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Title: Lecture 7: Antimicrobial therapy Definition Antibiotics are


1
Lecture 7 Antimicrobial therapy
2
  • Definition
  • Antibiotics are antibacterial substances produced
    by various species of microorganisms (bacteria,
    fungi, and actinomycetes) that suppress the
    growth of other microorganisms. Common usage
    often extends the term antibiotics to include
    synthetic antimicrobial agents.
  • - Antibiotics differ markedly in physical,
    chemical, and pharmacological properties, in
    antimicrobial spectra, and in mechanisms of
    action.
  • - Antimicrobial drugs are effective in the
    treatment of infections because of their
    selective toxicity.
  • - Antimicrobial agents are among the most
    commonly used and misused of all drugs.

3
Bacterial Resistance
  • Bacterial resistance to an antimicrobial
    agent is attributable to three general mechanisms
  • 1- The drug does not reach its target
    (deactivation of transport mechanisms or
    activation of efflux mechanisms).
  • 2- The drug is not active (inactivation of the
    drug or failure to activate prodrug).
  • 3- The target is altered.

4

5
Clinical uses of antimicrobial agents
  • - Antimicrobials have three general uses
  • 1- Empirical therapy or initial therapy the
    antimicrobial should cover all the likely
    pathogens because the infecting organism(s) has
    not yet been defined.
  • 2- Definitive therapy or pathogen-directed
    therapy once the infecting microorganism is
    identified, definitive antimicrobial therapy
    should be instituted with a narrow-spectrum,
    low-toxicity agent to complete the course of
    treatment.
  • 3- Prophylactic or preventive therapy.

6
icated
Figure (5) Some clinical situations in which
prophylactic antibiotics are indicated
7
Antimicrobial regimen selection
  • Optimal and judicious selection of antimicrobial
    agents for the therapy of infectious diseases
    requires clinical judgment and detailed knowledge
    of pharmacological and microbiological factors.
  • - A generally accepted systematic approach to the
    selection and evaluation of an antimicrobial
    regimen involves the following steps
  • Confirming the presence of infection.
  • Identification of the pathogen.
  • Selection of rational antimicrobial therapy.
  • Monitor therapeutic response.

8

1- Confirming the presence of infection
  • Careful history and physical examination
  • b) Fever
  • c) White blood cell count
  • d) Pain and inflammation

9
2. Identification of pathogen
  • 3. Selection of rational
    antimicrobial therapy
  • - To select rational antimicrobial therapy for
    a given clinical situation, a variety of factors
    must be considered. These include the severity
    and acuity of the disease, host factors, drug
    factors, and the necessity for using multiple
    agents.
  • - In addition, there are generally accepted
    drugs of choice for the treatment of most
    pathogens .

10
  • a) Drug factors
  • Pharmacodynamic factors
  • Pharmacodynamic factors include pathogen
    susceptibility testing, drug bactericidal versus
    bacteriostatic activity, and drug synergism,
    antagonism, and postantibiotic effects.
  • - Bactericidal agents can be divided into two
    groups agents that exhibit
  • Concentration-dependent killing (eg,
    aminoglycosides and quinolones) and agents that
    exhibit
  • Time dependent killing (eg, -lactams and
    vancomycin).
  • Postantibiotic effect
  • - Persistent suppression of bacterial growth
    after limited exposure to an antimicrobial agent
    is known as the postantibiotic effect (PAE).

11
Table. Bacteriostatic and bactericidal
antibacterial agents.
12
  • 2. Pharmacokinetic factors
  • - Successful therapy depends on achieving a drug
    concentration that is sufficient to inhibit or
    kill bacteria at the site of the infection
    without harming the patient. To accomplish this
    therapeutic goal, several pharmacokinetic
    factors must be evaluated.
  • - The location of the infection to a large extent
    may dictate the choice of drug and the route of
    administration. The minimal drug concentration
    achieved at the infected site should be
    approximately equal to the MIC for the infecting
    organism, although in most instances it is
    advisable to achieve multiples of this
    concentration if possible.
  • - Penetration of drugs into sites of infection
    almost always depends on passive diffusion. The
    rate of penetration is thus proportional to the
    concentration of free drug in the plasma or
    extracellular fluid. Drugs that are extensively
    bound to protein thus may not penetrate to the
    same extent as those bound to a lesser extent.
  • b- Status of the patient
  • c- Safety factor
  • d- Cost factor

13
Chemotherapeutic Spectra
  • A. Narrow-spectrum antibiotics
  • Chemotherapeutic agents acting only on a single
    or a limited group of microorganisms are said to
    have a narrow spectrum. For example, isoniazid is
    active only against mycobacteria .
  • B. Extended-spectrum antibiotics
  • Extended spectrum is the term applied to
    antibiotics that are effective against
    gram-positive organisms and also against a
    significant number of gram-negative bacteria. For
    example, ampicillin is considered to have an
    extended spectrum, because it acts against
    gram-positive and some gram-negative bacteria .
  • C. Broad-spectrum antibiotics
  • Drugs such as tetracycline and chloramphenicol
    affect a wide variety of microbial species and
    are referred to as broad-spectrum antibiotics
  • . Administration of broad-spectrum antibiotics
    can drastically alter the nature of the normal
    bacterial flora and precipitate a superinfection
    of an organism such as Candida albicans, the
    growth of which is normally kept in check by the
    presence of other microorganisms.

