumulate to
toxic levels in patients with impaired kidney function
3-Macrolides
-The macrolides are a group of antibiotics with a macrocyclic lactone
structure to which one or more deoxy sugars are attached. Erythromycin
was the first of these drugs to find clinical application, both as a drug of
first choice and as an alternative to penicillin in individuals who are
allergic to penicillin .
-The newer members of this family include clarithromycin and azithromycin
(semisynthetic derivatives of erythromycin).
The structural modifications in these drugs:
 improved acid stability
 Enhanced absorption & tissue penetration
 broadened the spectrum of activity
-Ketolides and macrolides have very similar antimicrobial coverage.
However, the ketolides are active against many macrolide resistant
gram-positive strains . Telithromycin is a semisynthetic derivative of
erythromycin, is the first ketolide antimicrobial agent that has been
approved and is now in clinical use
Mechanism of action
– The macrolides bind to a site on the
50S subunit of the bacterial ribosome,
thus inhibiting the translocation
steps(Where the newly synthesized
peptidyl tRNA molecule moves from the
A site on the ribosome to the P site) of
protein synthesis.
•
They may also interfere at other steps,
such as transpeptidation.
• Generally considered to be
bacteriostatic, they may be bactericidal
at higher doses.
•
Their binding site is either identical or
in close proximity to that for
clindamycin and chloramphenicol
Resistance
1. Drug efflux by an active pump mechanism
2. Ribosomal protection by inducible or constitutive
production of methylase enzymes, which modify the
ribosomal target and decrease drug binding
3. Macrolide hydrolysis by esterases
4. Chromosomal mutations that alter 50S ribosomal
protein
 Because the mechanisms producing resistance to
erythromycin affect all macrolides, cross-resistance
among them is complete
Pharmacokinetics
 Erythromycin base is incompletely but adequately
absorbed from the upper small intestine. Because it is
inactivated by gastric acid, the drug is administered
with enteric coating that dissolves in the duodenum, or
as an ester
 Food, which increases gastric acidity, may delay
absorption
 Erythromycin diffuses readily into intracellular fluids,
achieving antibacterial activity in essentially all sites
except the brain and CSF
 Large amounts of an administered dose are excreted
in the bile and lost in feces, and only 5% is excreted
in the urine
 Clarithromycin is absorbed rapidly from the GIT
after oral administration, but first-pass
metabolism reduces its bioavailability to ~ 50%. It
may be given with or without food
 The extended-release form, typically given
once-daily as a 1-g dose, should be
administered with food to improve
bioavailability
 It distributes widely and achieve high
intracellular concentrations equal to or
exceeding serum concentrations throughout
the body
 Clarithromycin is eliminated by renal and
nonrenal mechanisms. It is metabolized in the
liver to several metabolites, the active 14hydroxy metabolite being the most significant
Pharmacokinetics, contd.
 Azithromycin's unique pharmacokinetic properties
include extensive tissue distribution and high drug
concentrations within cells, resulting in much greater
concentrations of drugs in tissue compared to
simultaneous serum concentrations
 Tissue fibroblasts act as the natural reservoir for the
drug in vivo
 The drug is slowly released from tissues (tissue halflife of 2–4 days) to produce an elimination half-life
approaching 3 days. These unique properties permit
once-daily dosing and shortening of the duration of
treatment in many cases
 It undergoes some hepatic metabolism to inactive
metabolites, but biliary excretion is the major route
of elimination. Only 12% of drug is excreted
unchanged in the urine
Antimicrobial actions:
 Erythromycin usually is bacteriostatic, but may be bactericidal in
high concentrations against very susceptible organisms
G+ve bacteria accumulate about 100 times more erythromycin
than do G-ve bacteria
It is most active in vitro against aerobic G+ve cocci and bacilli
Erythromycin is inactive against most aerobic enteric G-ve
bacilli. It has modest activity in vitro against other G-ve
organisms (e.g., H. influenzae, N. meningitidis and N.
gonorrhoeae)
 Clarithromycin is slightly more potent than erythromycin against
sensitive strains of streptococci and staphylococci
 Azithromycin is less active than erythromycin against G+ve
organisms and slightly more active than either erythromycin or
clarithromycin against H. influenzae and N. gonorrhoeae
 Azithromycin and clarithromycin are activity against some
protozoa (e.g., Toxoplasma gondii and Plasmodium spp.).
Clarithromycin has good activity against Mycobacterium leprae
Therapeutic Uses:
 Erythromycin is the drug of choice for treating persons with B.
pertussis disease and for postexposure prophylaxis of household
members and close contacts
 Erythromycin is very effective in corynebacterial infections
 Erythromycin is useful as a penicillin substitute in penicillinallergic individuals with infections caused by streptococci or
pneumococci
 Chlamydial infections can be treated effectively with any of the
macrolides
 During pregnancy, erythromycin is recommended as first-line
therapy for chlamydial urogenital infections
 A macrolide or tetracycline is the drug of choice for mycoplasma
infections
 Clarithromycin 500 mg, in combination with omeprazole, 20 mg,
and amoxicillin, 1 g, each administered twice daily for 10 to 14
days, is effective for treatment of peptic ulcer disease caused by
H. pylori
Side effects :
 Serious untoward effects are rarely caused by
erythromycin
 Among the allergic reactions observed are fever,
eosinophilia and skin eruptions, which may occur
alone or in combination; each disappears shortly
after therapy is stopped
 Cholestatic hepatitis is the most striking side effect
(fever, jaundice, impaired liver function), probably as a
hypersensitivity reaction
 Anorexia, nausea, vomiting, and diarrhea occasionally
accompany oral administration (due to a direct
stimulation of gut motility).
