Mechanisms of antimicrobial drug action:
- Inhibition of cell wall synthesis
- Cell membrane function inhibitors
- Inhibition of protein synthesis
- Inhibition of nucleic acid synthesis
- Antimetabolites
Mechanisms of resistance to antibiotics - Production of enzymes that inactivate the drug (eg. β -lactamase, which inactivates beta
lactam antibiotics; acetyl transferases, which inactivate chloramphenicol; kinases and
other enzymes, which inactivate aminoglycosides.
146 - Alteration of the drug-binding site: this occurs with penicillins, aminoglycosides and
erythromycin. - Reduction of drug uptake by the bacterium: eg. Tetracyclines
- Alteration of enzymes: eg. Dihydrofolate reductase becomes insensitive to trimethoprim.
Anibacterial agents
Cell wall synthesis inhibitors
Members the group: Beta-lactam antibiotics, vancomycin, bacitracine, and cycloserine
Beta-lactam antibiotics: Penicillins, cephalosporins, carbapenems, and monobactams are
members of the family. All members of the family have a beta-lactam ring and a carboxyl group
resulting in similarities in the pharmacokinetics and mechanism of action of the group members.
They are water-soluble, elimination is primary renal and organic anion transport system is used.
Penicillins
Penicillins have similar structure, pharmacological and toxicological properties. The prototype
of penicillins is penicillin G and is naturally derived from a genus of moulds called penicillium.
Classification: Penicillins can be classified into three groups: Natural Penicillins,
Antistaphylococcal penicillins, and Extended-spectrum penicillins.
Mechanism of Action: Penicillins inhibit bacterial growth by interfering with a specific step in
bacterial cell wall synthesis (block the transpeptidation reaction). Sensitive pencillins are
inactivatived by betalactamase enzymes.
Pharmacokinetics: Penicillin G is unstable in acid media, hence destroyed by gastric juice.
Ampicillin, amoxicillin, and dicloxacillin are acid-stable and relatively well absorbed after oral
adminstraion. Oral penicillins should be given 1-2 hours before or after meals to minimize
binding to food proteins and acid inactivation (except ampicilin). The absorption of most
penicillin is complete and rapid after IM administration. The kidneys rapidly excrete penicillin.
Renal excretion is by glomerular filtration (10%) and by tubular secretion (90%). Blood levels of
all penicillins can be raised by simultaneous administration of probenecid orally, which impairs
tubular secretion of weak acids.
Clinical Uses
Natural Penicillins: Penicillin G and penicillin V are natural penicillins. Penicillin G is the drug of
choice for infections caused by streptococci, meningococci, enterococci, penicillin-susceptible
pneumococci, non-beta-lactamase-producing staphylococci, Treponema pallidum and many
other spirochetes, Bacillus anthracis, Clostridium species, Actinomyces, and other grampositive rods and non-beta-lactamase-producing gram-negative anaerobic organisms. Penicillin
V is acid stable but it is less potent than penicillin G.
Antistaphylococcal Penicillins: [Methicillin, Nafcillin, isoxazolyl penicillins (Oxacillin, cloxacillin,
and dicloxacillin)]. The only indication is infections caused by beta-lactamase-producing
staphylococci. Oral isoxazolyl penicillin is suitable for treatment of mild localized staphylococcal
infections, for serious systemic staphylococcal infections, oxacillin or nafcillin, is given by
intermittent intravenous infusion.
Extended Spectrum Penicillins: Aminopenicillins (ampicillin, amoxicillin), Carboxypenicillins
(Carbenicillin, ticarcillin, effective at lower doses), and Ureidopenicillins (piperacillin, mezlocillin,
and azlocillin): Spectrum of activity similar to penicillin G, though having greater activity against
gram-negative bacteria due to their enhanced ability to penetrate the gram-negative outer
membrane. The aminopenicillins have the same spectrum and activity, but amoxicillin is better
absorbed from the gut. These drugs are given orally to treat urinary tract infections, sinusitis,
otitis, and lower respiratory tract infections. Ampicillin IV is useful for treating serious infections
caused by penicillin-susceptible organisms, including anaerobes, enterococci, Listeria
monocytogenes, and susceptible strains of gram-negative cocci and bacilli such as E coli, H
influenzae, and Salmonella species. Carboxypenicillins extend the ampicillin spectrum of
activity to include Pseudomonas aeruginosa and Enterobacter species. The ureidopenicillins
resemble ticarcillin except that they are also active against selected gram-negative bacilli, such
as Klebsiella pneumoniae. Because of the tendency of P aeruginosa to develop resistance
during monotherapy, antipseudomonal penicillins generally is used in combination with an
aminoglycoside for pseudomonal infections.
Adverse Reactions: Grouped into three: Allergy: Cross sensitivity and cross reactivity among
beta-lactams is common. Reactions include: Skin rashes, fever, bronchospasm, Oral lesions,
interstitial nephritis (autoimmune reaction to penicillin-protein complex), eosinophilia, hemolytic
anemia, vasculitis and anaphylactic shock. Biological: antibiotic assoicated enterocolitis
(ampicillin), and Toxic: diarrhea (ampicillin), nephritis, especially methicillin, and platelet
dysfunction (antipseudomonal penicillins).