14
Combination antimicrobial therapy
  • Combinations of antimicrobials generally are used
    to
  • 1- Broaden the spectrum of coverage for empirical
    therapy
  • 2- Synergism
  • 3- Prevent the emergence of resistance
  • Disadvantages of combination therapy
  • 1- Some combination of antimicrobial are
    potentially antagonistic.
  • 2- Increased risk of toxicity from two or more
    agents.
  • 3- Selection of multiple-drug-resistant
    microorganisms.
  • 4- Eradication of normal host flora with
    subsequent superinfection.
  • 5- Increased cost to the patient.

15
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16
I- Inhibitors of cell wall synthesis
  • A- ß- Lactam cell wall inhibitors
  • 1- Penicillins
  • - All ß-lactam antibiotics have the same
    bactericidal mechanism of action. They block a
    critical (last) step in bacterial cell wall
    synthesis ( transpeptidation or cross- linkage).
  • - After penicillins have attached to receptors,
    peptidoglycan (murein) synthesis is inhibited
    because the activity of transpeptidation enzymes
    (transpeptidases) is blocked.
  • Only organisms actively synthesizing
    peptidoglycan (in the process of multiplication)
    are susceptible to ß- lactam antibiotics.
    Nonmultiplying organisms or those lacking cell
    walls (Mycobacteria, Protozoa, fungi, and virus)
    are not susceptible.

17
Figure (8)Summary of antimicrobial agents
affecting cell wall synthesis.
18
  • Mechanism of resistance
  • Microbial resistance to penicillins is caused by
    four factors
  • 1- Production of ß-lactamases (penicillinases).
  • 2- Lack of penicillin-binding proteins or
    decreased affinity of penicillin-binding protein
    for ß-lactam antibiotic receptors or
    impermeability of cell envelope.
  • 3- Failure of activation of autolytic enzymes in
    the cell wall (tolerance).
  • 4- Cell wall-deficient (L) forms or mycoplasmas,
    which do not synthesize peptidoglycans.

19
  • Classification of penicillins
  • Penicillins may be classified into four groups
    1- natural penicillins (G and V),
  • 2- antistaphylococcal penicillins
    (penicillinase resistant),
  • 3- aminopenicillins, and
  • 4- antipseudomonal penicillins.

20
Figure (3) stability of the penicillins to acid
or the action of penicillinase.
21
Therapeutic uses of penicillin G
22
Adverse effects
  • Hypersensitivity reactions
  • - Hypersensitivity reactions are by far the most
    common adverse effects noted with the
    penicillins, and these agents probably are the
    most common cause of drug allergy. penicillins
    includemaculopapular rash, urticarial rash,
    fever, bronchospasm, vasculitis, and anaphylaxis.
  • - It must be stressed that fatal episodes of
    anaphylaxis have followed the ingestion of very
    small doses of this antibiotic or skin testing
    with minute quantities of the drug.
  • Other toxicities
  • - The penicillins have minimal direct toxicity.
    Apparent toxic effects that have been reported
    include bone marrow depression, granulocytopenia,
    and hepatitis.
  • - All penicillins in excessive doses,
    particularly in renal insufficiency, have been
    associated with seizures.
  • - - Many persons who take various penicillin
    preparations by mouth experience nausea, with or
    without vomiting, and some have mild to severe
    diarrhea.
  • - Superinfection.

23
2- Cephalosporin
  • Mechanism of action
  • - The mechanism of action of cephalosporins is
    analogous to that of the penicillins binding to
    specific penicillin-binding proteins, inhibition
    of cell wall synthesis, and activation of
    autolytic enzymes in the cell wall.
  • Mechanism of resistance
  • Resistance to cephalosporins may be due to poor
    permeability of the drug into bacteria, lack of
    penicillin-binding proteins, or degradation by
    ß-lactamases.

