Transcript Antimicrobial1

Antimicrobial
General Information
-Medications used to treat bacterial infections.
-Antibacterial is a natural, semi-synthetic or synthetic substance that kills or inhibits
bacterial growth.
Bacteriocidal – kills the bacteria
Bacteriostatic – inhibit growth of bacteria
N.B.: Either after arresting the growth of the bacteria by a bacteriostatic or decreasing the
number of viable bacteria by a bactericidal ,the body's immune system attacks, immobilizes,
and eliminates the
pathogens. If the drug is removed before the immune system has
scavenged the organisms, enough viable organisms may remain to begin a second cycle of
infection.
Antimicrobial drugs are effective in the treatment
of infections because of their selective toxicity.
(i.e): they have the ability to injure or kill an
invading microorganism without harming the cells
of the host.
This term is is relative rather than absolute, requiring that the
concentration of the drug be carefully controlled to attack the
microorganism while still being tolerated by the host.
Factors Controlling Selection of
the Antimicrobial Agent:
1) The organism's identity
2) The organism's susceptibility to a particular agent
3) The site of the infection
4) Patient factors
5) Safety of the Agent
6) The cost of therapy.
1-Identification of the infecting organism
A-Gram staining
A rapid assessment of the nature of the pathogen can
sometimes be made on the basis of the Gram stain,
which is particularly useful in identifying the presence
as well identifying the morphologic features of
microorganisms in body fluids that are normally sterile
(CSF, pleural fluid, synovial fluid, peritoneal fluid, and
urine).
B-Culture
it is essential to obtain a sample culture of the organism
prior to initiating treatment.
for definitive identification of the infecting organism to
arrive at a conclusive diagnosis
Sometimes , for definitive identification of the infecting
organism ,other laboratory techniques,
such as detection of microbial antigens, microbial DNA it or
RNA, or detection of an inflammatory or host
immune response to the microorganism is performed.
However, some critically ill patients require empiric therapy that is,
immediate administration of drug(s) prior to bacterial
identification and susceptibility testing.
Ex. patient with severe headache, a rigid neck, and sensitivity to
bright lights (symptoms characteristic of meningitis)”require
immediate treatment.
The choice of drug in the absence of susceptibility data is
influenced by the site of infection and the patient's history (for
example, whether the infection was hospital- or communityacquired, whether the patient is immuno-compromised, as well
as the patient's travel record and age). Generally, broadspectrum therapy are needed initially for serious infections
when the identity of the organism is unknown
2-Determination of antimicrobial susceptibility of
infective organisms
After a pathogen is cultured, its susceptibility to specific antibiotics
serves as a guide in proper choosing antimicrobial therapy.
Even some pathogens, such as Streptococcus usually have predictable
susceptibility patterns to certain antibiotics , others as gramnegative bacilli, enterococci, and staphylococcal species often show
unpredictable susceptibility patterns to various antibiotics and
require susceptibility testing to determine appropriate
antimicrobial therapy.
3-Site of infection
Adequate levels of an antibiotic must reach
the site of infection for the invading
microorganisms to be effectively
eradicated. This is affected by :
1-Lipid solubility of the drug.
2- Molecular weight of the drug
3-Plasm Protein Binding.
4-Patient factors
In selecting an antibiotic, attention must be paid to the condition of the patient. For example,
the status of the patient's immune system, kidneys, liver, circulation, And age must be
considered. In women, pregnancy or breastfeeding also selection of The antimicrobial
agent
Immune system: Elimination of infecting organisms from the body depends on an
intact immune system.
the host defense system must ultimately eliminate the invading organisms. Alcoholism,
diabetes, infection with the human immunodeficiency virus, malnutrition, or
advanced age can affect a patient's immunocompetence, as can therapy with
immunosuppressive drugs. Higher-than-usual doses of bactericidal
agents or longer courses of treatment are required to eliminate infective organisms in
these individuals.