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Cephalosporins
Cephalosporins can be classified into four generations depending mainly on the spectrum of
antimicrobial activity. First-generation compounds have better activity against gram-positive
organisms and the later compounds exhibit improved activity against gram-negative aerobic
organisms.
First-generation cephalosporins
Members: Cefadroxil, cefazolin, cephalexin, and cephalothin. These drugs are very active
against gram-positive cocci (pneumococci, streptococci, and staphylococci). Escherichia coli,
Klebsiella pneumoniae, and Proteus mirabilis are often sensitive, but activity against
Pseudomonas aeruginosa, indole-positive Proteus, Enterobacter, Serratia marcescens,
Citrobacter, and Acinetobacter is poor. Anaerobic cocci (eg, Peptococcus, Peptostreptococcus)
are usually sensitive, but B fragilis is not.
Cephalexin, and cefadroxil are absorbed from the gut to a variable extent. Urine concentration
is usually very high, but in most tissues levels are and generally lower than in serum. Cefazolin
is given IM/IV (the only first generation administered parentrally). Excretion is via the kidney
and probenecid may increase serum levels substantially.
Clinical Uses: Oral drugs may be used for the treatment of urinary tract infections, for minor
staphylococcal lesions, or for minor polymicrobial infections such as cellulitis or soft tissue
abscess.
Second-generation cephalosporins
Members: Cefaclor, cefamandole, and cefuroxime. The group is heterogeneous, with marked
individual differences in activity, pharmacokinetics, and toxicity. All second-generation
cephalosporins are less active against gram-positive bacteria than the first-generation drugs;
however, they have an extended gram-negative coverage. Klebsiella and H influenzae are
usually sensitive. Can be given orally or parentrally
Clinical Uses: Sinusitis, otitis, or lower respiratory tract infections, mixed anaerobic infections,
and community-acquired pneumonia.
Third-generation cephalosporins
Members: cefotaxime, ceftazidime, ceftriaxone, and proxetil.
Antimicrobial activity: The major features of these drugs are the ability of some to cross the
blood-brain barrier and their expanded gram-negative coverage (active against Citrobacter,
Serratia marcescens, Providencia, and beta-lactamase-producing strains of Haemophilus and
Neisseria). Ceftazidime is effective in pseudomonas infections.
They can be given orally or IM or IV. They penetrate body fluids and tissues well. Cefotaxime,
ceftazidim, and ceftriaxone crosses blood brain barrier, hence inhibit most pathogens, including
gram-negative rods.
Clinical uses: Gonorrhea (ceftriaxone and cefixime), meningitis (pneumococci, meningococci, H
influenzae, and susceptible enteric gram-negative rods), penicillin-resistant strains of
pneumococci (ceftriaxone, cefotaxime), and sepsis
Fourth-generation cephalosporins (e.g.cefepime)
It is similar to third-generation agents; however, it is more resistant to hydrolysis by betalactamases. It has good activity against P aeruginosa.
Adverse Effects: Cephalosporins are sensitizing and may elicit a variety of hypersensitivity
reactions that are identical to those of penicillins. Overgrowth of resistant organisms and fungi
may induce superinfection.
Monobactams contain a monocyclic beta-lactam ring(e.g. aztreonam). They are relatively
resistant to beta-lactamases and active against gram-negative rods. It resembles
aminoglycosides in its spectrum of activity.
Carbapenems include imipenem and meropenem and have a broad spectrum of activity
(against most Gram-positive and negative bacteria). Imipenem is inactivated by a renal
proteolytic enzyme and must therefore be combined with cilastatin which inhibits the enzyme.
Beta-lactamase inhibitors: (clavulanic acid, sulbactam, and tazobactam).
They have no antimicrobial activity, and usually combined with beta lactamase labile antibiotics,
irreversibly inhibit beta-lactamases. Examples: Ticarcillin and clavulanate [Timentin], Ampicillin
and sulbactam [Unasyn], Amoxicillin and clavulanate [Augmentin]
Vancomycin
Vancomycin is active only against gram-positive bacteria, particularly staphylococci. It inhibits
cell wall synthesis.
Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the
treatment of antibiotic-associated enterocolitis caused by Clostridium difficile. Parenteral doses
must be administered intravenously. The drug is widely distributed in the body. Ninety percent
of the drug is excreted by glomerular filtration.
Clinical Uses: Parenteral vancomycin is indicated for sepsis or endocarditis caused by
methicillin-resistant staphylococci. It irritates the tissues surrounding the injection site and is
known to cause a red man or red neck syndrome.
Bacitracin
Bacitracin is active against gram-positive microorganisms. It inhibits cell wall formation. It is
markedly nephrotoxic if administered systemically, thus limited to topical use. Bacitracin is
poorly absorbed.
Cycloserine
Cycloserine inhibits many gram-positive and gram-negative organisms, but it is used almost
exclusively to treat tuberculosis caused by strains of M tuberculosis resistant to first-line agents.
It is widely distributed in tissues. Most of the drug is excreted in active form into the urine.
Cycloserine causes serious dose-related central nervous system toxicity with headaches,
tremors, acute psychosis, and convulsions.