24
Classification and therapeutc uses of
cephalosporin
25
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26
Pharmacokinetics

- Cephalexin, cephradine, cefaclor, cefadroxil,
cefprozil, ceftibuten, and cefuroxime axetil are
absorbed readily after oral administration.
Cefprozil, cefdinir, ceftibuten, and cefditoren
are also effective orally. The other
cephalosporins can be administered
intramuscularly or intravenously. -
Cephalosporins are excreted primarily by the
kidney dosage thus should be altered in
patients with renal insufficiency. Probenecid
slows the tubular secretion of most
cephalosporins. Cefpiramide and cefoperazone are
exceptions because they are excreted
predominantly in the bile. Cefotaxime is
deacetylated in vivo.
27
  • - Several cephalosporins penetrate into CSF in
    sufficient concentration to be useful for
    thetreatment of meningitis. These include
    cefotaxime, ceftriaxone, and cefepime.
  • - Cephalosporins also cross the placenta, and
    they are found in high concentrations in synovial
    and pericardial fluids. Penetration into the
    aqueous humor of the eye is relatively good
    after systemic administration of third-generation
    agents.
  • - Concentrations in bile usually are high, with
    those achieved after administration of
    cefoperazone and cefpiramide being the highest.
  • - Drugs like ceftriaxone that have extensive
    protein binding (8595) may displace bilirubin
    from serum albumin. - Cefuroxime and cefadroxil
    have long half-lives that permit twice-daily
    dosing

28
Adverse effects
  • Hypersensitivity
  • - Immediate reactions such as anaphylaxis,
    bronchospasm, and urticaria are observed. More
    commonly, maculopapular rash develops, usually
    after several days of therapy. - Because of the
    similar structures of the penicillins and
    cephalosporins, patients who are allergic to
    one class of agents may manifest cross-reactivity
    to a member of the other class. Other
    toxicities
  • - The cephalosporins have been implicated as
    potentially nephrotoxic agents.
  • - Diarrhea can result from the administration of
    cephalosporins.
  • - Serious bleeding related either to
    hypoprothrombinemia, thrombocytopenia, and/or
    platelet dysfunction has been reported with
    several ß-lactam antibiotics especially
    cefotetan, cefomandole and cefoperazone.
  • - Disufiram- like reactions. When cefomandole and
  • .

29
  • II - Protein synthesis inhibitors

30
1- Chloramphenicol
Antimicrobial Activity Chloramphenicol is a
potent inhibitor of microbial protein synthesis.
It binds reversibly to the 50S subunit of the
bacterial ribosome (Figure9). It inhibits the
peptidyl transferase step of protein synthesis.
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 but not chlamydiae. Most
Haemophilus influenzae, Neisseria meningitidis,
and some strains of bacteroides are highly
susceptible, and for them chloramphenicol may be
bactericidal .
31

Figure (12) Site of action of
different protein synthesis inhibitors.
32
Resistance Resistance is conferred is due to
production of chloramphenicol acetyltransferase,
a plasmid-encoded enzyme that inactivates the
drug. Another mechanism for resistance is
associated with an inability of the antibiotic to
penetrate the organism. This change in
permeability may be the basis of multidrug
resistance. Pharmacokinetics Chloramphenicol
may be administered either intravenously or
orally. It is completely absorbed via the oral
route because of its lipophilic nature, and is
widely distributed throughout the body. It
readily enters the normal CSF. The drug inhibits
the hepatic mixed-function oxidases. Excretion of
the drug depends on its conversion in the liver
to a glucuronide, which is then secreted by the
renal tubule. Only about 10 percent of the parent
compound is excreted by glomerular filtration.
Chloramphenicol is also secreted into breast
milk.
33
Adverse Reactions 1-Gastrointestinal
Disturbances Adults occasionally develop nausea,
vomiting, and diarrhea. This is rare in children.
Oral or vaginal candidiasis may occur as a
result of alteration of normal microbial
flora. 2- Bone Marrow Disturbances
Chloramphenicol commonly causes a dose-related
reversible suppression of red cell production at
dosages exceeding 50 mg/kg/d after 12 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. Aplastic anemia probably develops
in one of every 24,00040,000 patients who have
taken chloramphenicol. 3-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. 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.
34
4- Interaction with other drugs Chloramphenicol
inhibits hepatic microsomal enzymes that
metabolize several drugs. Half-lives are
prolonged, and the serum concentrations of
phenytoin, tolbutamide, chlorpropamide, and
warfarin are increased. Like other bacteriostatic
inhibitors of microbial protein synthesis,
chloramphenicol can antagonize bactericidal drugs
such as penicillins or aminoglycosides.