 Ototoxicity: Transient deafness has been associated
with erythromycin, especially at high dosages
• Contraindications:
Patients with hepatic dysfunction should be treated cautiously with
erythromycin, telithromycin, or azithromycin, because these drugs
accumulate in the liver. Similar situation with patients who are renally
compermized. Telithromycin has the potential to prolongate the QTc
interval in some patients. Therefore, it should be avoided in patients
with congenital prolongation of the QTc interval and in those patients
with proarrhythmic conditions
• Interactions:
Erythromycin, telithromycin, and clarithromycin inhibit the hepatic
metabolism of a number of drugs, which can lead to toxic
accumulations of these compounds including theophylline,
warfarin, cyclosporine, corticosteroids and digoxin
Azithromycin appears to be free of these drug interactions
III-Miscellaneous
Antibiotics
1-Chloramphenicol
An antibiotic produced by Streptomyces venezuelae, an
organism first isolated from a soil sample in Venezuela.
Chloramphenicol
inhibits protein synthesis in bacteria and, to a lesser
extent, in eukaryotic cells
The drug is either bacteriostatic, or bactericidal
depending on the organism.
Mechanism of Action
-It readily penetrates bacterial cells, by
facilitated diffusion.
-It acts primarily by binding reversibly to the 50S
ribosomal subunit. The drug prevent the
interaction between peptidyltransferase and
its amino acid substrate, and peptide bond
formation is inhibited .
Because of the similarity of mammalian
mitochondrial ribosomes to those of
bacteria(70S),protein synthesis in these
organelles may be inhibited at high
circulating chloramphenicol levels, producing
bone marrow toxicity as mammalian
erythropoietic cells are particularly sensitive
to the drug
Antimicrobial Actions:
 It is a bacteriostatic broad-spectrum antibiotic
that is active against both aerobic and anaerobic
G+ve and G-ve organisms
 It is active also against rickettsiae and
mycoplasma
 Haemophilus influenzae, Neisseria meningitidis
and Bordetella pertussis are highly susceptible
 Strains of S. aureus tend to be less susceptible
 P. aeruginosa is resistant to even very high
concentrations of the drug
Resistance
1-Resistance is conferred by the presence of plasmid –encoded
acetyltransferase. This enzyme inactivates chloramphenicol .
Acetylated derivatives of chloramphenicol fail to bind to bacterial
ribosomes.
2-Resistance also can result from decreased permeability and from
ribosomal mutation.
Adverse effects
1-Nausea, vomiting, unpleasant taste, and diarrhea may follow the oral
administration of chloramphenicol. Among the rare toxic effects
produced by this antibiotic are blurring of vision and paresthesias.
2-Oral or vaginal candidiasis may occur as a result of alteration of
normal microbial flora
3-Hematologic Toxicity
The most important adverse effect of chloramphenicol is on the bone
marrow cells. Chloramphenicol affects the hematopoietic system in two
ways:
1- by an non-dose-related idiosyncratic response manifested by
aplastic anemia, leading in many leading in many cases to fatal
pancytopenia
2-by a dose-related toxic effect that presents as anemia, It seems to
occur more commonly in individuals who undergo prolonged therapy.
This is due to reversible erythroid suppression due to an inhibitory
action of chloramphenicol on mitochondrial protein synthesis in
erythroid precursors, which in turn impairs iron incorporation into
heme
3-Gray baby syndrome
• Fatal chloramphenicol toxicity may develop in neonates,
especially premature babies, when they are exposed to
excessive doses of the drug (above 50 mg/kg/d).
• The gray baby syndrome, usually begins 1-2 days after
treatment is started.
• The manifestations in the first 24 hours are vomiting,
refusal to suck, irregular and rapid respiration, abdominal
distention, periods of cyanosis, and passage of loose,
green stools. Soon they become flaccid, turn an ashengray color, and become hypothermic.
• Death occurs in about 40% of patients within 2 days of
initial symptoms. Those who recover usually exhibit no
sequelae
Two mechanisms are apparently responsible for chloramphenicol
toxicity in neonates
(1) failure of the drug to be conjugated with glucuronic acid, owing
to inadequate activity of glucuronyl transferase in the liver of the
infant , which is characteristic of the first 3 to 4 weeks of life.
(2) inadequate renal excretion of unconjugated drug in the
newborn.
 Exchange transfusion and charcoal hemoperfusion have been used to
treat overdose with chloramphenicol in infants
 To avoid this toxic effect, chloramphenicol should be used with caution
in infants, and the dosage limited to 50 mg/kg/d or less (during the first
week of life) in full-term infants and 25 mg/kg/d in premature infants.
 Toxic effects have not been observed in the newborns when as much as
1 g of the antibiotic has been given every 2 hours to the mothers during
labor
Drug interactions
 It inhibits hepatic microsomal enzymes that metabolize
several drugs such as warfarin
 Conversely, other drugs may alter the drug elimination.
Concurrent administration of phenobarbital or rifampin,
which potently induce CYPs, shortens its t1/2 and may
result in subtherapeutic drug concentrations
 Like other bacteriostatic inhibitors of microbial protein
synthesis, chloramphenicol can antagonize bactericidal
effect of drugs such as penicillins or aminoglycosides
Therapeutic Uses
Chloramphenicol has a wide range activity that includes gram+, gram-,
aerobic and anaerobic bacteria
But because of potential toxicity, bacterial resistance, and the
availability of many other effective alternatives, chloramphenicol is
rarely systemically used.