Cell Membrane Function Inhibitors
Antimirobials such as polymyxins acting on gram negative bacteria and affects the functional
integrity of the cytoplasmic membrane, macromolecules and ions escape from the cell and cell
damage and death occurs. The two most well known agents are poymyxin B and colistin.
Polymyxins are effective against Gram-negative bacteria, particularly pseudomonas species.
The major adverse effects are nephrotoxicity dizziness, alterd sensation and neuromuscular
paralysis.
Protien Synthesis Inhibitors
Bacteria have two ribosomal subunits; 30S and 50S. The 30S subunit binds mRNA in initiation
and holds growing peptide chain. The 50S subunit accepts / translocates charged tRNAs.
Protien synthesis inhibitors are divided into two groups: bacteriostatic and bactericidal.
Chloramphenicol, macrolides, clindamycin (Lincosamides), and tetracyclines are bacteriostatic
whereas aminoglycosides are bactericidal.
Mechanisms of action:
Chloramphenicol blocks proper binding of 50S site which, stops protein synthesis. It does
inhibit mitochondrial ribosomal protein synthesis because these ribosomes are 70S, the same
as those in bacteria. It does not bind to the 80S mammalian ribosomes. This may be
responsible for the dose related anemia caused by chloramphenicol.
Macrolides, clindamycin, prevent transfer of the growing polypeptide chain within the 50S site so
a new charged tRNA cannot bind to the ribosome so, stops protein synthesis.
Tetracyclines bind to 30S ribosomal subunit at a site that blocks binding of charged tRNA to the
50S site of the ribosome. Tetracyclines can inhibit mammalian protein synthesis, but because
they are “pumped” out of most mammalian cells do not usually reach concentrations needed to
significantly reduce mammalian protein synthesis.
Aminoglycosides: Protein synthesis is inhibited by aminoglycosides in at least three ways: (1)
They interfere with the “initiation complex” of peptide formation; (2) they induce misreading of
mRNA, which causes incorporation of incorrect amino acids into the peptide, resulting in a nonfunctional or toxic protein; and (3) they cause a breakup of polysomes into nonfunctional
monosomes. These activities occur more or less simultaneously, and the overall effect is
irreversible and lethal for the cell.
Chloramphenicol
Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic
and anaerobic gram-positive and gram-negative organisms. It is active also against rickettsiae.
Haemophilus influenzae, N. meningitidis, and some strains of Bacteroides are highly
susceptible, and for them chloramphenicol may be bactericidal. Clinically significant resistance
emerges and may be due to production of chloramphenicol acetyltransferase, an enzyme that
inactivates the drug.
Pharmacokinetics: Following oral administration, chloramphenicol is rapidly and completely
absorbed. It is widely distributed to virtually all tissues and body fluids. The drug penetrates cell
membranes readily. Excretion of active chloramphenicol and of inactive degradation products
occurs by way of the urine. A small amount of active drug is excreted into bile or feces.
Newborns less than a week old and premature infants clear chloramphenicol inadequately.
Clinical Uses: Because of potential toxicity, bacterial resistance, and the availability of other
effective drugs, chloramphenicol may be considered mainly for treatment of serious rickettsial
infections, bacterial meningitis caused by a markedly penicillin-resistant strain of pneumococcus
or meningococcus, and thyphoid fever.
Adverse Reactions
Gastrointestinal disturbances: Adults occasionally develop nausea, vomiting, and diarrhea. Oral
or vaginal candidiasis may occur as a result of alteration of normal microbial flora.
Bone marrow disturbances: Chloramphenicol commonly causes a dose-related reversible
suppression of red cell production at dosages exceeding 50 mg/kg/d after 1-2 weeks. Aplastic
anemia is a rare consequence of chloramphenicol administration by any route. It is an
idiosyncratic reaction unrelated to dose, though it occurs more frequently with prolonged use. It
tends to be irreversible and can be fatal.
Toxicity for newborn infants: Newborn infants lack an effective glucuronic acid conjugation
mechanism for the degradation and detoxification of chloramphenicol. Consequently, when
infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray
baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse.
Interaction with other drugs: Chloramphenicol inhibits hepatic microsomal enzymes that
metabolize several drugs. Like other bacteriostatic inhibitors of microbial protein synthesis,
chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides.
Tetracyclines
The tetracyclines are a large group of drugs with a common basic structure and activity.
Tetracyclines are classified as short acting (chlortetracycline, tetracycline, oxytetracycline),
intermediate acting (demeclocycline and methacycline), or long-acting (doxycycline and
minocycline) based on serum half-lives.
Antimicrobial activity: Tetracyclines are broad-spectrum antibiotics. They are active against for
many gram-positive and gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae,
mycoplasmas, and are active against some protozoa. The main mechanisms of resistance to
tetracycline is decreased intracellular accumulation due to either impaired influx or increased
efflux by an active transport protein pump.