35
2. Tetracyclines Mechanism of action Entry of
these agents into susceptible organisms is
mediated both by passive diffusion and by an
energy-dependent active transport mechanism .
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, and inhibiting
protein synthesis. Resistance Three
mechanisms of resistance to tetracycline have
been described (1) decreased intracellular
accumulation due to either impaired influx or
increased efflux by an active transport protein
pump (2) ribosome protection due to production
of proteins that interfere with tetracycline
binding to the ribosome and (3) enzymatic
inactivation of tetracyclines. Antibacterial
spectrum As broad-spectrum bacteriostatic
antibiotics, the tetracyclines are effective
against gram-positive and gram-negative bacteria
as well as against organisms other than bacteria.
36
Figure (14) Typical therapeutic applications
of tetracyclines.
37
Pharmacokinetics Absorption All tetracyclines
are adequately but incompletely absorbed after
oral ingestion . However, taking these drugs
concomitantly with dairy foods in the diet
decreases absorption due to the formation of
nonabsorbable chelates of the tetracyclines with
calcium ions. Nonabsorbable chelates are also
formed with other divalent and trivalent cations
(for example, those found in magnesium and
aluminum antacids and in iron preparations).
Note This presents a problem if a patient
self-treats the epigastric upsets caused by
tetracycline ingestion with antacids.
Doxycycline and minocycline are almost totally
absorbed on oral administration. Currently,
doxycycline is the preferred tetracycline for
parenteral administration. Distribution The
tetracyclines concentrate in the liver, kidney,
spleen, and skin, and they bind to tissues
undergoing calcification (for example, teeth and
bones) or to tumors that have a high calcium
content (for example, gastric carcinoma).
Penetration into most body fluids is adequate.
Although all tetracyclines enter the
cerebrospinal fluid (CSF), levels are
insufficient for therapeutic efficacy, except for
minocycline. Minocycline enters the brain in the
absence of inflammation and also appears in tears
and saliva. Although useful in eradicating the
meningococcal carrier state, minocycline is not
effective for central nervous system infections.
All tetracyclines cross the placental barrier and
concentrate in fetal bones and dentition.
38
Fate All the tetracyclines concentrate in the
liver, where they are, in part, metabolized and
conjugated to form soluble glucuronides. The
parent drug and/or its metabolites are secreted
into the bile. Most tetracyclines are reabsorbed
in the intestine via the enterohepatic
circulation and enter the urine by glomerular
filtration. Obstruction of the bile
duct and hepatic or renal dysfunction can
increase their half-lives. Unlike other
tetracyclines, doxycycline can be employed for
treating infections in renally compromised
patients, because it is preferentially excreted
via the bile into the feces. Note Tetracyclines
are also excreted in breast milk..
39
Oral Dosage The oral dosage for rapidly
excreted tetracyclines, equivalent to
tetracycline hydrochloride, is 0.250.5 g four
times daily for adults and 2040 mg/kg/d for
children (8 years of age and older). For severe
systemic infections, the higher dosage is
indicated, at least for the first few days. The
daily dose is 600 mg for demeclocycline or
methacycline, 100 mg once or twice a day for
doxycycline, and 100 mg twice a day for
minocycline. Doxycycline is the tetracycline of
choice because it can be given as a once-daily
dose and its absorption is not significantly
affected by food. All tetracyclines chelate with
metals, and none should be administered with
milk, antacids, or ferrous sulfate. To avoid
deposition in growing bones or teeth,
tetracyclines should be avoided for pregnant
women and for children under 8 years. Parenteral
Dosage Several tetracyclines are available for
intravenous injection in doses of 0.10.5 g every
612 hour (similar to oral doses), depending on
the agent. Intramuscular injection is not
recommended because of pain and inflammation at
the injection site. Doxycycline is the preferred
agent, at a dosage of 100 mg every 1224 hours .
40
Adverse Reactions
1-Gastric discomfort Epigastric distress
commonly results from irritation of the gastric
mucosa and is often responsible for noncompliance
in patients treated with these drugs. The
discomfort can be controlled if the drug is taken
with foods other than dairy product 2- Effects on
calcified tissues Deposition in the bone and
primary dentition occurs during calcification in
growing children. This causes discoloration and
hypoplasia of the teeth and a temporary
stunting of growth. 3- Fatal hepatotoxicity
This side effect has been known to occur in
pregnant women who received high doses of
tetracyclines, especially if they were
experiencing pyelonephritis. 4- Phototoxicity
Phototoxicity, such as severe sunburn, occurs
when a patient receiving a tetracycline is
exposed to sun or ultraviolet rays. This toxicity
is encountered most frequently with tetracycline
doxycycline, and demeclocycline. 4- Vestibular
problems These side effects (for example,
dizziness, nausea, and vomiting) occur
particularly with minocycline, which
concentrates in the endolymph of the ear and
affects function. Doxycycline may also cause
vestibular effects.
41
5- Pseudotumor cerebri Benign, intracranial
hypertension characterized by headache and
blurred vision may occur rarely in adults.
Although discontinuation of the drug reverses
this condition, it is not clear whether permanent
sequelae may occur. 6- Superinfections
Overgrowths of Candida (for example, in the
vagina) or of resistant staphylococci (in the
intestine) may occur. Pseudomembranous colitis
due to an overgrowth of Clostridium difficile has
also been reported. 7- Contraindications
Renally impaired patients should not be treated
with any of the tetracyclines except doxycycline.
Accumulation of tetracyclines may aggravate
preexisting azotemia (a higher-than-normal level
of urea or other nitrogen-containing compounds in
the blood) by interfering with protein synthesis,
thus promoting amino acid degradation. The
tetracyclines should not be employed in pregnant
or breast-feeding women or in children less than
8 years of age .
42
Figure (15) Summary of side effects of
Tetracyclines
43
3. Macrolides
Erythromycin
Mechanism of action The macrolides bind
irreversibly to a site on the 50S subunit of the
bacterial ribosome, thus inhibiting the
translocation steps 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.
44
Figure( 9) Typical therapeutic applications
of macrolides.
45
  • Clarithromycin This antibiotic has a
    spectrum of antibacterial activity similar to
    that of erythromycin, but it is also effective
    against Haemophilus influenzae. Its activity
    against intracellular pathogens, such as
    Chlamydia, Legionella, Moraxella, and Ureaplasma
    species and Helicobacter pylori, is higher than
    that of erythromycin.
  • 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. Azithromycin is now the
    preferred therapy for urethritis caused by
    Chlamydia trachomatis. It also has activity
    against Mycobacterium avium-intra cellular
    complex in patients with acquired
    immunodeficiency syndrome anddisseminated
    infections.
  • Telithromycin This ketolide drug has an
    antibacterial spectrum similar to that of
    azithromycin. Moreover, the structural
    modification within ketolides neutralizes the
    most common resistanmechanisms (methylasemediated
    and efflux-mediated) that make macrolides
    ineffective.

