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
(No Transcript)
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
(No Transcript)
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.