1
Aminoglycosides
.
are used for the treatment of serious infections due to aerobic gram-negative
bacilli. However, their clinical utility is limited by serious toxicities. The term
―aminoglycoside‖ stems from their structure—two amino sugars joined by a
glycosidic linkage to a central hexose nucleus. Aminoglycosides are derived
from either Streptomyces sp. (have –mycin suffixes) or Micromonospora sp.
Mechanism of action Aminoglycosides diffuse through porin channels in the
outer
membrane of
susceptible
organisms. Antibiotics
that
disrupt protein
synthesis
are
generally
bacteriostatic,
however
aminoglycosides
may
be
bactericidal against some microorganisms. The aminoglycosides are effective
for the majority of aerobic gram negative bacilli, including those that may be
multidrug resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae,
and Enterobacter sp.
Absorption: The highly polar, polycationic structure of the aminoglycosides
prevents adequate absorption after oral administration. It is administered
topically for skin infections or orally for bowel preparation. More than 90% of
the parenteral aminoglycosides are excreted unchanged in the urine.
Adverse effects
Therapeutic drug monitoring of gentamicin, tobramycin, and amikacin plasma
levels is imperative to ensure adequacy of dosing and to minimize dose-related
toxicities.The
elderly
are
particularly
susceptible
to
nephrotoxicity
and
ototoxicity.
1. Ototoxicity: Ototoxicity (vestibular and auditory) is directly related to high
peak plasma levels and the duration of treatment. The antibiotic accumulates in
the endolymph and perilymph of the inner ear. Deafness may be irreversible and
has been known to affect developing fetuses. Patients simultaneously receiving
concomitant ototoxic drugs, such as cisplatin or loop diuretics, are particularly
at risk. Vertigo (especially in patients receiving streptomycin) may also occur.
2. Nephrotoxicity: Retention of the aminoglycosides by the proximal tubular
cells disrupts calcium-mediated transport processes. This results in kidney
damage ranging from mild, reversible renal impairment to severe, potentially
irreversible, acute tubular necrosis.
3. Neuromuscular paralysis: This adverse effect is associated with a rapid
increase in concentrations (for example, high doses infused over a short period.)
or
concurrent
administration
with
neuromuscular
blockers.
Patients
with
myasthenia gravis are particularly at risk. Prompt administration of calcium
2
gluconate or neostigmine can reverse the block that causes neuromuscular
paralysis.
4. Allergic reactions: Contact dermatitis is a common reaction to topically
applied neomycin.
Spectinomycin
Spectinomycin is an aminocyclitol antibiotic that is structurally related to
aminoglycosides. It lacks amino sugars and glycosidic bonds. spectinomycin is
used almost solely as an alternative treatment for gonorrohea in patients who are
allergic to penicillin or whose gonococci are resistant to other drugs. Strains of
gonococci may be resistant to spectinomycin, but there is no cross-resistance
with other drugs used in gonorrhea. Spectinomycin is rapidly absorbed after
intramuscular injection. Side effects ( pain at the injection site , fever , nausea,
nephrotoxicity and anemia ).
*****************************************************
TETRACYCLINES
Tetracyclines consist of four fused rings with a system of conjugated double
bonds. Substitutions on these rings alter the individual pharmacokinetics and
spectrum of antimicrobial activity.
A. Mechanism of action
Tetracyclines enter susceptible organisms via passive diffusion and also by an
energy-dependent
transport
protein
mechanism
to
the
inner
bacterial
cytoplasmic membrane. Tetracyclines concentrate intracellularly in susceptible
organisms. The drugs bind reversibly to the bacterial ribosome. This action
prevents binding of tRNA to the mRNA–ribosome complex, thereby inhibiting
bacterial protein synthesis.
B. Antibacterial spectrum
The tetracyclines are bacteriostatic antibiotics effective against a wide variety of
organisms,
including
gram-positive
and
gram-negative
bacteria,
protozoa,
spirochetes, mycobacteria, and atypical species. They are commonly used in the
treatment of acne and Chlamydia infections (doxycycline).