46
  • 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 to
    stomach acid and are readily absorbed. Food
    interferes with the absorption of erythromycin
    and azithromycin but can increase that of
    clarithromycin. Azithromycin is available for
    intravenous infusion, but intravenous
    administration of erythromycin is associated
    with a high incidence of thrombophlebitis.
  • 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 has
    the unique characteristic of accumulating in
    macrophages. Similarly, clarithromycin,
    azithromycin, and telithromycin are widely
    distributed in the tissues. Serum levels of
    azithromycin are low the drug is concentrated
    in neutrophils, macrophages, and fibroblasts.
    Azithromycin has the longest half-life and
    largest volume of distribution of the four drugs.
  • 3- Fate
  • Erythromycin and telithromycin are
    extensively metabolized and are known to inhibit
    the oxidation of a number of drugs through
    their interaction with the cytochrome P450
    system. Interference with the metabolism of
    drugs such as theophylline and carbamazepine has
    been reported for clarithromycin.
  • 4- Excretion
  • Erythromycin and azithromycin are primarily
    concentrated and excreted in an active form in
    the bile. Partial reabsorption occurs through the
    enterohepatic circulation. Inactive metabolites
    are excreted into the urine. In contrast,
    clarithromycin and its metabolites are eliminated
    by the kidney as well as the liver, and it is
    recommended that the dosage of this drug be
    adjusted in patients with compromised renal
    function.

47
Adverse effects
  • 1- Epigastric distress This side effect is
    common and can lead to poor patient compliance
    for erythromycin.Clarithromycin and azithromycin
    seem to be better tolerated by the patient, but
    gastrointestinal problems are their most common
    side effects .
  • 2- Cholestatic jaundice This side effect occurs
    especially with the estolate form of
    erythromycin, presumably as the result of a
    hypersensitivity reaction to the estolate form
    (the lauryl salt of the propionyl ester of
    erythromycin). It has also been reported for
    other forms of the drug.
  • 3- 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.
    Recent cases of severe hepatotoxicity with
    telithromycin use have emphasized
  • the caution needed when utilizing this agent.
    Additionally, 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.
    Similarly, patients who are renally compromised
    should be given telithromycin with caution.
    Telithromycin is contraindicated in patients with
    myasthenia gravis.
  • Interactions Erythromycin, telithromycin, and
    clarithromycin inhibit the hepatic metabolism of
    a number of drugs, which can lead to toxic
    accumulations of these compounds. An interaction
    with digoxin may occur in some patients. In this
    case, the antibiotic eliminates a species of
    intestinal flora that ordinarily inactivates
    digoxin, thus leading to greater reabsorption of
    the drug from the enterohepatic circulation. No
    interactions have been reported for azithromycin.

48
4- Clindamycin
  • Antibacterial Activity
  • Streptococci, staphylococci, and pneumococci
    are inhibited by clindamycin, 0.55 g/mL.
  • Enterococci and gram-negative aerobic organisms
    are resistant (in contrast to their
    susceptibility to erythromycin). Bacteroides
    species and other anaerobes, both gram-positive
    and gram-negative, are usually susceptible.
    Clostridium difficile, an important cause of
    pseudomembranous colitis is resistant.
    Clindamycin, like erythromycin, inhibits protein
    synthesis by interfering with the formation of
    initiation complexes and with aminoacyl
    translocation reactions. The binding site for
    clindamycin on the 50S subunit of the bacterial
    ribosome is identical with that for erythromycin.

49
  • Resistance to clindamycin, which generally
    confers cross-resistance to other macrolides, is
    due to
  • (1) mutation of the ribosomal receptor site
  • (2) modification of the receptor by a
    constitutively expressed methylase (see section
    on erythromycin resistance,
  • (3) enzymatic inactivation of clindamycin.