Renal dysfunction: Poor kidney function (10 percent or less of normal) causes
accumulation in the body of
antibiotics that ordinarily are eliminated by this route. This may lead to serious
adverse effects of drugs eliminated by the kidneys. Antibiotics that undergo
extensive metabolism or are excreted via the biliary route may be favored in such
patients.
Hepatic dysfunction: Antibiotics that are concentrated or eliminated by the
liver (for example, erythromycin and tetracycline) are contraindicated
intreating patients with liver disease.
Age: Renal or hepatic elimination processes are often poorly developed in
newborns, making neonates particularly vulnerable to the toxic effects of
chloramphenicol and sulfonamides. Young children should not be treated
with tetracyclines, which affect bone growth.
Pregnancy: All antibiotics cross the placenta. Adverse effects to the fetus are
rare, except the for tooth dysplasia and inhibition of bone growth
encountered with the tetracyclines. Of course, all drugs should be used
only during pregnancy under the supervision of a patient's physician.
lactation: Drugs administered to a lactating mother may enter the nursing
infant via the breast milk. Although the concentration of an antibiotic in
breast milk is usually low, the total dose to the infant may be enough to
cause problems.
5-Safety of the agent
Many of the antibiotics, such as the penicillins, are among
the least toxic of all drugs, because they interfere with a
site unique to the growth of microorganisms. Other
antimicrobial agents (for example, chloramphenicol) are
reserved for life-threatening infections because of the
drug's potential for serious toxicity to the patient.
Note: safety is related not only to the inherent nature of the drug but
also to patient factors that can predispose to toxicity
6-Cost of therapy
Often, several drugs may show similar efficacy in
treating an infection but vary widely in cost. It
is more preferable to select suitable agent in
its coast for treatment of certain infectious
disease.
Ideal characteristics of antibiotics
-selective toxicity with minimal side effects to host
-easy to tolerate without a complex drug regimen
-bactericidal rather than bacteriostatic
-narrow spectrum rather than broad
-low cost of production for consumer
-stable (shelf-life)
-adequate bioavailability: drug much reach adequate
concentrations in relevant tissues or body sites
A single agent is unlikely to meet all of these criteria
Combinations of Antimicrobial Drugs
It is therapeutically advisable to treat patients with the single agent that is most
specific for the infecting organism.This strategy reduces the possibility of
superinfection, decreases the emergence of resistant organisms,and minimizes
toxicity. However, situations in which combinations of drugs are employed do
exist. For example, the treatment of tuberculosis benefits from drug
combinations.
Advantages of drug combinations
Certain combinations of antibiotics, such as β-lactams and aminoglycosides, show
synergism; that is, the combination is more effective than either of the drugs used
separately.
B. Disadvantages of drug combinations
A number of antibiotics act only when organisms are multiplying. Thus,
coadministration of an agent that causes bacteriostasis plus a second agent that is
bactericidal may result in the first drug interfering with the action of the
second. For example, bacteriostatic tetracycline drugs may interfere with the
bactericidal effect of penicillins and cephalosporins
Mechanisms of Antibiotic Resistance
Many species of bacteria have evolved resistance to
certain antibiotics and synthetic agents
- Resistance may develop if the target bacterial enzyme changes or
if the bacteria evolves an alternate metabolic pathway
Antibiotic Assays and Resistance
- Bacteria may evolve the ability to enzymatically inactivate an
antibiotic e.g. Β-lactamase
- Bacteria may evolve the ability to prevent drug entry into the
cytoplasm or to pump the drug out of the cytoplasm
- Bacteria can evolve changes in drug targets like 30 S ribosomes
binding site.
Complications of Antibiotic Therapy
The drug may produce an allergic response or be toxic in ways unrelated to
the drug's antimicrobial activity.
A. Hypersensitivity
Hypersensitivity reactions to antimicrobial drugs or their metabolic products
frequently occur. For example, the
penicillins, despite their almost absolute selective microbial toxicity, can
cause serious hypersensitivity problems,
ranging from urticaria (hives) to anaphylactic shock.
B. Direct toxicity
High serum levels of certain antibiotics may cause toxicity by directly affecting
cellular processes in the host. For
example, aminoglycosides can cause ototoxicity by interfering with
membrane function in the hair cells of the organ
of Corti.