It may be considered for treatment of :
-Typhoid Fever
-Bacterial Meningitis :alternative to a beta-lactams for treatment of
meningococcal meningitis occurring in patients who have major
hypersensitivity reactions to penicillin or bacterial meningitis caused by
penicillin-resistant strains of pneumococci
-Rickettsial Diseases :alternative to tetracycline especially in children <8
years old
-It is used topically in the treatment of eye infections because of its wide
antibacterial spectrum and its penetration of ocular tissues and the aqueous
humor
2-Clindamycin
Clindamycin is a chlorine-substituted derivative
of lincomycin, an antibiotic produced by
Streptomyces lincolnensis
Lincomycin, although structurally distinct,
resembles erythromycin in activity, but it is toxic
and no longer used
Mechanism of action
• Clindamycin has a mechanism of action that is the same as that
of erythromycin. (i.e) Inhibiting the translocation steps of
protein synthesis. They may also interfere at other steps, such
as transpeptidation
• The binding site for clindamycin on the 50S subunit of the
bacterial ribosome is identical with that for erythromycin
• Although clindamycin, erythromycin and chloramphenicol are
not structurally related, they act at sites in close proximity, and
binding by one of these antibiotics to the ribosome may inhibit
the interaction of the others
• There are no clinical indications for the concurrent use of these
antibiotics
Antimicrobial actions:
•
Clindamycin generally is similar to erythromycin in its in vitro activity against
susceptible strains of pneumococci and streptococci
•
Some strains of streptococci that are macrolide-resistant remain susceptible
to clindamycin
•
Clindamycin is more active than erythromycin or clarithromycin against
anaerobic bacteria
•
Methicillin-susceptible strains of S. aureus usually are susceptible to
clindamycin, but MRSA are resistant
•
Essentially all aerobic G-ve bacilli are resistant
Resistance mechanisms:
1. Mutation of the ribosomal receptor site
2. Modification of the receptor by a constitutively expressed methylase
3. Enzymatic inactivation of clindamycin
4. G-ve aerobic species are intrinsically resistant because of poor permeability
of the outer membrane
 Resistance to clindamycin generally confers cross-resistance to macrolides
Pharmacokinetics
 Clindamycin is nearly completely absorbed
following oral administration. The presence of
food in the stomach does not reduce absorption
significantly
 It penetrates well into most tissues, with brain and
CSF (even when the meninges are inflamed!)
being important exceptions. It penetrates well into
abscesses and is actively taken up and
concentrated by phagocytic cells
 The drug is about 90% protein-bound. It is
metabolized by the liver, and both active drug and
active metabolites are excreted in bile
Therapeutic Uses:
 Clindamycin is indicated in the treatment of serious
infections due to susceptible strains of streptococci,
pneumococci and staphylococci
The high incidence of diarrhea and the occurrence of
pseudomembranous colitis limit its use to infections in which it
is clearly superior to other agents
 It is effective topically (or orally) for acne vulgaris and
bacterial vaginosis
 It is particularly valuable for the treatment of infections with
anaerobes
 It has replaced penicillin as the drug of choice for treatment
of lung abscess and anaerobic lung and pleural space
infections
Adverse effect
-Skin rashes occure in 10% of the patients.
- Abdominal pain, esophagitis, nausea, vomiting and diarrhea
-The most serious adverse effect is potentially fatal pseudomembranous
colitis caused by overgrowth of Clostridium difficile, which elaborates
necrotizing toxins. Oral administration of either metronidazole (the
preferred therapy) or vancomycin is usually effective in controlling this
serious problem.
[Note: Vancomycin should be reserved for a condition that does not
respond to metronidazole.]
-Impaired liver function (with or without jaundice) and neutropenia
sometimes occur
-It can inhibit neuromuscular transmission and may potentiate the effect
of a neuromuscular blocking agent administered concurrently
3-Quinupristin/Dalfopristin
 Quinupristin/dalfopristin is a combination of quinupristin, a streptogramin
B, with dalfopristin, a streptogramin A, in a 30:70 ratio respectively.
 These compounds are semisynthetic derivatives of naturally occurring
pristinamycins, produced by Streptomyces pristinaespiralis
 Quinupristin and dalfopristin are more soluble derivatives of pristinamycin
IA and pristinamycin IIA, respectively, and therefore are suitable for
intravenous administration.
 This combination is normally reserved for the treatment of vancomycinresistant Enterococcus faecium VRE.
 The combination drug is active primarily against gram-positive cocci,
including those resistant to other antibiotics (for example, methicillinresistant staphylococci). Its primary use is in the treatment of E. faecium
infections, including VRE strains. The drug is not effective against
Enterococcus faecalis
Mechanism of action
Each component of this combination drug binds to a separate site on
the 50S bacterial ribosome, and they synergistically interrupt
protein synthesis. The combination drug is bactericidal and has
a long postantibiotic effect.
B. Resistance
1-Due to, the presence of a ribosomal enzyme that methylates the
target bacterial ribosomal RNA site can interfere in quinupristin
binding. This enzymatic modification can change the action from
bactericidal to bacteriostatic.
2-Plasmid-associated acetyltransferase inactivates dalfopristin.
3-An active efflux pump can also decrease levels of the antibiotics in
bacteria.