50
  • Pharmacokinetics.
  • Oral dosages of clindamycin, 0.150.3
    g every 6 hours (1020 mg/kg/d for children),
    yield serum levels of 23 g/mL. When
    administered intravenously, 600 mg of clindamycin
    every 8 hours gives levels of 515 g/mL. The
    drug is about 90 protein-bound. Excretion is
    mainly via the liver, bile, and urine.
    Clindamycin penetrates well into most tissues,
    with brain and cerebrospinal fluid being
    important exceptions. It penetrates well into
    abscesses and is actively taken up and
    concentrated by phagocytic cells. Clindamycin is
    metabolized by the liver, and both active drug
    and active metabolites are excreted in bile. The
    half-life is about 2.5 hours in normal
    individuals, increasing to 6 hours in patients
    with anuria. No dosage adjustment is required for
    renal failure.

51
  • Clinical Uses
  • - Clindamycin is indicated for treatment of
    severe anaerobic infection caused by bacteroides
    an other anaerobes that often participate in
    mixed infections.
  • - Clindamycin, sometimes in combination with an
    aminoglycoside or cephalosporin, is used to treat
    penetrating wounds of the abdomen and the gut
    infections originating in the female genital
    tract, e.g., septic abortion and pelvic
    abscesses or aspiration pneumonia.
  • - Clindamycin is now recommended instead of
    erythromycin for prophylaxis of endocarditis in
    patients with valvular heart disease who are
    undergoing certain dental procedures.
    - Clindamycin plus primaquine is an effective
    alternative to trimethoprim-sulfamethoxazole for
    moderate to moderately severe Pneumocystis
    carinii pneumonia in AIDS patients.

52
Adverse Effects
  • 1- Common adverse effects are diarrhea, nausea,
    and skin rashes.
  • 2- Impaired liver function (with or without
    jaundice) and neutropenia sometimes occur. Severe
    diarrhea and pseudomembranous coloitis have
    followed clindamycin administration.
    Antibiotic-associated colitis that has followed
    administration of clindamycin and this caused
    by toxigenic C difficile. This potentially fatal
    complication must be recognized promptly and
    treated with metronidazole, 500 mg orally or
    intravenously three times a day (the preferred
    therapy), or vancomycin, 125 mg orally four times
    a day.

53
5- Aminoglycosides
  • Aminoglycosides are a group of bactericidal
    antibiotics originally obtained from various
  • streptomyces species and sharing chemical,
    antimicrobial, pharmacologic, and toxic
    characteristics. The group includes
    streptomycin, neomycin, kanamycin, amikacin,
    gentamicin, tobramycin, sisomicin, netilmicin,
    and others.
  • Aminoglycosides are used most widely against
    gram-negative enteric bacteria, especially in
    bacteremia and sepsis, in combination with
    vancomycin or a penicillin for endocarditis, and
    for treatment of tuberculosis. Streptomycin is
    the oldest and best-studied of the
    aminoglycosides. Gentamicin, tobramycin, and
    amikacin are the most widely employed
    aminoglycosides at present. Neomycin and
    kanamycin are now largely limited to topical or
    oral use.

54
  • .

Figure (12) Mechanism of action of the
aminoglycosides
55
Figure (13) Typical therapeutic applications of
aminoglycosides.
56
  • Pharmacokinetics
  • Administration The highly polar, polycationic
    structure of the aminoglycosides prevents
    adequate absorption after oral administration.
  • Therefore, all aminoglycosides (except neomycin
    must be given parenterally to achieve adequate
    serum levels. 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. Because of these properties, once-daily
    dosing with the aminoglycosides can be employed.
    This results in fewer toxicities and is less
    expensive to administer. The exceptions are
    pregnancy, neonatal infections, and bacterial
    endocarditis, in which these agents are
    administered in divided doses every 8 hours.
    Note The dose that is administered is
    calculated based on lean body mass, because these
    drugs do not distribute into fat..
  • 2- Distribution
  • All the aminoglycosides have similar
    pharmacokinetic properties. Levels achieved in
    most tissues are low, and penetration into most
    body fluids is variable. Concentrations in CSF
    are inadequate, even when the meninges are
    inflamed. All
    aminoglycosides cross the placental barrier and
    may accumulate in fetal plasma and amniotic
    fluid.
  • Metabolism of the aminoglycosides does not occur
    in the host. All are rapidly excreted into the
    urine, predominantly by glomerular filtration.
    Accumulation occurs in patients with renal
    failure and requires dose modification.