C. Superinfections
Drug therapy, particularly with broad-spectrum
antimicrobials or combinations of agents, can
lead to alterations of the normal microbial
flora of the upper respiratory, intestinal, and
genitourinary tracts, permitting the
overgrowth of opportunistic organisms,
especially fungi or resistant bacteria. These
infections are often difficult to treat
Mechanism of antimicrobial Agents
1. Inhibition of cell wall synthesis
e.g. Penicillins, cephalosporins & vancomycin
Human cells do not have a cell wall, so these drugs are specific
only for bacteria. They will kill or stop replication of the bacteria
without damaging the host.
2. Inhibition of protein synthesis
e.g. Tetracycline, aminoglycosides, chloramphenicol, erythromycin
Selective toxicity relies on the fact that the bacterial ribosome
differs in size to the human ribosome
3. Inhibition of nucleic acid synthesis
Affect microbial specific enzymes, e.g. DNA
dependent RNA polymerase.
4. Antimetabolites
Affect the metabolism of the organism by having a
negative effect on some vital metabolite. Humans
are unable to synthesize foliate and so must get it
from the food, whereas bacteria must make their
own. Hence, inhibition of foliate metabolism can
hinder bacterial growth. e.g. Trimethoprim
I-Antimetabolites
Folate Antagonists
Folate-derived cofactors are essential for the synthesis
of purines and pyrimidines (precursors of RNA and
DNA) and other compounds necessary for cellular
growth and replication. Therefore, in the absence of
folate, cells cannot grow or divide. To synthesize the
critical folate derivative, tetrahydrofolic acid, humans
must first obtain preformed folate in the form of folic
acid as a vitamin from the diet. In contrast, many
bacteria are impermeable to folic acid and other folates
and, therefore, must rely on their ability to synthesize
folate de novo. The sulfonamides (sulfa drugs) are a
family of antibiotics that inhibit this de novo synthesis
of folate.
Cont; Sulfonamides
-One of the first groups of antibiotics
-Bacteriostatic in action
-Prevent synthesis of folic acid required for
synthesis of purines and pyrimidines.
-Does not affect human cells or certain bacteria
that can use preformed folic acid
-Examples:
Short acting: sulfadiazine, sulfamethazine
Intermediate acting : sulfamethoxazole
Long acting : sulfathiazole , sulfasalazine
F. Spectrum of Activity
-Broad range of Gm+ and Gm-They are also active against some protozoa as
toxoplasmosis and chloroquine-resistant
malaria.
G. Resistance
- common due to:
1) an altered dihydropteroate synthetase.
2)decreased cellular permeability to sulfa drugs
3) enhanced production of the natural
substrate, PABA.
H. Uses
1- Respiratory and urinary tract infection. 2-Ulcerative colitis
3-Skin wounds and skin burns.
4-Toxoplasmosis and malaria.
5-in burn units, creams of silver sulfadiazine or mafenide acetate
have been effective in reducing burn-associated sepsis, because
they prevent colonization of bacteria. However,Silver sulfadiazine is
preferred, because mafenide produces pain on application.
I. Side effects
-Hypersensitivity reactions (e.g., rashes and drug fever) in a small
number of patients. Other cause allergic reactions include
photosensitivity.
-Stevens-Johnson syndrome is also associated with sulfonamide
use; it is characterized by fever, malaise, erythema ,and
ulceration of the mucous membranes of the mouth and
genitalia.
-Hemolytic anemia may develop in persons with a genetic
deficiency of red blood cell glucose-6-phosphate dehydrogenase
(G6PD).
-High concentration of sulfonamides with aqueous solubility which is
sufficiently low, the free drug or its metabolites may form crystals
and cause bleeding or complete obstruction of the kidneys.
i-Combinations of sulfa (for lowering the dosage of
individual agents)
ii- A lot of fluids intake
iii-Alkalinization of the urine (to increase excretion)
to reduce the chance of crystalluria
-Sulfonamides compete for sites on plasma proteins that are
responsible for the binding of bilirubin. As a result, less bilirubin is
bound, and in the newborn, the unbound bilirubin can be
deposited in the basal ganglia, causing kernicterus, a toxic
encephalopathy. For this reason, sulfonamides should not be
administered to newborns or to women during the last 2 months
of pregnancy or lactating females.