Pharmacokinetics: Tetracyclines mainly differ in their absorption after oral administration and
their elimination. Doxycycline better absorbed after oral administration than tetracycline. A
portion of an orally administered dose of tetracycline remains in the gut lumen, modifies
intestinal flora, and is excreted in the feces. 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; and by alkaline pH. They are distributed widely to tissues and body fluids except for
cerebrospinal fluid. Minocycline reaches very high concentrations in tears and saliva, which
makes it useful for eradication of the meningococcal carrier state. Tetracyclines cross the
placenta to reach the fetus and are also excreted in milk. Doxycycline, in contrast to other
tetracyclines, is eliminated by nonrenal mechanisms.
Clinical uses: A tetracycline is the drug of choice in infections with Mycoplasma pneumoniae,
chlamydiae, rickettsiae, and some spirochetes. They are used in combination regimens to treat
gastric and duodenal ulcer disease caused by Helicobacter pylori. They may be employed in
various gram-positive and gram-negative bacterial infections, including Vibrio infections. A
tetracycline in combination with an aminoglycoside is indicated for plague, tularemia, and
brucellosis. Tetracyclines are sometimes employed in the treatment of E. histolytica or P.
falciparum.
Adverse reactions
Gastrointestinal adverse effects: Nausea, vomiting, and diarrhea are the most common and
these effects are attributable to direct local irritation of the intestinal tract. Tetracyclines
suppress susceptible coliform organisms and causes overgrowth of Pseudomonas, Proteus,
staphylococci, resistant coliforms, clostridia, and Candida. This can result in intestinal functional
disturbances, anal pruritus, vaginal or oral candidiasis, or enterocolitis (associated with
Clostridium difficile) with shock and death. Pseudomembranous enterocolitis should be treated
with metronidazole.
Bony structures and teeth: Tetracyclines are readily bound to calcium deposited in newly
formed bone or teeth in young children. It causes discoloration, and enamel dysplasia; they can
also be deposited in bone, where it may cause deformity or growth inhibition. If the drug is given
to children under 8 years of age for long periods, similar changes can result.
They are hepato and nephrotoxic drug, the also induce sensitivity to sunlight (demeclocycine)
and vestibular reactions (doxycycline, and minocycline).
Macrolides: include erythromycin, clarithromycin and azithromycin.
Erythromycin
Erythromycin is poorly soluble in water but dissolves readily in organic solvents. They
Erythromycins are usually dispensed as various esters and salts.
Antimicrobial Activity: Erythromycin is effective against gram-positive organisms, especially
pneumococci, streptococci, staphylococci, and corynebacteria. Mycoplasma, Legionella,
Chlamydia trachomatis, Helicobacter, Listeria, Mycobacterium kansasii, and Mycobacterium
scrofulaceum are also susceptible. Gram-negative organisms such as Neisseria species,
Bordetella pertussis, Treponema pallidum, and Campylobacter species are susceptible.
Pharmacokinetics: Erythromycin base is destroyed by stomach acid and must be administered
with enteric coating. Food interferes with absorption. Stearates and esters are fairly acidresistant and somewhat better absorbed. Large amounts of an administered dose are excreted
in the bile and lost in feces. Absorbed drug is distributed widely except to the brain and
cerebrospinal fluid.
Clinical Uses: Erythromycin is the drug of choice in corynebacterial infections (diphtheria,
corynebacterial sepsis, erythrasma); in respiratory, neonatal, ocular, or genital chlamydial
infections; and in treatment of community-acquired pneumonia because its spectrum of activity
includes the pneumococcus, Mycoplasma, and Legionella. Erythromycin is also useful as a
penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci,
streptococci, or pneumococci.
Adverse Reactions
Gastrointestinal Effects: Anorexia, nausea, vomiting, and diarrhea.
Liver Toxicity: Erythromycins, particularly the estolate, can produce acute cholestatic hepatitis
(reversibile).
155
Drug Interactions: Erythromycin metabolites inhibit cytochrome P450 enzymes; hence increase
the serum concentrations of theophylline, oral anticoagulants, and terfenadine. It increases
serum concentrations of oral digoxin by increasing its bioavailability.
Clarithromycin
Clarithromycin is derived from erythromycin. It is better absorbed compared with erythromycin.
Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity
except that clarithromycin has high activity against H. influenzae, M. leprae and T. gondii.
Clarithromycin penetrates most tissues, with concentrations equal to or exceeding serum
concentrations. It is metabolized in the liver. A portion of active drug and major metabolite is
eliminated in the urine. It has drug interactions similar to those described for erythromycin. The
advantages of clarithromycin compared with erythromycin are lower frequency of
gastrointestinal intolerance and less frequent dosing.
Azithromycin
The spectrum of activity and clinical uses of azithromycin is identical to those of clarithromycin.It
is rapidly absorbed and well tolerated orally. Azithromycin does not inactivate cytochrome P450
enzymes like erythromycin.
Clindamycin
Clindamycin is active against streptococci, staphylococci, bacteroides species and other
anaerobes, both grampositive and gram-negative. It resembles erythromycin in activity and
mechanisms of resistance. Clindamycin is well absorbed orally and about 90% protein-bound.
Excretion is mainly via the liver, bile, and urine. It penetrates well into most tissues.