Pharmacokinetics
• The combination of quinupristin/dalfopristin is administered
only by i.v. infusion over at least 1 h
• Quinupristin and dalfopristin are rapidly metabolized, with
half-lives of 0.85 and 0.7 h, respectively
• Elimination of approximately 75-80% of the parent
compounds and their metabolites is by biliary excretion
(fecal route)
• No dosage adjustment is necessary for renal insufficiency
• Patients with hepatic insufficiency may not tolerate the
quinupristin/dalfopristin at usual doses, necessitating a dose
reduction in some patients
• Quinupristin and dalfopristin are not metabolized by
cytochrome P450 enzymes but significantly inhibit CYP 3A4,
which metabolizes many drugs e.g., warfarin
Antibacterial Activity
• Quinupristin/dalfopristin is active against G+ve cocci,
including penicillin-resistant strains of S. pneumoniae,
Enterococcus faecium (but not E. faecalis) and staphylococci
(both methicillin-susceptible and methicillin-resistant
strains)
• The combination is largely inactive against G-ve organisms
• Quinupristin/dalfopristin is bactericidal against streptococci
and many strains of staphylococci, but bacteriostatic against
E. faecium
• It has a prolonged postantibiotic effect (up to 10 h for S.
aureus) that may account for its prolonged antibacterial
activity despite relatively short half-lives of the parent drugs
Uses
• Quinupristin/dalfopristin is normally reserved for the treatment of
vancomycin-resistant E. faecium (VRE), but not E. faecalis, which is
intrinsically resistant, probably because of an efflux-type resistance
mechanism
• Quinupristin/dalfopristin also is likely to be approved for treatment of
bacteremia or respiratory tract infections caused by MRSA,
streptococci, and penicillin-susceptible and penicillin-resistant strains
of S. pneumoniae
Adverse effects
• Infusion-related events, such as pain and phlebitis at the infusion site,
and arthralgia and myalgia
• Hyperbilirubinemia: Total bilirubin is elevated in about 25% of
patients, resulting from a competition with the antibiotic for excretion
• The concomitant administration of other CYP3A4 substrates such as
warfarin with quinupristin/dalfopristin may result in significant toxicity
4-Linezolid
The antibacterial action of linezolid is directed primarily against grampositive organisms, such as staphylococci, streptococci, and
enterococci.
It is also moderately active against Mycobacterium tuberculosis.
It is primarily a bacteriostatic agent except for streptococci for which it is
bactericidal
However, its main clinical use is against the resistant gram-positive
organisms, such as methicillin (MRSA ) and vancomycin-resistant
Staphylococcus aureus VRS, vancomycin-resistant E. faecium and E.
faecalis VRE, and penicillin resistant streptococci
Like other agents that interfere with bacterial protein synthesis, linezolid
is bacteriostatic.
Mechanism of action
The drug inhibits bacterial protein
synthesis. Specifically, it binds to a
site on the bacterial 23S ribosomal
RNA of the 50S subunit, near the
interface with the 30S subunit , thus
inhibiting the formation of the 70S
initiation complex.
Resistance
Resistance is caused by mutation
of the linezolid binding site on 23S
ribosomal RNA, with subsequent
decreased binding to the target site
. Cross-resistance with other
antibiotics does
not occur.
Pharmacokinetics
• Linezolid is 100% bioavailable after oral administration, thus
dosing for oral & i.v. preparations is the same. It may be
administered without regard to food
• It is 30% protein-bound and has a half-life of about 4–6 hours
• It is metabolized by nonenzymatic oxidative metabolism, yielding
two inactive metabolites; aminoethoxyacetic acid and hydroxyethyl
glycine derivatives
• It is neither an inducer nor an inhibitor of cytochrome P450
enzymes
• Approximately 80% of the dose of linezolid appears in the urine,
30% as active compound, and 50% as the two primary oxidation
products. Ten percent of the administered dose appears as
oxidation products in feces
• No dose adjustment in renal insufficiency is recommended
• Peak serum concentrations average 18 mg/mL 1 to 2 hours
following a 600 mg oral dose. The recommended dose for most
indications is 600 mg twice daily, either orally or intraveneously
Uses
Linezolid is FDA approved for treatment of:
• Infections caused by VRE
• Nosocomial pneumonia caused by methicillin-susceptible
and-resistant strains of S. aureus
• Community-acquired pneumonia caused by penicillinsusceptible strains of S. pneumoniae
• Complicated or uncomplicated skin and skin-structure
infections caused by streptococci & methicillin-susceptible
and -resistant strains of S. aureus
• The dermatologic preparations are indicated for treatment of
traumatic skin lesions and impetigo secondarily infected with
S. aureus or S. pyogenes
Adverse effects
1-Gastrointestinal upset, nausea, and diarrhea, as well as
headaches and rash.
2-Thrombocytopenia was found to occur in about 2 % of patients
who were on the drug for longer than 2 weeks.
3-linezolid can inhibit monoamine oxidase activity, so patients are
cautioned not to consume large quantities of tyraminecontaining foods (100 mg of tyramine/day).
• Those patients may experience palpitations, headache, or
hypertensive crisis
• Reversible enhancement of the pressor effects of
pseudoephedrine was shown to occur
5-Spectinomycin
• Spectinomycin is an antibiotic marketed as the
hydrochloride salt (spectinomycin hydrochloride)
under the trade name Trobicin.
• It is in aminocyclitol class, closely related to the
aminoglycosides, produced by the by
Streptomyces spectabilis.
Mechanism of Action
• Spectinomycin is a bacteriostatic agent, Its
action is similar to that of the aminoglycosides,
but spectinomycin is not bactericidal.
• Spectinomycin selectively inhibits protein
synthesis in gram-negative bacteria.
• The antibiotic binds to the16S rRNA part of the
30S ribosomal subunit, and inhibits
translocation of the peptidyl tRNA from the A
site to the P site.
Resistance
• Bacterial resistance may be
mediated by mutations in the
16S rRNA part of the 30S
ribosom.
• Modification of the drug by
adenylyltransferase.
Pharmacokinitics
• The recommended dose for men and women
is a single, deep intramuscular injection of 2 g.
• Spectinomycin is rapidly absorbed after
intramuscular injection.
• The single IM dose produces peak serum
concentrations AFTER 1 hour.
• The drug is not significantly bound to plasma
protein.
• All of an administered dose is recovered in the
urine within 48 hours.