-Significant drug–drug interactions are those that potentiate the
effects of other agents and require dosage reduction. These
include certain anticoagulants, and hypoglycemic
D.
Antibacterial spectrum
-The antibacterial spectrum of trimethoprim is
similar to that of sulfamethoxazole. It is active against most gram-
positive and gram negative organisms. There is little activity against
anaerobic bacteria.However, trimethoprim is 20-to 50-fold more
potent than the sulfonamide.
E. Uses
Trimethoprim may be used alone in the treatment of acute UTIs and in the
treatment
of bacterial prostatitis and vaginitis is used in the treatment of genitourinary,
GI,
and respiratory tract infections.
F. Resistance
Resistance in gram-negative bacteria is due to the presence of an altered
dihydrofolate
reductase that has a lower affinity for trimethoprim. Overproduction of the
enzyme
may also lead to resistance, because this can decrease drug permeability.
G. Adverse effects
Trimethoprim can produce the effects of folic acid deficiency.6 These effects
include megaloblastic anemia, leukopenia, and granulocytopenia,
especially in pregnant
patients and those having very poor diets. These blood disorders can be
reversed by the simultaneous administration of folinic acid, which does
not enter bacteria.
III-Cotrimoxazole
The combination of trimethoprim with sulfamethoxazole, called cotrimoxazole shows
greater antimicrobial activity than equivalent quantities of either drug used alone .The
combination was selected because of the similarity in the half-lives of the two drugs.
Rationally, by blocking the first stepin folic acid synthesis, there is no real reason to
block further steps. However, there are some bacteria which can inhibits the initial
blockage, and so this may be the rationale for the use of such combination.
-There is synergy between the two drugs - the combined effect is greater that the
expected sum of their activities
-Individually the drugs are bacteriostatic; however, in combination they are
bactericidal
-The use of two drugs will delay the emergence of resistance.
Mechanism of action
Resistance
-The bacteria by gentic mutation they do not need to make folic acid they utilize
already formed folic acid.
--Overproduce the target e.g. To overcome trimethoprim, bacteria can
overproduce DHFR to overcome the inhibition of trimethoprim.
-Bacteria produce mutated DHFR
Side effects
TMP-SMX can cause the same adverse effects as those associated with
sulfonamide administration. Most of the adverse effects of this combination are
due to the sulfamethoxazole component.
Uses
TMP-SMX is used in the treatment of infection caused by ampicillin-resistant
Shigella and for antibiotic-resistant Salmonella.
-Successful in treatment of traveler’s diarrhea due to susceptible E. coli.
-Because trimethoprim accumulates in the prostate, TMP-SMX is used to treat
prostatitis caused by sensitive organisms.
- Used n Pneumocystis jiroveci pneumonia occur in HIV patients.
Uses of Cotrimoxazol
II-Drugs Inhibit nucleic
acid synthesis
Fluoroquinolones
Fluoroquinolones were first introduced in 1986, they are
modified quinolones, a class of antibiotics, whose accidental
discovery occurred in the early 1960.
The fluoroquinolones are a family of synthetic, broad-spectrum
antibacterial agents with bactericidal activity.
The parent of the group is nalidixic acid, discovered in 1962 by
Lescher and colleagues. It was used orally for the treatment
of infections caused by gram-negative organisms.
The newer fluoroquinolones have a wider clinical use and a
broader spectrum of antibacterial activity including grampositive and gram-negative aerobic and anaerobic organisms
Mechanism of Action
The fluoroquinolones enter the bacterium by
passive diffusion through water-filled protein
channels (porins) in the outer membrane. Once
inside the cell, they inhibit the replication of
bacterial DNA by interfering with the action of
DNA gyrase (topoisomerase II) and topoisomerase
IV during bacterial growth Binding of the
quinolone to both the enzyme and the DNA forms
a ternary complex that inhibits the resealing step,
and can cause cell death.