D. Pharmacokinetics
1. Absorption: Tetracyclines are adequately absorbed after oral ingestion .
Administration with dairy products or other substances that contain divalent and
trivalent cations (for example,magnesium and aluminum antacids or iron
supplements) decreases absorption, particularly for tetracycline due to the
3
formation of nonabsorbable chelates . Both doxycycline and minocycline are
available as oral and intravenous (IV) preparations.
2. Distribution: The tetracyclines concentrate well in the bile, liver, kidney,
gingival fluid, and skin. Moreover, they bind to tissues undergoing calcification
(for example, teeth and bones) or to tumors that have a high calcium content.
Penetration
into
most
body
fluids
is
adequate.
Only
minocycline
and
doxycycline
achieve
therapeutic
levels
in
the
cerebrospinal
fluid
(CSF).
Minocycline also achieves high levels in saliva and tears, rendering it useful in
eradicating the meningococcal carrier state. All tetracyclines cross the placental
barrier and concentrate in fetal bones and dentition.
3. Elimination: Tetracycline and doxycycline are not hepatically metabolized.
Tetracycline is primarily eliminated unchanged in th urine, whereas minocycline
undergoes hepatic metabolism and is eliminated to a lesser extent via the
kidney. In renally compromised patients, doxycycline is preferred, as it is
primarily eliminated via the bile into the feces.
E. Adverse effects
1. Gastric discomfort: Epigastric distress commonly results from irritation of
the gastric mucosa and is often responsible for noncompliance with
tetracyclines. Esophagitis may be minimized through coadministration with
food (other than dairy products) or fluids and the use of capsules rather than
tablets. [Note: Tetracycline should be taken on an empty stomach.]
2. Effects on calcified tissues: Deposition in the bone and primary dentition
occurs during the calcification process in growing children. This may cause
discoloration and hypoplasia of teeth and a temporary stunting of growth. The
use of tetracyclines is limited in pediatrics.
3.
Hepatotoxicity:
Rarely
hepatotoxicity
may
occur
with
high
doses,
particularly in pregnant women and those with preexisting hepatic dysfunction
or renal impairment.
4. Phototoxicity: Severe sunburn may occur in patients receiving a tetracycline
who are exposed to sun or ultraviolet rays. This toxicity is encountered with any
tetracycline, but more frequently with tetracycline and demeclocycline .Patients
should be advised to wear adequate sun protection.
5.
Vestibular
dysfunction:
Dizziness,
vertigo,
and
tinnitus
may
occur
particularly with minocycline, which concentrates in the endolymph of the ear
and affects function. Doxycycline may also cause vestibular dysfunction.
6. Pseudotumor cerebri: Benign, intracranial hypertension characterized by
headache
and
blurred
vision
may
occur
rarely
in
adults.
Although
4
discontinuation of the drug reverses this condition, it is not clear whether
permanent sequelae may occur.
7. Contraindications: The tetracyclines should not be used in pregnant or
breast-feeding women or in children less than 8 years of age.
=====================================================================================================
MACROLIDES AND KETOLIDES
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 with an allergy to β-lactam
antibiotics. Clarithromycin (a methylated form of erythromycin) and azithromycin (having a larger
lactone ring) have some features in common with, and others that improve upon, erythromycin.
Telithromycin
a semisynthetic derivative of erythromycin, is the first ―ketolide‖ antimicrobial agent.
Ketolides and macrolides have similar antimicrobial coverage. However, the ketolides are active
against many macrolide-resistant gram-positive strains.
Mechanism of action
The macrolides bind irreversibly to the bacterial ribosome, thus inhibiting protein synthesis. Generally
considered to be bacteriostatic, they may be bactericidal at higher doses.
Antibacterial spectrum
1. Erythromycin: This drug is effective against many of the same organisms as penicillin G
.Therefore, it may be used in patients with penicillin allergy.
2. Clarithromycin: Clarithromycin has activity similar to erythromycin,
but it is also effective
against Haemophilus influenzae. Its activity
against intracellular pathogens, such as Chlamydia,
Legionella,
Moraxella, Ureaplasma species and Helicobacter pylori, is higher
than that of
erythromycin.