Clinical uses: Clindamycin is used for the treatment of severe anaerobic infection caused by
Bacteroides. It is used for prophylaxis of endocarditis in patients with valvular heart disease who
are undergoing certain dental procedures. Clindamycin plus primaquine is an effective for
moderate to moderately severe Pneumocystis carinii pneumonia. It is also used in combination
with pyrimethamine for AIDS-related toxoplasmosis of the brain.
Adverse effects: Diarrheas, nausea, and skin rashes, impaired liver functions are common.
Severe diarrhea and enterocolitis is caused by toxigenic C difficile (infrequently part of the
normal fecal flora but is selected out during administration of oral antibiotics).
Aminoglycosides:
Members: Streptomycin, neomycin, kanamycin, amikacin, gentamicin, netilmicin.
Pharmacokinetics: Aminoglycosides are absorbed very poorly from the intact gastrointestinal
tract. After intramuscular injection, aminoglycosides are well absorbed. They are highly polar
compounds that do not enter cells readily. The kidney clears aminoglycosides, and excretion is
directly proportionate to creatinine clearance.
Adverse effects: Aminoglycosides damage the VIII nerve and the kidneys. 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. Nephrotoxicity
results in rising serum creatinine levels or reduced creatinine clearance. Neomycin, kanamycin,
and amikacin are the most ototoxic agents. Streptomycin and gentamicin are the most
vestibulotoxic.
Streptomycin
Streptomycin is mainly used as a first-line agent for treatment of tuberculosis.
Adverse Reactions: Disturbance of vestibular function (vertigo, loss of balance) is common. The
frequency and severity of this disturbance are proportionate to the age of the patient, the blood
levels of the drug, and the duration of administration. Vestibular dysfunction may follow a few
weeks of unusually high blood levels or months of relatively low blood levels. Vestibular toxicity
tends to be irreversible. Streptomycin given during pregnancy can cause deafness in the
newborn.
Gentamicin
Gentamicin inhibits many strains of staphylococci and coliforms and other gram-negative
bacteria. It is a synergistic companion with beta-lactam antibiotics, against Pseudomonas,
Proteus, Enterobacter, Klebsiella, Serratia, Stenotrophomonas, and other gram-negative rods
that may be resistant to multiple other antibiotics.
Gentamicin is also used concurrently with penicillin G for bactericidal activity in endocarditis due
to viridans streptococci. Creams, ointments, or solutions gentamicin sulfate are for the
treatment of infected burns, wounds, or skin lesions.
Amikacin
Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the parent molecule. It
is resistant to many enzymes that inactivate gentamicin and tobramycin, and it therefore can be
employed against some microorganisms resistant to the latter drugs. Strains of multidrugresistant Mycobacterium tuberculosis, including streptomycin-resistant strains, are usually
susceptible to amikacin.
Kanamycin, Neomycin, Paromomycin
These drugs are closely related is also a member of this group. All have similar properties.
Neomycin and kanamycin are too toxic for parenteral use and are now limited to topical and oral
use. Neomycin is given orally in preparation for elective bowel surgery. In hepatic coma, the
coliform flora can be suppressed for prolonged periods by giving 1 g every 6-8 hours together
with reduced protein intake, thus reducing ammonia intoxication. Paromomycin has been
effective in intestinal amebiasis.
Spectinomycin
Spectinomycin is an aminocyclitol antibiotic that is structurally related to aminoglycosides.
Spectinomycin is used almost solely as an alternative treatment for gonorrhea in patients who
are allergic to penicillin or whose gonococci are resistant to other drugs. It is rapidly absorbed
after intramuscular injection. A single dose of 2 g (40 mg/kg) is given. There is pain at the
injection site and occasionally fever and nausea.
Nucleic Acid Synthesis Inhibitors
Nalidixic acid
Nalidixic acid is the first antibacterial quinolone. It is not fluorinated and is excreted too rapidly
to have systemic antibacterial effects. They inhibit normal transcription and replication of
bacterial DNA. Because of their relatively weak antibacterial activity, these agents were useful
only for the treatment of urinary tract infections and shigellosis.
Fluoroquinolones
Quinolones are synthetic fluorinated analogs of nalidixic acid, that nucleic acid synthesis.
Ofloxacin and ciprofloxacin inhibit gram-negative cocci and bacilli, including
Enterobacteriaceae, Pseudomonas, Neisseria, Haemophilus, and Campylobacter. Many
staphylococci also are sensitive these drugs. Intracellular pathogens such as Legionella,
Chlamydia, M tuberculosis and M avium complex, are inhibited by fluoroquinolones.
158
Pharmacokinetics: After oral administration, the fluoroquinolones are well absorbed and
distributed widely in body fluids and tissues. Oral absorption is impaired by divalent cations,
including those in antacids. The fluoroquinolones are excreted mainly by tubular secretion and
by glomerular filtration. All fluoroquinolones accumulate in renal failure.
Clinical Uses: Fluoroquinolones are effective in urinary tract infections even when caused by
multidrug-resistant bacteria, eg, Pseudomonas. Norfloxacin 400 mg, ciprofloxacin 500 mg, and
ofloxacin 400 mg given orally twice daily and all are effective. These agents are also effective
for bacterial diarrhea caused by Shigella, Salmonella, toxigenic E coli, or Campylobacter.