In gram-negative organisms ,the inhibition of DNA
gyrase is more significant than that of
topoisomerase IV, whereas in gram-positive organisms the opposite is
true.
•Basis for Selective Toxicity
- Quinolones have a relatively low affinity for
mammalian DNA topoisomerase
Mechanisms of bacterial resistance
– change in target enzyme (DNA gyrase or topoisomerase IV)
– change in permeability of organism (decrease in number of
porin channles).
-Increase in efflux of the AB.
Classification of Fluoroquinolones
First Generation
The first-generation agents include cinoxacin, pipdemic
acid and nalidixic acid, which are the oldest and least
often used quinolones. These drugs had poor
systemic distribution , limited activity (against gramnegative bacteria not including psudomionas sp),and
were used primarily simple urinary tract infections.
- Cinoxacin and nalidixic acid require more frequent
dosing (4 times daily) than the newer quinolones,
and they are more susceptible to the development
of bacterial resistance.
Nalidixic acid
Second Generation.
-The second-generation fluoroquinolones have increased gram-negative
activity, as well as some gram-positive and atypical respiratory pathogen
coverage. This is mainly due to inserion of F atom in position 6 in the
naphthyridine core.
-Compared with first-generation quinolones, these drugs have broader clinical
applications in the treatment of :complicated urinary tract infections
,pyelonephritis, sexually transmitted diseases , and skin infections.
-Agents of Second-generation include norfloxacin ,ciprofloxacin, enoxacin,
lomefloxacin, and ofloxacin.
-Ciprofloxacin and ofloxacin are the most widely used second-generation
quinolones because of their availability in oral and intravenous formulations
and their broad set of FDA-labeled indications.
N-cyclopropyle moity
increased bioavilibility
Ciprofloxacin
*Secound generation Fluoroquinolones advantages:
-Active against gram-negative including Pseudomonas
species and some gram- positive aerobic organism
-Twice daily dosing.
-Excellent oral absorption reached in some members
to 99%
-Excellent tissue penetration with prolonged half-lives
-Overall safety
Third Generation.
The third-generation fluoroquinolones are separated into a third
class because of their expanded activity against gram-positive
organisms (particularly penicillin-sensitive and penicillinresistant S. pneumoniae) and atypical pathogens such as
Mycoplasma pneumoniae and Chlamydia pneumoniae.
-Although the third-generation agents retain broad gram-negative
coverage, they are less active than ciprofloxacin against
Pseudomonas species.
-Because of their expanded antimicrobial spectrum, thirdgeneration fluoroquinolones are useful in the treatment of
community-acquired pneumonia
-The third-generation fluoroquinolones include levofloxacin,
gatifloxacin, moxifloxacin and gemifloxacin (maine adverse
effect is rash in females under 40 years old).
Levofloxacin (Levo- enantiomer of ofloxacin)
Fourth Generation.
The fourth-generation fluoroquinolones add significant antimicrobial
activity against anaerobes while maintaining the gram-positive and
gram-negative activity of the third-generation drugs. They also
retain activity against Pseudomonas species comparable to that of
ciprofloxacin. The fourth-generation fluoroquinolones include
trovafloxacin (Trovan).
-Because of concern about hepatotoxicity, trovafloxacin therapy
should be reserved for life-threatening infections requiring in
patient treatment (hospital or long-term care facility), and the drug
should be taken for no longer than 14 days.
Side effects
The fluoroquinolones as a class are generally well tolerated. Most
adverse effects are mild in severity, self-limited, and rarely result in
treatment discontinuation. However, they can have some serious
adverse effects.
-Fluoroquinolones are approved for use only in people older than 18.
They can affect the growth of cartilage in a child or fetus. The FDA
has assigned fluoroquinolones to pregnancy risk category C,
indicating that these drugs have the potential to cause teratogenic
or embryocidal effects.