3. Azithromycin: Although less active against streptococci and staphylococci than erythromycin,
azithromycin is far more active against respiratory infections due to H. influenzae and Moraxella
catarrhalis.
4. Telithromycin: This drug has an antimicrobial spectrum similar to that of azithromycin.
Pharmacokinetics
1. Administration: The erythromycin base is destroyed by gastric acid. Thus, either enteric-coated
tablets or esterified forms of the antibiotic are administered. All are adequately absorbed upon oral
administration . Clarithromycin, azithromycin, and telithromycin are stable in stomach acid and are
readily absorbed. Erythromycin and azithromycin are available in IV formulations.
2. Distribution: Erythromycin distributes well to all body fluids except the CSF. It is one of the few
antibiotics that diffuses into prostatic fluid, and it also accumulates in macrophages. All four drugs
concentrate in the liver. Clarithromycin, azithromycin, and telithromycin are widely distributed in the
tissues. Azithromycin concentrates in neutrophils, macrophages, and fibroblasts, and serum levels are
low. It has the longest half-life and the largest volume of distribution of the four drugs .
5
3. Excretion: Erythromycin and azithromycin are primarily concentrated and excreted in the bile as
active drugs . Partial reabsorption occurs through the enterohepatic circulation. In contrast,
clarithromycin and its metabolites are eliminated by the kidney as well as the liver. The dosage of this
drug should be adjusted in patients with renal impairment.
Adverse effects
1. Gastric distress and motility: Gastric upset is the most common adverse effect of the macrolides
and may lead to poor patient compliance (especially with erythromycin). Clarithromycin and
azithromycin seem to be better tolerated . Higher doses of erythromycin lead to smooth muscle
contractions that result in the movement of gastric contents to the duodenum, an adverse effect
sometimes used therapeutically for the treatment of gastroparesis or postoperative ileus.
2. Cholestatic jaundice: This side effect occurs especially with the estolate form (not used in the
United States) of erythromycin.
3. Ototoxicity: Transient deafness has been associated with erythromycin,
especially at high dosages.
Azithromycin has also been associated with irreversible sensorineural hearing loss.
4. Contraindications: Patients with hepatic dysfunction should be treated cautiously with
erythromycin, telithromycin, or azithromycin, because these drugs accumulate in the liver.
==================================================================
CHLORAMPHENICOL
The use of chloramphenicol a broad-spectrum antibiotic, is restricted to life-threatening infections for
which no alternatives exist.
Mechanism of action
Chloramphenicol binds reversibly to the bacterial ribosom and inhibits protein synthesis. Due to some
similarity of mammalian mitochondrial ribosomes to those of bacteria, protein and ATP synthesis in
these organelles may be inhibited at high circulating chloramphenicol levels, producing bone marrow
toxicity. [Note: The oral formulation of chloramphenicol was removed from the US market due to this
toxicity.]
Antibacterial spectrum
Chloramphenicol is active against many types of microorganisms including chlamydiae, rickettsiae,
spirochetes, and anaerobes. The drug is primarily bacteriostatic, but depending on the dose and
organism, it may be bactericidal.
Pharmacokinetics
Chloramphenicol is administered intravenously and is widely distributed throughout the body. It
reaches therapeutic concentrations in the CSF. Chloramphenicol primarily undergoes hepatic
metabolism (glucuronidation) and secreted by the renal tubule and eliminated in the urine. Dose
reductions are necessary in patients with liver dysfunction or cirrhosis. It is also secreted into breast
milk and should be avoided in breast feeding mothers.
6
Adverse effects
1. Anemias: Patients may experience dose-related anemia, hemolytic anemia (seen in patients with
glucose-6-phosphate dehydrogenase deficiency), and aplastic anemia. [Note: Aplastic anemia is
independent of dose and may occur after therapy has ceased.]
2. Gray baby syndrome: Neonates have a low capacity to glucuronidate the antibiotic, and they have
underdeveloped renal function. Therefore, neonates have a decreased ability to excrete the drug,
which accumulates to levels that interfere with the function of mitochondrial ribosomes. This leads to
poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term ―gray baby‖),
and death. Adults who have received very high doses of the drug can also exhibit this toxicity.