Antibacterial Activity and Uses
• Spectinomycin is active against a number of
gram-negative bacterial species, but it is
inferior to other drugs to which such
microorganisms are susceptible.
• Its only therapeutic use is in the treatment of
gonorrhea caused by strains resistant to firstline drugs, or if there are contraindications to
the use of these drugs.
• Recommended as an alternative regimen for
uncomplicated gonococcal patients who are
intolerant to beta lactams or quinolones
• Spectinomycin also is useful in pregnancy
when patients are intolerant to beta-lactams
and when quinolones are contraindicated.
• Spectinomycin has no effect on incubating or
established syphilis, and it is not active against
Chlamydia spp. It also is less effective for
pharyngeal infections.
• Follow-up cultures to document cure should
be obtained.
Adverse Effects
Spectinomycin, when given as a single
intramuscular injection, produces few significant
adverse effects as
• Dizziness, nausea
• Urticaria
• Chills
• Stomachache
• Fever
• Insomnia
• The injection may be painful.
6-Mupirocin
• It is an antibiotic of the monoxycarbolic acid class, derived from
a fermentation product of Pseudomonas fluorescens.
• Mupirocin (pseudomonic acid) is bacteriostatic at low
concentrations and bactericidal at high concentrations.
• It shares no structural homology with other antibiotics in
clinical practice and consists of a short fatty acid (nonanoic
acid) ester linked to monic acid, with the tail portion closely
resembling the isoleucyl moiety of the isoleucyl-adenylate
reaction intermediate (Ile-AMP).
• It is used topically and is effective against Gram-positive
bacteria, including MRSA.
• Mupirocin is inactive for most anaerobic bacteria,
mycobacteria, mycoplasma, chlamydia, yeast and fungi.
Mupirocin
Mechanism of Action
• Mupirocin inhibits bacterial protein synthesis
by reversible binding and inhibiting isoleucyl
transfer-RNA synthetase.
• The inhibition of RNA synthesis was shown to
be a protective mechanism in response to a
lack of one amino acid, isoleucine.
Mechanism of Action
• Mupirocin inhibits bacterial protein synthesis by reversible
binding and inhibiting bacterial isoleucyl transfer-RNA
synthetase, with subsequent inhibition of the incorporation of
isoleucine into bacterial proteins
• This is because the tail portion of monic acid closely
resembles the isoleucyl moiety of the isoleucyl-adenylate
reaction intermediate (Ile-AMP)
• Because this mechanism of action is not shared with any
other antibiotic, mupirocin has few problems of antibiotic
cross-resistance
• Mupirocin is currently the only clinically available aminoacyltRNA synthetase inhibitor and therefore acts as the model for
the prospective clinical development of future aminoacyltRNA synthetase inhibitors
Risistance
• Low-level resistance MuL(MIC = 8–256 mg/L),
which is not clinically significant, THAT is due
to mutations of the host gene encoding
isoleucyl transfer-RNA synthetase or an extra
chromosomal copy of a gene encoding a
modified isoleucyl transfer-RNA synthetase.
• High-level resistance MuH (MIC >256 mg/L)
is mediated by a plasmid or chromosomal
copy of mupA gene, which encodes a "bypass"
synthetase that binds mupirocin poorly .
• Mupirocin is not a viable antibiotic against
MuH strains. Other antibiotic agents such as
nitrofurazone, silver sulfadiazine have been
shown to be effective against MuH strains.
• The mechanism of mupirocin differs from
other clinical antibiotics, rendering crossresistance to other antibiotics unlikely.
• However, the MupA gene may co-transfer with
other antibacterial resistance genes. This has
been observed already with resistance genes
for triclosan, tetracycline, and trimethoprim.
Antibacterial Activity
• Mupirocin is active against many gram-positive and
selected gram-negative bacteria.
• It has good activity against Streptococcus pyogenes and
methicillin-susceptible and methicillin-resistant strains of
S. aureus.
• It is bactericidal at concentrations achieved with topical
application.
• Mupirocin cannot be used for extended periods of time,
or indiscriminately, as resistance does develop, and
could, if it becomes widespread, destroy mupirocin's
value as a treatment for MRSA
Therapeutic Uses
• Mupirocin is available as a 2% cream and
ointment for dermatologic use and as a 2%
ointment for intranasal use. The dermatologic
preparations are indicated for treatment of
traumatic skin lesions and impetigo secondarily
infected with S. aureus or S. pyogenes.
The nasal ointment is approved for eradication
of S. aureus nasal carriage. Mupirocin is highly
effective in eradicating S. aureus carriage.
Adverse Effects
• Mupirocin may cause irritation and sensitization at
the site of application.
• Contact with the eyes should be avoided because
mupirocin causes tearing, burning, and irritation that
may take several days to resolve.
• Systemic reactions to mupirocin occur rarely, if at all.
Polyethylene glycol present in the ointment can be
absorbed from damaged skin. Application of the
ointment to large surface areas should be avoided in
patients with moderate to severe renal failure to
avoid accumulation of polyethylene glycol.
Anti-tuberculous
drugs
Mycobacterial organisms cause:
• Tuberculosis, Mycobacterium avium complex (MAC)
disease, and leprosy.
• These diseases are chronic and necessitate prolonged
treatment.
• Tuberculosis is the primary worldwide cause of death due to
infectious disease.
• Nowadays , there is an increased incidence of tuberculosis
due to HIV associated Mycobateria
As:
1-Mycobacteria grow slowly and may be dormant in the host for long
periods.
2-Many antibacterial agents do not penetrate the cell walls of
mycobacteria, and a portion of mycobacteria can reside inside
macrophages, adding another permeability barrier that effective agents
must cross.