-These agents are also excreted in breast milk and should be avoided
during breast-feeding if at all possible
Gastrointestinal effects.
The most common adverse events experienced with fluoroquinolone
administration are gastrointestinal (nausea, vomiting, diarrhea,
constipation, and abdominal pain), which occur in 1 to 5% of
patients.
CNS effects.
-Headache, dizziness, and drowsiness have been reported with all
fluoroquinolones.
-Insomnia was reported in 3-7% of patients with ofloxacin.
-Severe CNS effects, including seizures, have been reported in patients
receiving some members of fluoroquinolones. Seizures may
develop within 3 to 4 days of therapy but resolve with drug
discontinuation. Although seizures are infrequent,
fluoroquinolones should be avoided in patients with a history of
convulsion, cerebral trauma, or anoxia.
Phototoxicity.
Exposure to ultraviolet rays from direct or indirect sunlight should be
avoided during treatment and several days (5 days) after the use of
the drug. The degree of phototoxic potential of fluoroquinolones is
as follows: lomefloxacin > sparfloxacin > ciprofloxacin
Tendon damage (tendon rupture). Although fluoroquinolone-related
tendinitis generally resolves within one week of discontinuation of
therapy, spontaneous ruptures have been reported as long as nine
months after cessation of fluoroquinolone use. Potential risk
factors for tendinopathy include age >60 years, male gender, and
concomitant use of corticosteroids.
Hepatoxicity.
Trovafloxacin use has been associated with rare liver damage, which
prompted the withdrawal of the oral preparations from the U.S.
market.
Cardiovascular effects.
The newer quinolones have been found to produce additional
toxicities to the heart that were not found with the older
compounds. Evidence suggests that grapifloxacin may have the
most cardiotoxic potential.
Glucose homostasis abnormalities (Hypoglycemia or hyperglycemia).
Recently, rare cases of hypoglycemia have been reported with
ciprofloxacin in patients also receiving oral diabetic medications,
primarily sulfonylureas. Although hypoglycemia has been reported
with other fluoroquinolones (levofloxacin and moxifloxacin), the
effects have been mild. On the other hand, hyperglycemia can
occur in other patients receiving fluoroquinolones .
Indications and uses
The newer fluoroquinolones have a wider clinical use and a broader spectrum of
antibacterial activity including gram-positive and gram-negative aerobic and
anaerobic organisms.
All of the fluoroquinolones are effective in treating urinary tract infections caused
by susceptible organisms. They are the first-line treatment of acute
uncomplicated cystitis in patients who cannot tolerate sulfonamides or TMP.
-Urinary tract infections
-Lower respiratory tract infections
-Skin and skin-structure infections
-Urethral and cervical gonococcal infections
-Prostatitis
-Acute exacerbations of chronic bronchitis
-Inhalation anthrax
-Community-acquired pneumonia
III-Protein Synthesis
Inhibitors
Reason For Selective Toxicity
A number of antibiotics exert their antimicrobial effects
by targeting the bacterial ribosome, which has
components that differ structurally from those of the
mammalian cytoplasmic ribosome. In general, the
bacterial ribosome is smaller (70S) than the
mammalian ribosome (80S) and is composed of 50S
and 30S subunits (as compared to 60S and
40S subunits in human).
1-Aminoglycosides
They are highly polar, polycationic structure that prevents adequate absorption
after oral administration Therefore, all aminoglycosides (except neomycin
)must be given parenterally to achieve adequate serum levels.
Note: The severe nephrotoxicity associated with neomycin precludes parenteral
administration, and its current use is limited to topical application for skin
infections or oral administration to prepare the bowel prior to surgery.
The bactericidal effect of aminoglycosides is concentration and time dependent;
that is, the greater the concentration of drug, the
greater the rate at which the organisms die. They also have a postantibiotic
effect. Because of these properties:
once-daily dosing with the aminoglycosides can be employed.