3. Drug interactions: Chloramphenicol inhibits some of the hepatic mixed-function oxidases and,
thus, blocks the metabolism of drugs such as warfarin and phenytoin, thereby elevating their
concentrations and potentiating their effects.
CLINDAMYCIN
Clindamycin has a mechanism of action that is the same as that of erythromycin. Clindamycin is used
primarily in the treatment of infections caused by gram-positive organisms, including MRSA
(methislin res. Staph.) and streptococcus, and anaerobic bacteria. Resistance mechanisms are the same
as those for erythromycin, and cross-resistance has been described. C. difficile is always resistant to
clindamycin, and the utility of clindamycin for gram-negative anaerobes (for example, Bacteroides
sp.) is decreasing due to increasing resistance. Clindamycin is available in both IV and oral
formulations, but use of the oral form is limited by gastrointestinal intolerance. It distributes well into
all body fluids including bone,but exhibits poor entry into the CSF. Clindamycin undergoes extensive
oxidative metabolism to inactive products and is primarily excreted into the bile. Low urinary
elimination limits its clinical utility for urinary tract infections . Accumulation has been reported in
patients with either severe renal impairment or hepatic failure. In addition to skin rashes, the most
common adverse effect is diarrhea, which may represent a serious pseudomembranous colitis caused
by overgrowth of C. difficile. Oral administration of either metronidazole or vancomycin is usually
effective in the treatment of C. difficile.
=====================================================================
Antifolate
Drugs Sulfonamides (
Sulfacytine, Sulfisoxazole, Sulfamethizole, Sulfadiazine,
Sulfamethoxazole, Sulfapyridine, Sulfadoxine, Pyrimidines,
Trimethoprim).
Susceptible microorganisms require extracellular PABA(p-aminobenzoic acid) in order to
form dihydrofolic acid an essential step in the production of purines and the synthesis of
nucleic acids. Sulfonamides are structural analogs of PABA that competitively inhibit
dihydropteroate synthase.
7
Sulfonamides inhibit both gram- positive and gram-negative bacteria, nocardia, Chlamydia
trachomatis, and some protozoa. Some enteric bacteria, such as E coli, klebsiella,
salmonella, shigella, and enterobacter, are inhibited.
Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral,
nonabsorbable; and (3) topical. Sodium salts of sulfonamides in 5% dextrose in water can
be given intravenously. They are absorbed from the stomach and small intestine and
distributed widely to tissues and body fluids (including the central nervous system and
cerebrospinal fluid), placenta, and fetus. Sulfonamides are excreted into the urine.
Clinical Uses
Oral Absorbable Agents
1.urinary tract infections, sulfisoxazole or sulfamethoxazole.
2.acute toxoplasmosis: Sulfadiazine with pyrimethamine .Folinic acid, should also be
administered to minimize bone marrow suppression.
Oral Nonabsorbable Agents
Sulfasalazine is widely used in ulcerative colitis, enteritis, and other inflammatory bowel
disease.
Topical Agents
1.Bacterial conjunctivitis and : Sodium sulfacetamide.
2.Burn wounds : Silver sulfadiazine is a much less toxic topical sulfonamide and is used for
prevention of infection of burn wounds.
Adverse Reactions:
fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and
difficulties referable to the urinary tract. Stevens-Johnson syndrome, potentially fatal type (eruption
of skin & mucous membrean)in 1%.
Trimethoprim & Trimethoprim-Sulfamethoxazole Mixtures
Trimethoprim, inhibits bacterial dihydrofolic acid reductase leading to inhibition of the synthesis of
purines and ultimately to DNA. Trimethoprim & pyrimethamine, given together with sulfonamides,
resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is
bactericidal, compared to the bacteriostatic activity of a sulfonamide alone.
Pharmacokinetics
Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, the
latter chosen because it has a similar half-life. Trimethoprim-sulfamethoxazole can also be
given intravenously. Trimethoprim is absorbed efficiently from the gut and distributed
widely in body fluids and tissues, including cerebrospinal fluid, sulfonamide and of the
trimethoprim (or their respective metabolites) are excreted in the urine within 24
hours.Trimethoprim concentrates in prostatic fluid and in vaginal fluid, which are more
8
acidic than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal
fluids than many other antimicrobial drugs.