3-Mycobacteria easily can develope resistance to single chemotherapeutic
agents.
As a consequence, The essential elements of the treatment of
mycobacterial disease are to always treat with at least 2 different drugs
to which the organism is susceptible and to treat for sufficient duration
(months to years) to prevent relapse
.
Anti-tuberculous drugs
First-line
– Isoniazid
– Rifampicin
– Ethambutol
– Pyrazinamide
Second-line
– Clarithromycin
– Ciprofloxacin
– Capreomycin
– Cycloserine
– Kanamycin
– Amikacin
– streptomycin
1-Isoniazid
• Isoniazid is the hydrazide of isonicotinic acid.
• Isoniazid is considered the primary drug for the chemotherapy of
tuberculosis.
• It interferes with mycolic acid synthesis (unique to mycobacterial
cell wall structure).
• Passes freely to mammalian cell wall=Effective for intracellular
organism
• It is bacteriostatic – to resting organism, and bactericidal – to
multiplying organism
Mechanism of Action.
• Isoniazid is a prodrug; mycobacterial catalase-peroxidase converts
isoniazid into an active metabolite.
• A primary action of isoniazid is to inhibit the biosynthesis of mycolic
acids-long, branched lipids that are attached to a unique
polysaccharide, arabino galactan, to form part of the mycobacterial
cell wall.
• Its main targets are 2-trans-enoyl-acyl carrier protein reductase
enzyme InhA and β-ketoacyl-acyl carrier protein synthases KasA
enzyme.
• Isoniazid also inhibits mycobacterial catalase-peroxidase (the
isoniazid-activating enzyme), which may increase the likelihood of
damage to the mycobacteria from reactive oxygen species and
H2O2.
Resistance
• The most common mechanism of isoniazid resistance is
mutations in catalase-peroxidase (katg) gene
,preventing conversion of the prodrug isoniazid to its
active metabolite .
• Mutation in the mycobacterial inhA and KasA genes
involved in mycolic acid biosynthesis.
• cross-resistance between isoniazid and other agents
used to treat tuberculosis (except ethionamide, which is
structurally related to isoniazid) does not occur.
Pharmacokinetics
• Isoniazid is readily absorbed when administered
either orally or parenterally
• Fatty food & aluminum-containing antacids may
reduce absorption
• Isoniazid diffuses readily into all body fluids and
cells, CSF penetration: 20% of plasma
concentration with non-inflamed meninges
• Penetrate well into caseous material and
macrophages so it is effective against intra and
extracellular organisms.
• Metabolized in liver by acetylation
• Metabolism By enzymatic acetylation – genetically
determined
-Slow acetylation – better response (Scandinavians, Jews,
and North African Caucasians)- t ½ - 2-5h
-Fast acetylation(Japanese) – t ½ - 70 min
• The half-life of the drug may be prolonged by hepatic
insufficiency.
• Because isoniazid is relatively nontoxic????, a sufficient
amount of drug can be administered to fast acetylators to
achieve a therapeutic effect equal to that seen in slow
acetylators.
• Excreted mainly in urine within 24 hours, mostly as
metabolites.
Therapeutic Uses
• Mycobacterial infections (it is recommended to be given
with pyridoxine to avoid peripheral and CNS toxicity in
malnourished patients and those predisposed to
neuropathy , elderly, pregnant women, HIV-infected
individuals, diabetics, alcoholics, and uremics).
• Latent tuberculosis in patients with positive tuberculin
skin test.
• Prophylaxis against active TB in individuals who are in
great risk as very young or immunocompromised
individuals.
Adverse Effects
• Peripheral neuritis (most commonly paresthesias
of feet and hands). Neuropathy is more frequent
in slow acetylators and in individuals with
diabetes mellitus, poor nutrition, or anemia
• Optic neuritis.
• Allergic reactions ( fever,skin rash,systemic lupus
erythematosus )
• Hepatitis
• Gastric upset
• Haemolytic anaemia
• Enzyme inhibitor
• CNS toxicity
Rifamycins
Rifampin, rifabutin and
rifapentine
• Rifampin, rifabutin, and rifapentine are all
considered to be rifamycins, a group of
structurally similar macrocyclic antibiotics,
which are first-line drugs for tuberculosis.
• Any of these rifamycins must always be used
in conjunction with at least one other
antituberculosis drug to which the isolate is
susceptible
Rifampin
• It has a broader antimicrobial activity , but
due to resistant strains rapidly emerge during
therapy, it is never given as a single agent in
the treatment of active tuberculosis.
• Rifampin is bactericidal for both intracellular
and extracellular microorganisms
• Rifampin and isoniazid are the most effective
drugs available for the treatment of
tuberculosis.
Mechanism of action
• Rifampin blocks transcription by interacting
with bacterial but not human DNA-dependent
RNA polymerase.
• Rifampin inhibits mRNA synthesis by
suppressing the initiation step (suppression of
initiation of chain formation (but not chain
elongation) in RNA synthesis.
• High concentrations of rifamycin antibiotics
can inhibit RNA synthesis in mammalian
mitochondria.
Resistance
• Resistance to rifampin can be caused by a mutation in
the affinity of the bacterial DNA-dependent RNA
polymerase for the drug
• Decreased permeability.
Pharmacokinetics
• Well absorbed orally.
• Highly protein bind .
• Penetrates macrophages so affect extra and intracellular
organisms.
• Adequate CSF conc. Only in meningeal inflammation.
• Excreted mainly through liver into bile.
Antimicrobial spectrum
• Rifampin is bactericidal for both intracellular and
extracellular mycobacteria including M. tuberculosis,
and atypical mycobacteria, such as M. kansasii.