Fluoroquinolones (except norfloxacin, which does not achieve adequate systemic
concentrations) have been employed in infections of soft tissues, bones, and joints and in intraabdominal and respiratory tract infections, including those caused by multidrug-resistant
organisms such as Pseudomonas and Enterobacter. Ciprofloxacin and ofloxacin are effective
for gonococcal infection, including disseminated disease, and ofloxacin is effective for
chlamydial urethritis or cervicitis.
Adverse Effects: The most common effects are nausea, vomiting, and diarrhea. Concomitant
administration of theophylline and quinolones can lead to elevated levels of theophylline with
the risk of toxic effects, especially seizures. Fluoroquinolones may damage growing cartilage
and cause an arthropathy. Thus, they are not routinely recommended for use in patients under
18 years of age. Since fluoroquinolones are excreted in breast milk, they are contraindicated for
nursing mothers.
Rifampin
Rifampin binds strongly to the bacterial DNA-dependent RNA polymerase and thereby inhibits
RNA synthesis. It is well absorbed after oral administration and excreted mainly through the liver
into bile. Rifampin is distributed widely in body fluids and tissues. It is relatively highly proteinbound, and so adequate cerebrospinal fluid concentrations are achieved only in the presence of
meningeal inflammation. Rifampin is used in the treatment of mycobacterial infections.
Rifampin causes a harmless orange color to urine, sweat, and tears. Occasional adverse
effects include rashes, thrombocytopenia, nephritis, cholestatic jaundice and occasionally
hepatitis. Rifampin induces microsomal enzymes (cytochrome P450), which increases the
elimination of anticoagulants, anticonvulsants, and contraceptives. Administration of rifampin
with ketoconazole, or chloramphenicol results in significantly lower serum levels of these drugs.
Antimetabolites
Sulfonamides
Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral,
nonabsorbable; and (3) topical. The oral, absorbable sulfonamides can be classified as short-,
medium-, or long acting on the basis of their half-lives.
Mechanisms of action: Microorganisms require extracellular para-aminobenzoic acid (PABA) 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. They inhibit growth by reversibly blocking folic acid synthesis.
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.
Pharmacokinetics: They are absorbed from the stomach and small intestine and distributed
widely to tissues and body fluids, placenta, and fetus. Absorbed sulfonamides become bound to
serum proteins to an extent varying from 20% to over 90%. A portion of absorbed drug is
acetylated or glucuronidated in the liver. Sulfonamides and inactivated metabolites are then
excreted into the urine, mainly by glomerular filtration.
Clinical Uses
Oral Absorbable Agents: Sulfisoxazole and sulfamethoxazole are short- to medium-acting
agents that are used to treat urinary tract infections, respiratory tract infections, sinusitis,
bronchitis, pneumonia, otitis media, and dysentery. Sulfadiazine in combination with
pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. Sulfadoxine, longacting sulfonamide, in combination with pyrimethamine used as a second-line agent in
treatment for malaria.
Oral Nonabsorbable Agents: Sulfasalazine is widely used in ulcerative colitis, enteritis, and
other inflammatory bowel disease. Sulfasalazine is split by intestinal microflora to yield
sulfapyridine and 5-aminosalicylate. Salicylate released in the colon in high concentration is
responsible for an antiinflammatory effect. Comparably high concentrations of salicylate cannot
be achieved in the colon by oral intake of ordinary formulations of salicylates because of severe
gastrointestinal toxicity.
Topical Agents: Sodium sulfacetamide ophthalmic solution or ointment is effective treatment for
bacterial conjunctivitis and as adjunctive therapy for trachoma. Silver sulfadiazine is a much
less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn
wounds.
Adverse Reactions: The most common adverse effects are fever, skin rashes, exfoliative
dermatitis, photosensitivity, urticaria, nausea, vomiting, and diarrhea. Stevens-Johnson
syndrome, crystalluria, hematuria, hemolytic or aplastic anemia, granulocytopenia, and
thrombocytopenia occur less frequently. Sulfonamides taken near the end of pregnancy
increase the risk of kernicterus in newborns.
Trimethoprim
Trimethoprim inhibits bacterial dihydrofolic acid reductase. Dihydrofolic acid reductases convert
dihydrofolic acid to tetrahydrofolic acid, a stage leading to the synthesis of purines and
ultimately to DNA.
Trimethoprim is usually given orally. It is absorbed well from the gut and distributed widely in
body fluids and tissues, including cerebrospinal fluid. Trimethoprim concentrates in prostatic
fluid and in vaginal fluid, which are more acid than plasma. Therefore, it has more antibacterial
activity in prostatic and vaginal fluids than many other antimicrobial drugs.
Trimethoprim can be given alone in acute urinary tract infections, because most communityacquired organisms tend to be susceptible to the high concentrations.
Trimethoprim produces the predictable adverse effects of an antifolate drug, especially
megaloblastic anemia, leukopenia, and granulocytopenia. This can be prevented by the
simultaneous administration of folinic acid, 6-8 mg/d.