57
  • Adverse effects
  • It is important to monitor plasma levels of
    gentamicin, tobramycin, and amikacin to avoid
    concentrations that cause dose-related toxicity.
    Patient factors, such as old age, previous
    exposure to aminoglycosides, and liver disease,
    tend to predispose patients to adverse reactions.
    The elderly are particularly susceptible to
    nephrotoxicity and ototoxicity.
  • 1- Ototoxicity It is directly related to high
    peak plasma levels and the duration of
    treatment. Patients simultaneously receiving
    another ototoxic drug, such as cisplatin or the
    loop diuretics, furosemide, bumetanide, or
    ethacrynic acid, are particularly at risk.
  • 2- Nephrotoxicity Retention of the
    aminoglycosides by the proximal tubular cells
    disrupts calcium-mediated transport processes,
    and this results in kidney damage ranging from
    mild reversible renal impairment to severe acute
    tubular necrosis, which can be irreversible.
  • 3. Neuromuscular paralysis This side effect most
    often occurs after direct intraperitoneal or
    intrapleural application of large doses of
    aminoglycosides. 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. Prompt administration of calcium gluconate
    or neostigmine can reverse the block.
  • 4. Allergic reactions Contact dermatitis is a
    common reaction

58
  • Spectinomycin
  • - Spectinomycin is an aminocyclitol antibiotic
    (related to aminoglycosides) for intramuscular
    administration.
  • - Spectinomycin selectively inhibits protein
    synthesis in gram-negative bacteria. The
    antibiotic binds to and acts on the 30S
    ribosomal subunit. Its action is similar to that
    of the aminoglycosides, but spectinomycin is not
    bactericidal.
  • - Its only therapeutic use is in the treatment of
    gonorrhea caused by strains resistant to first-
    line drugs (Penicillins, cephalosporins, and
    flouroquinolones), or if there are
    contraindications to the use of these drugs.
  • Linezolid
  • - It is a synthetic antimicrobial agent that is
    available for oral and parenteral administration.
  • - Linezolid inhibits protein synthesis by binding
    to 50S ribosomal subunit.
    - Linezolid is active against gram-positive
    organisms but it has poor activity against most
    gram-negative bacteria.
  • - Because of its unique mechanism of action,
    linezolid is active against strains that are
    resistant to multiple other agents.
  • - Linezolid should be reserved as an alternative
    agent for treatment of infections caused by
    multiple-drug-resistant strains. It should not be
    used when other agents are likely to be
    effective.

59
  • - Mupirocin is active against many gram-positive
    and selected gram-negative bacteria -
    Mupirocin inhibits bacterial protein synthesis by
    reversible binding and inhibition of certain
    transfer-RNA synthetase. - It is for topical use
    only.
  • - Mupirocin is available as a 2 cream and a 2
    ointment for dermatologic use and as a 2
    ointment for intranasal use. The dermatologic
    preparations are indicated for treatment of
    traumatic skin lesions secondarily infected with
    S. aureus or S. pyogenes.
  • Fusidic acid
  • - Fusidic acid is protein synthesis inhibitor in
    susceptible bacteria.
  • - It is used for skin and soft tissue infections
    caused by susceptible bacteria including
    S. aureus (penicillinase-producing and
    non-penicillinase strains).
  • - It is used also topically for treatment of
    primary and secondary infections and for
    superfacial infections of the eye and
    conjunctiva.
  • - Available for oral, I.V., and topical
    administration but not for I.M. as local tissue
    injury may occur.

60
III - Nucleic acid inhibitors
61
  • 1-Sulfonamides
  • The term sulfonamide is employed here in as a
    generic name for derivatives of para-
    aminobenzenesulfonamide (sulfanilamide).

Figure(15). Actions of sulfonamides and
trimethoprim
62
  • Pharmacokinetics
  • - Sulfonamides have good oral absorption and
    bioavailability.
  • - All sulfonamides are bound in varying degree to
    plasma proteins, particularly to albumin.
  • - Sulfonamides are distributed throughout all
    tissues of the body.
  • - Sulfonamides pass readily through the placenta
    and reach the fetal circulation.
  • The concentrations attained in the fetal tissues
    are sufficient to cause both antibacterial and
    toxic effects. - Sulfonamides are eliminated
    from the body partly as the unchanged drug and
    partly as metabolic products.

63
  • Classification
  • The sulfonamides may be classified into three
    groups on the basis of the rapidity with which
    they are absorbed and excreted
  • 1- Agents that are absorbed and excreted rapidly,
    such as sulfisoxazole, sulfadiazine, and
    sulfamethoxazole they are administered orally
    and employed for both systemic and urinary tract
    infections.
  • 2- Agents that are absorbed very poorly when
    administered orally and hence are active in the
    bowel lumen, such as sulfasalazine. It is used in
    the therapy of ulcerative colitis and regional
    enteritis. Sulfasalazine is broken down by
    intestinal bacteria to sulfapyridine, an active
    sulfonamide that is absorbed and eventually
    excreted in the urine, and 5-aminosalicylate,
    which reaches high levels in the feces.
    5-Aminosalicylate is the effective agent in
    inflammatory bowel disease, whereas sulfapyridine
    is responsible for most of the toxicity.
  • 3- Agents that are used mainly topically, such as
    sulfacetamide, mafenide, and silver sulfadiazine.
    Solutions of the sodium salt of sulfacetamide are
    employed extensively in the management of
    ophthalmic infections. Mafenide, and silver
    sulfadiazine are used topically to reduce
    microbial colonization and the incidence of
    infections of wounds from burns.
  • 4- Long-acting sulfonamides, such as sulfadoxine,
    that are absorbed rapidly but excreted slowly and
    has a particularly long half-life (7 to 9 days).
    It is used in combination with pyrimethamine (as
    Fansidar) for the prophylaxis and treatment of
    malaria.