• It is effective against many gram-positive and gramnegative organisms as Escherichia coli, Pseudomonas,
Proteus, and Klebsiella. and is frequently used
prophylactically for individuals exposed to meningitis
caused by meningococci or Haemophilus influenzae.
• To delay the emergence of resistant strains, it is
usually given in combination with other drugs.
Therapeutic Uses
• Mycobacterial infections; Rifampin for oral
administration is available alone and as a fixed-dose
combination with isoniazid (150 mg of isoniazid, 300
mg of rifampin; RIFAMATE) or with isoniazid and
pyrazinamide (50 mg of isoniazid, 120 mg of rifampin,
and 300 mg pyrazinamide; RIFATER).
• Prophylaxis in contacts of children with meningococcal
disease and meningitis due to Haemophilus influenzae
type b disease.
• Treatment of serious staphylococcal infections as
osteomyelitis and endocarditis.
• Meningitis by highly resistant penicillin pneumococci.
Adverse effects
• Nausea, vomiting, and rash
• Harmless red-orange colour urine, sweat, tears, and
contact lenses.
• Hepatitis and death due to liver failure is rare; however,
the drug should be used judiciously in patients who are
alcoholic, elderly, or have chronic liver disease due to the
increased incidence of severe hepatic dysfunction when
rifampin is administered alone or concomitantly with other
anti TB drugs as isoniazid.
• a flu-like syndrome is associated with fever, chills, and
myalgias and sometimes is associated with interstitial
nephritis, acute tubular necrosis, thrombocytopenia,
hemolytic anemia, acute renal failure, and shock.
• Potent CYP-P450 inducer- reduce the serum
level of drugs as warfarin, oestrogen, nonnucleoside reverse transcriptase inhibitors,
digitoxin, digoxin, quinidine, disopyramide,
mexiletine, tocainide, ketoconazole,
propranolol, metoprolol, clofibrate, verapamil,
methadone, cyclosporine, corticosteroids, oral
anticoagulants, theophylline, barbiturates, oral
contraceptives, halothane, fluconazole, and
the sulfonylureas
-Rifabutin (orphan Drug):
• It is the preferred drug for use in tuberculosis infected
•
•
•
•
with the human immunodeficiency virus (HIV) patients
treated concurrently with protease inhibitors.
Rifabutin is a less potent inducer of CYPs.
It has the same mechanism of action as rifampin, and
utilized for treatment of Mycobacterium avium complex.
Rifabutin has adverse effects similar to those of rifampin
but can also cause skin hyperpigmentation, and
neutropenia.
About one-fourth of rifampin-resistant M. tuberculosis
isolates are rifabutin-sensitive, so it may have a role in th
treatment of multidrug-resistant tuberculosis.
-Rifapentine:
• It has activity comparable to that of rifampin
but has a longer half-life than rifampin and
rifabutin, which permits weekly dosing.
• It used alone but, rather, be included in a
three to four-drug regimen.
• It is intermediate in its induction of CYPs.
• Its use in the treatment of tuberculosis in HIVinfected patients was associated with the
selection of rifamycin resistance; rifabutin is
therefore preferred in this situation
Ethambutol
• Inhibits mycobacterial cell wall synthesis by inhibiting
arabinosyl transferase .
• Ethambutol is bacteriostatic against actively growing
TB bacilli.
• Ethambutol is used only in mycobacterial infections as
Tuberculosis, Mycobacterium avium complex (MAC)
and atypical mycobacteria, such as M. kansasii. .
• Ethambutol has no effect on other bacteria.
• It suppresses the growth of most isoniazid- and
streptomycin-resistant tubercle bacilli.
Mechanism of action
• It inhibits the formation of cell wall. Mycolic acids
attach to the 5'-hydroxyl groups of D-arabinose
residues of arabinogalactan and form mycolylarabinogalactan-peptidoglycan complex in the cell
wall. It disrupts arabinogalactan synthesis by inhibiting
the enzyme arabinosyl transferase. Disruption of the
arabinogalactan synthesis inhibits the formation of this
complex and leads to increased permeability of the
cell wall.
Resistance
• Bacterial resistance to ethambutol develops via single
amino acid mutations in the embA gene when
ethambutol is given in the absence of other effective
agents.
Pharmacokinetics
• Active against intra & extracellular bacilli.
• Well absorbed from gut.
• Crosses BBB in meningitis.
• 20% excreted in feces and 50% in urine in unchanged form
Therapeutic Uses
•
Ethambutol has been used with notable success in the therapy of
tuberculosis of various forms when given concurrently with
isoniazid.
• Because of a lower incidence of toxic effects and better
acceptance by patients, ethambutol has essentially replaced
aminosalicylic acid.
Adverse effects
• Optic neuritis causing loss of visual acuity and difficulty
to differentiate between red and green colors (redgreen color blindness). The intensity of the visual
difficulty is related to the duration of therapy. Recovery
usually occurs when ethambutol is withdrawn.
• Numbness and tingling of the fingers owing to
peripheral neuritis.
• It is relatively contraindicated in children, because of
concern about the ability to test their visual acuity.
• GIT .upset, malaise, headache, dizziness, mental
confusion, disorientation, and possible hallucinations .
• Hyperuricemia
Pyrazinamide
• Pyrazinamide is the synthetic pyrazine analog of
nicotinamide.
• It is converted to pyrazinoic acid ,the active form
(prodrug)
• Mechanism is unknown. However, the target of
pyrazinamide appears to be the mycobacterial fatty acid
synthase I enzyme nvolved in mycolic acid biosynthesis.
• Bactericidal in acidic pH. Activity at acid pH is ideal,
since M. tuberculosis resides in an acidic phagosome
within the macrophage=Acting on intracellular
organisms.
• Well absorbed orally ,metabolized in liver ,excreted
mainly through kidney.