Trimethoprim-Sulfamethoxazole( Cotrimoxazole)
The half-life of trimethoprim and sulfamethoxazole is similar. Trimethoprim, given together with
sulfamethoxazole, produces sequential blocking in this metabolic sequence, resulting in marked
enhancement of the activity of both drugs. The combination often is bactericidal, compared to
the bacteriostatic activity of a sulfonamide alone.
Clinical uses: Trimethoprim-sulfamethoxazole is effective treatment for Pneumocystis carinii
pneumonia, shigellosis, systemic Salmonella infections, urinary tract infections, and prostatitis.
It is active against many respiratory tract pathogens; Pneumococcus, Haemophilus species,
Moraxella catarrhalis, and Klebsiella pneumoniae.
ANTIMYCOBACTERIAL DRUGS
Mycobacterial infections are the most difficult of all bacterial infections to cure. Mycobacteria are
slowly growing organisms (can also be dormant) and thus completely resistant to many drugs,
or killed only very slowly by the few drugs that are active. The lipid-rich mycobacterial cell wall is
impermeable to many agents. A substantial proportion of mycobacterial organisms are
intracellular, residing within macrophages, and inaccessible to drugs that penetrate poorly.
Finally, mycobacteria are notorious for their ability to develop resistance to any single drug.
Combinations of drugs are required to overcome these obstacles and to prevent emergence of
resistance during the course of therapy. The response of mycobacterial infections to
chemotherapy is slow, and treatment must be administered for months to years depending on
which drugs are used. Antimycobacterial drugs can be devided into three groups: drugs used in
the treatmen of tuberculosis, drugs used in the treatment of atypical mycobacterial infection,
and drugs used in the treatment of leprosy.
Drugs Used In Tuberculosis
First-Line Antimycobacterial Drugs
Members: Isoniazid (INH), rifampin, pyrazinamide, ethambutol, and streptomycin are the five
first-line agents for treatment of tuberculosis. INH and rifampin are the two most active drugs.
Isoniazid (INH)
INH is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is
structurally similar to pyridoxine. It is bactericidal for actively growing tubercle bacilli. INH is able
to penetrate into phagocytic cells and thus is active against both extracellular and intracellular
organisms.
INH inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell
walls.
INH is readily absorbed from the gastrointestinal tract, and it diffuses readily into all body fluids
and tissues. Metabolism of INH, especially acetylation by liver N-acetyltransferase, is
genetically determined. INH metabolites and a small amount of unchanged drug are excreted
mainly in the urine. The dose need be adjusted in severe hepatic insufficiency.
Clinical Uses: Used in the treatment and prevention of tuberculosis.
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Adverse Reactions: The incidence and severity of untoward reactions to INH are related to
dosage and duration of administration. INH-induced hepatitis is the most frequent major toxic
effect and the risk of hepatitis greater in old age, alcoholics and possibly during pregnancy and
the post-partum period.
Peripheral neuropathy is more likely to occur in slow acetylators and patients with predisposing
conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a
relative pyridoxine deficiency. INH promotes excretion of pyridoxine, and this toxicity is readily
reversed or can be prevented by administration of pyridoxine. CNS system toxicity, which is
less common, includes memory loss, psychosis, and seizures, and may also respond to
pyridoxine.
Rifampin
Rifampin is administered together with INH, ethambutol, or another antituberculous drug in
order to prevent emergence of drug resistant mycobacteria. Rifampin is an alternative to INH for
prophylaxis in patients who are unable to take INH or who have had close contact with a case of
active tuberculosis caused by an INH-resistant, rifampin-susceptible strain.
Ethambutol
Ethambutol inhibits synthesis of mycobacterial cell wall. Ethambutol is well absorbed from the
gut. It accumulates in renal failure. Ethambutol crosses the blood-brain barrier only if the
meninges are inflamed.
Ethambutol hydrochloride given as a single daily dose in combination with INH or rifampin for
the treatment of tuberculosis. The higher dose is recommended for treatment of tuberculous
meningitis.
The most common serious adverse event is retrobulbar neuritis causing loss of visual acuity
and red-green color blindness is a dose-related side effect. Ethambutol is relatively
contraindicated in children too young to permit assessment of visual acuity and red-green color
discrimination.
Pyrazinamide
Pyrazinamide (PZA) is a relative of nicotinamide, stable, slightly soluble in water. Drug is taken
up by macrophages and kills bacilli residing within this acidic environment. PZA is well
absorbed from the gastrointestinal tract and widely distributed in body tissues, including
inflamed meninges. Tubercle bacilli develop resistance to pyrazinamide fairly readily. Major
adverse effects of pyrazinamide include hepatotoxicity, nausea, vomiting, drug fever, and
hyperuricemia. Hyperuricemia may provoke acute gouty arthritis.
Streptomycin
Most tubercle bacilli are inhibited by streptomycin. Streptomycin penetrates into cells poorly,
and thus it is active mainly against extracellular tubercle bacilli. Streptomycin crosses the bloodbrain barrier and achieves therapeutic concentrations with inflamed meninges. It is employed
principally in individuals with severe, possibly life-threatening forms of tuberculosis (meningitis
and disseminated disease), and in treatment of infections resistant to other drugs.