Clinical Uses
a.Oral Trimethoprim
Trimethoprim can be given alone in acute urinary tract infections.
b.Oral Trimethoprim-Sulfamethoxazole
combination of trimethoprim-sulfamethoxazole (cotrimoxazole)is effective treatment for
pneumonia,
shigellosis,
systemic
salmonella
infections
(caused
by
ampicillin-
or
chloramphenicol-resistant organisms), complicated urinary tract infections, prostatitis,
some nontuberculous mycobacterial infections, , upper respiratory tract infections
and community-acquired bacterial pneumonia.
c.Intravenous Trimethoprim-Sulfamethoxazole
A solution of the mixture containing trimethoprim plus sulfamethoxazole diluted in 5%
dextrose in water can be administered by intravenous infusion s. It is the agent of choice
for moderately severe to severe pneumocystis pneumonia, gram-negative bacterial
sepsis; shigellosis; typhoid fever; or urinary tract infection caused by a susceptible
organism when the patient is unable to take the drug by mouth.
Adverse Effects
megaloblastic anemia, leukopenia, and granulocytopenia. This can be prevented by the
simultaneous administration of folinic acid. In addition, the combination trimethoprim-
sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides.
Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system
disturbances occasionally occur also.
==================================================================
DNA Gyrase Inhibitors
Fluoroquinolones (Ciprofloxacin, Clinafloxacin, Enoxacin, Gatifloxacin, Levofloxacin,
Lomefloxacin, Moxifloxacin, Norfloxacin, Ofloxacin, Sparfloxacin, Trovafloxacin).They
are active against a variety of gram-positive and gram-negative bacteria. Quinolones
block bacterial DNA synthesis by inhibiting bacterial DNA gyrase. Inhibition of DNA
gyrase prevents the normal transcription and replication.
Pharmacokinetics
After
oral
administration,
the
fluoroquinolones
are
well
absorbed
and
distributed widely in body fluids and tissues. Serum half-lives range from 3
hours up to 10. The relatively long half-lives of levofloxacin, moxifloxacin,
sparfloxacin, and trovafloxacin permit once-daily dosing.
. Most fluoroquinolones are eliminated by renal mechanisms, either tubular
secretion or glomerular filtration. Nonrenally cleared fluoroquinolones are
contraindicated in patients with hepatic failure.
9
Clinical Uses
1-urinary tract infections Norfloxacin, ciprofloxacin, and ofloxacin given
orally twice daily are all effective.
2-bacterial diarrhea ( shigella, salmonella, toxigenic E coli, or campylobacter)
3- infections of soft tissues, bones, and joints and in intra-abdominal and
respiratory tract infections Fluoroquinolones (except norfloxacin, which does
not
achieve
adequate
systemic
concentrations)
have
been
employed
in,
including those caused by multidrug-resistant organisms such as pseudomonas
and enterobacter.
4-gonococcal infection: Ciprofloxacin and ofloxacin
5-chlamydial urethritis or cervicitis ofloxacin is effective for.
Owing to their marginal activity against the pneumococcus, fluoroquinolones
have not been routinely recommended for empirical treatment of pneumonia
and other upper respiratory tract infections.
Adverse Effect
Fluoroquinolones are extremely well tolerated. The most common effects are
nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, insomnia,
skin rash, or abnormal liver function tests develop. Fluoroquinolones may
damage growing cartilage and cause an arthropathy. Thus, they are not
routinely recommended for use in patients under 18 years of age. However, the
arthropathy
is
reversible,
and
there
is
a
growing
consensus
that
fluoroquinolones may be used in children in some cases (eg, for treatment of
pseudomonal infections in patients with cystic fibrosis).
Nalidixic Acid & Cinoxacin
Nalidixic acid, the first antibacterial quinolone. It is excreted too rapidly to
be useful for systemic infections. Their mechanism of action is the same as
that of the fluoroquinolones. These agents were useful only for the treatment
of urinary tract infections and are rarely used now.