Therapeutic Uses
• Pyrazinamide has become an important
component of short-term (6-month) multipledrug therapy of tuberculosis.
Adverse Effects
• Hepatotoxic
• Hyperuricemia ( provoke acute gouty arthritis )
• Nausea & vomiting
• Drug fever & skin rash
Streptomycin
• Life threating forms of TB ( meningitis,
dissiminated disease) as one of four drug
regimen .
• Resistant cases (Multidrug resistance
tuberculosis at least to INH & rifampicin) .
• Amikacin can be used as alternative to
streptomycin.
• Both active mainly against extracellular bacilli.
Indication of 2nd line treatment
•
•
•
•
Resistance to the drugs of 1st line.
Failure of clinical response
Increase of risky effects.
Patient is not tolerating the drugs
first line drugs.
Ethionamide
• As isoniazid, it blocks the synthesis of mycolic acid .
• Available only in oral form.
• Metabolized by the liver ,excreted by kidney.
• It is poorly tolerated because of :
-intense gastric irritation
-neurologic symptoms
-hepatotoxicity
• Used in treatment TB & leprosy.
Mechanism of Action
• In the manner of isoniazid, ethionamide is also an
inactive prodrug that is activated by a mycobacterial
redux system. EtaA, an NADPH-specific, FADcontaining monooxygenase, converts ethionamide to
a sulfoxide, and thence to 2-ethyl-4-aminopyridine.
• Ethionamide inhibits mycobacterial growth by
inhibiting the activity of the inhA gene product, the
enoyl-ACP reductase of fatty acid synthase II. This is
the same enzyme that activated isoniazid inhibits.
• Although the exact mechanisms of inhibition may
differ, the results are the same: inhibition of mycolic
acid biosynthesis and consequent impairment of cellwall synthesis.
Resistance
• Mutation in the mycobacterial inhA involved in
mycolic acid biosynthesis.
• Resistance can develop when ethionamide is used as
a single-agent treatment, and can include low-level
cross-resistance to isoniazid.
Therapeutic Uses
• Ethionamide is a secondary agent for T.B. treatment,
to be used concurrently with other drugs only when
therapy with primary agents is ineffective or
contraindicated.
Adverse Effects
• Anorexia, nausea and vomiting, gastric irritation.
• Variety of neurologic symptoms as blurred vision,
diplopia, dizziness, paresthesias, headache,
restlessness, and tremors. Pyridoxine (vitamin B6)
relieves the neurologic symptoms and its
concomitant administration is recommended.
• Severe postural hypotension, mental depression, and
drowsiness are common.
• Severe allergic skin rashes, purpura, stomatitis,
gynecomastia, impotence, menorrhagia, acne, and
alopecia also have been observed.
• Hepatotoxicity clear when treatment is stopped.
Aminosalicylic Acid
• It has similar structure to sulfonamide
and p-aminobenzoic acid.(Folate
synthesis inhibitor).
• Aminosalicylic acid is bacteriostatic.
• It is highly specific to T.B., and
microorganisms other than M.
tuberculosis are unaffected.
Mechanism of Action
• Aminosalicylic acid is a structural analog of
para-aminobenzoic acid, and its mechanism of
action appears to be very similar to that of the
sulfonamides.
• The sulfonamides are ineffective against M.
tuberculosis, and aminosalicylic acid is inactive
against sulfonamide-susceptible bacteria. This
differential sensitivity presumably reflects
differences in the enzymes responsible for
folate biosynthesis in the various
microorganisms.
Therapeutic Uses
• Aminosalicylic acid is a second-line agent. However, its use
decreased nowadays.
Adverse Effects
• Anorexia, nausea, epigastric pain, abdominal distress, and
diarrhe are predominant and often limit patient adherence.
Patients with peptic ulcers tolerate the drug especially poorly.
• Hypersensitivity reactions and fever.
• Generalized malaise, joint pains, and sore throat may be
present at the same time.
• Hematological abnormalities that have been observed are
leukopenia, agranulocytosis, eosinophilia, lymphocytosis, and
thrombocytopenia. Acute hemolytic anemia may appear in
some instances.
Cycloserine
• It is inhibitor of cell wall synthesis. Cycloserine and Dalanine are structural analogs; thus, cycloserine inhibits
reactions in which D-alanine is involved in bacterial
cell-wall synthesis
• Cycloserine is rapidly absorbed, and distributed
throughout body fluids and tissues, CSF concentrations
are approximately the same as those in plasma. About
50% of cycloserine is excreted unchanged in the urine
• There is no cross-resistance between cycloserine and
other tuberculostatic agents.
• When cycloserine is employed to treat resistant strains
of tuberculosis, it must be given together with other
effective agents.
Adverse Effects
• The most serious side effects are peripheral
neuropathy and CNS dysfunction, including headache,
tremor, vertigo, confusion, nervousness, irritability,
psychotic states with suicidal tendencies, paranoid
reactions, hyperreflexia, visual disturbances, and tonicclonic seizures. Pyridoxine should be given.
• The concomitant ingestion of alcohol increases the risk
of seizures.
• Should be used with caution in individuals with a
history of depression, as suicide is a risk
• Contraindicated in epileptic patients.
Capreomycin
• It is an important injectable agent for
treatment of drug-resistant tuberculosis.
• It is nephrotoxic and ototoxic.
• Local pain & sterile abscesses may occur.
Amikacin
• Used as alternative to streptomycin.
• Used in multidrug- resistance tuberculosis.
• No cross resistance between streptomycin and
amikacin.
Ciprofloxacin & levofloxacin
• Effective against typical and atypical
mycobacteria.
• Used against resistant strains.
• Used in combination with other drugs.