Combination Chemotherapy of Tuberculosis
The duration of therapy for a patient with tuberculosis depends upon the severity of the disease,
the organ affected and the combination of agents. There are two phases in the treatment of
tuberculosis; the intensive phase, which lasts 8 weeks, makes the patients noninfectious. The
continuation phase, which lasts 6 months or more and at least two drugs should be taken. Four
types of drug regimen are currently employed in Ethiopia; Directly Observed Treatment Short
Course (DOTS), Re- treatment Regimen, and Short course Chemotherapy and long course
chemotherapy (LCC)
Drug Regimens and Treatment Categories - Directly Observed Treatment Short Course (DOTS)
Used in new Pulmonary TB smear positive patients; new Pulmonary TB smear negative and
Extrapulmonary TB patients who are seriously ill; TB in children < 6 years. It consists of 8 weeks
of treatment with Streptomycin, Rifampicin, Isoniazid and Pyrazinamide during the intensive
phase followed by 6 monthes of Ethambutol and Isoniazid or 4 months of rifampin and isoniazid
(RH). (2S (RHZ)/6(EH). Children <6 years receive 4 monthes of Rifampicin and INH (RH) in the
continuation phase. Drugs have to be collected daily during the intensive phase of DOTS and
taken under direct observation by the health worker. During the continuation phase drugs have
to be collected every month and self-administered by the patient. - Re- treatment Regimen
Used for patients previously treated for more than one month with short course chemotherapy
(SCC) and Long course chemotherapy (LCC) and are still smear positive. These patients are: –
Relapses; Treatment failures; Returns after default who are pulmonary tuberculosis positive. It
consists of 2 months of treatment using Streptomycin, INH, Ethambutol, Rifampicin and
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Pyrazinamide then 1month of INH, Ethambutol, Rifampicin and Pyrazinamide in the intensive
phase, Followed by 5 months of ethambutol, Rifampicin and INH. [2SE (RH) Z/1E (RH) Z/5E3
(RH) 3]. (Streptomycin should not be included in the retreatment regimen for pregnant women).
The drugs should be taken under direct observation of the health worker throughout the duration
of Retreatment including the continuation phase. - Short course Chemotherapy
Is recommended for new patients with smear negative pulmonary TB, new patients with extra
pulmonary tuberculosis and TB in children of 6 years and older. It consists of 8 weeks of
treatment with Rifampicin, Isoniazid and Pyrazinamide during the intensive phase followed by 6
months of Ethambutol and Isoniazid. [2(RHZ)/6(EH)]. - Long course chemotherapy (LCC)
Is to be prescribed in all cases of TB in regions/Zones where the DOTS program is not yet
started. 2 months of Streptomycin, Ethambutol and INH in the intensive phase followed by 10
months of Ethambutol and INH.
Second-line antitubercular drugs include ethionamide, para-aminosalicylic acid, capreomycin,
cycloserine, amikacin, ciprofloxacin, etc. These agents are considered during failure of clinical
response to first-line drugs under supervision of their adverse effects.
Drugs Active against Atypical Mycobacteria
Disease caused by “atypical” mycobacteria is often less severe than tuberculosis and not
communicable from person to person. M avium complex is an important and common cause of
disseminated disease in late stages of AIDS.
Azithromycin or clarithromycin, plus ethambutol are effective and well-tolerated regimen for
treatment of disseminated disease. Some authorities recommend use of a third agent,
ciprofloxacin or rifabutin. Rifabutin in a single daily dose of 300 mg has been shown to reduce
the incidence of M avium complex bacteremia in AIDS. Clarithromycin also effectively prevents
MAC bacteremia in AIDS patients.
Drugs used in Leprosy
Leprosy is caused by mycobacterium leprae. I t can be treated dapsone, rifampin, clofazimine,
ethionamide, etc.
Because of increasing reports of dapsone resistance, treatment of leprosy with combinations of
the drugs is recommended.
Dapsone
Dapsone (diaminodiphenylsulfone) is the most widely used drugs in the treatment of leprosy
and it inhibits folate synthesis. Resistance can emerge in large populations of M leprae.
Therefore, the combination of dapsone, rifampin, and clofazimine is recommended for initial
therapy. Sulfones are well absorbed from the gut and widely distributed throughout body fluids
and tissues. Excretion into urine is variable, and most excreted drug is acetylated.
Dapsone is usually well tolerated. Gastrointestinal intolerance, fever, pruritus, and rashes occur.
Erythema nodosum often develops during dapsone therapy in lepromatous leprosy. Erythema
nodosum leprosum may be suppressed by corticosteroids. Hemolysis and methemoglobinemia
can occur.
Rifampin
This drug is effective in lepromatous leprosy. Because of the probable risk of emergence of
rifampin-resistant M leprae, the drug is given in combination with dapsone or another
antileprosy drug.
Clofazimine
The absorption of clofazimine from the gut is variable, and a major portion of the drug is
excreted in feces. Clofazimine is stored widely in reticuloendothelial tissues and skin.
Clofazimine is given for sulfone-resistant leprosy or when patients are intolerant to sulfone. A
common dosage is 100 mg/d orally. The most prominent untoward effect is skin discoloration
ranging from red-brown to nearly black.
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