64
  • Adverse effects
  • 1-Disturbances of the urinary tract Although the
    risk of crystalluria was relatively high with the
    older, less soluble sulfonamides, the incidence
    of this problem is very low with more soluble
    agents such as sulfisoxazole. Fluid intake should
    be sufficient to ensure a daily urine volume of
    at least 1200 ml (in adults). Alkalinization of
    the urine may be desirable if urine volume or pH
    is unusually low because the solubility of
    sulfisoxazole increases greatly with slight
    elevations of pH.
  • 2- Disorders of the hematopoietic system such as
    acute hemolytic anemia, agranulocytosis, and
    aplastic anemia especially in patients with G 6-
    PD defieciency.
  • 3- Hypersensitivity reactions.
  • 4- Anorexia, nausea, and vomiting.
  • 5- The administration of sulfonamides to newborn
    infants, especially if premature, may lead to the
    displacement of bilirubin from plasma albumin. In
    newborn infants, free bilirubin can cause an
    encephalopathy called kernicterus.

65
Figure (16 Typical therapeutic applications of
co-trimoxazole (sulfamethoxazole plus
trimethoprim.
66
  • 2-Quinolones and Flouroquinolones
  • - The first quinolone, nalidixic acid, was
    isolated as a by-product of the synthe
    chloroquine. It has been available for the
    treatment of urinary tract infections for many
    years.
  • - The introduction of fluorinated 4-quinolones,
    (flouroquinolones) represents a particularly
    important therapeutic advance because these
    agents have broad antimicrobial activity and
    are effective after oral administration for the
    treatment of a wide variety of infectious
    diseases and have relatively few side effects.

67
Figure (16 ) Summary of antimicrobial spectrum
of quinolones.
68
Figure (17 Typical therapeutic applications of
ciprofloxacin.
69
  • Pharmacokinetics
  • - The quinolones are well absorbed after oral
    administration and are distributed widely in body
    tissues.
  • - Food does not impair oral absorption but may
    delay the time to peak serum concentrations.
  • - The volume of distribution of quinolones is
    high, with concentrations of quinolones in urine,
    kidney, lung and prostate tissue, stool, bile,
    and macrophages and neutrophils higher than
    serum levels.
  • - Most quinolones are cleared predominantly by
    the kidney.

70
  • Adverse effects
  • - Quinolones and fluoroquinolones generally are
    well tolerated.
  • - The most common adverse reactions involve the
    GI tract (nausea, vomiting, and/or abdominal
    discomfort).
  • - Diarrhea and antibiotic-associated colitis have
    been unusual.
  • - CNS side effects, predominately mild headache
    and dizziness.
  • - Rashes, including photosensitivity reactions,
    also can occur.
  • - All these agents can produce arlthropathy in
    several species of immature animals.
    Traditionally, the use of quinolones in children
    has been contraindicated for this reason.

71
  • 3-Antiseptic and analgesic of urinary tract
    infections
  • Methenamine
  • - Methenamine is a urinary tract antiseptic and
    prodrug that owes its at an acidic pH of 5.5 or
    less in the urine, thus producing formaldehyde
    and nearly all bacteria are
  • sensitive to free formaldehyde. It has
    bactericidal action
  • - Methenamine is not a primary drug for the
    treatment of acute urinary tract infections, but
    it is of value for chronic suppressive treatment
    for recurrent urinary tract infections.
  • - It is absorbed orally and gastrointestinal
    distress frequently is caused by doses greater
    than 500 mg four times a day.
  • - Because of the ammonia produced, methenamine is
    contraindicated in hepatic insufficiency.
  • Nitrofurantoin
  • - Nitrofurantoin inhibits several bacterial
    enzyme systems including acetyl coenzyme A
    interfering with metabolism and possibility cell
    wall synthesis.
  • - Nitrofurantoin is approved only for the
    treatment of urinary tract infections caused by
    microorganisms known to be susceptible to the
    drug. Currently, bacterial resistance to
    nitrofurantoin is more frequent than resistance
    to fluoroquinolones or trimethoprim-
    sulfamethoxazole, making nitrofurantoin a
    second-line agent for treatment of urinary tract
    infections. However, nitrofurantoin is
    effective for prophylaxis of recurrent urinary
    tract infections. The oral dosage of
    nitrofurantoin for adults is 50 to 100 mg four
    times a day with meals and at bedtime.
  • Phenazopyridine
  • - Phenazopyridine hydrochloride is not a urinary
    antiseptic. However, it does have an analgesic
    action on the urinary tract and alleviates
    symptoms of dysuria, frequency, burning
    sensation, and urgency. - The usual dose is 200
    mg three times daily.
  • - The compound is an azo dye, which colors urine
    orange or red the patient should be so
    informed.
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