Aminoglycosides that are derived from Streptomyces have -mycin suffixes,
whereas those derived from Micromonospora end in –micin ex. gentamicin
Mechanism of action
-The initial event is passive diffusion via porin channels across the cell wall. Drug is
then transported across the cell membrane into the cytoplasm. They are
concenterated in the bacteria by this active transport which require energy and O2
- Bind irreversibly to the 30s unit of the ribosome and distorts the reading frame.
Protein synthesis can still continue, but distortion results in either misense or
nonsense codons leading to the wrong amino acid being used and premature
termination· The proteins produced by the bacteria which are required in
maintaining cell integrity and functions are going to be non-functional ones.
-
Under anaerobic conditions, aminoglycosides are highly charged, and therefore
will be unable to work. Hence, anaerobic bacteria tend to be more resistant to
them.
-Note: The aminoglycosides synergize with β-lactam antibiotics because of the latter's
action on cell wall synthesis, which enhances diffusion of the aminoglycosides into
the bacterium.
Resistance
1-Resistance can occur by altering the 30s ribosome binding site of the drug / low
affinity of the drug.
2- Impaired intracellular transport: Decrease the active transport of the AB.
3- Inactivation by microbial enzymes :Bacteria can produce deactivating enzymes
as phosphotransferases, adenyltransferases and acetyltransferases Each of
these enzymes has its own aminoglycoside specificity; therefore, crossresistance is not an invariable rule. [Note: Amikacin is less vulnerable to these
enzymes than are the other antibiotics of this group
(mostly neomycin).
Spectrum and Uses
Aminoglycosides act
bactericidal on dividing and no
dividing microorganisms.They
are in general active against
aerobic Gram-negative
including Pseudomonas
aeruginosa.
The exact mechanism of their
lethality is unknown because
other antibiotics that affect
protein synthesis are generally
bacteriostatic
-Respiratory tract infection
-Their oral use are restricted to
their action against GIT
infections as amebiasis
(mostly neomycin).
Adverse effects
All aminoglycosides are ototoxic and nephrotoxic.
-Ototoxicity and nephrotoxicity are more likely to be encountered
when therapy is continued for more than 5 days, at higher doses,
in the elderly, and in the setting of renal insufficiency.
-Concurrent use with loop diuretics (eg, furosemide, ethacrynic
acid) or other nephrotoxic antimicrobial agents (vancomycin,
amphotericin) can potentiate nephrotoxicity and should be avoided.
-Ototoxicity can manifest itself either as auditory damage,
resulting in tinnitus and high-frequency hearing loss initially,
or as vestibular damage, evident by vertigo, ataxia, and loss of
balance.
Copnt.: Adverse effects
-Also they produce a curare-like effect with neuromuscular blocking
effect that results in respiratory paralysis. The mechanism
responsible is a decrease in both the release of acetylcholine from
prejunctional nerve endings and the sensitivity of the
postsynaptic site. Patients with myasthenia gravis are particularly
at risk.This paralysis is usually reversible by calcium gluconate or
neostigmine.
-Hypersensitivity occurs infrequently.
2- TETRACYCLINES
They are safe, inexpensive ,broad-spectrum, bacteriostatic
. antibiotics, that are effective against aerobic and anaerobic grampositive and gram-negative bacteria as well as against organisms
other than bacteria.
7
6
5
4
-The basic tetracycline structure consists of four benzene rings with various
substituent on each ring.
-They are faintly yellow, odorless, slightly bitter compounds.
Tetracyclines are classified as:
(1) short-acting :chlortetracycline, tetracycline,
oxytetracycline
(2) intermediate acting :demeclocycline and
methacycline
(3) long-acting :doxycycline and minocycline
The almost complete absorption and slow
excretion of doxycycline and minocycline
allow for once-daily dosing.
A newly approved tetracycline analog, tigecycline, Is a
semisynthetic derivative of minocycline.
-Many tetracycline-resistant strains are susceptible to tigecycline.
It has broad spectrum. Tigecycline was developed to overcome
the recent emergence of tetracycline “resistant organisms that
utilize efflux and ribosomal protection to infer resistance
WHY???.
Mechanism of action
-Tetracyclines enter microorganisms in part by passive
diffusion (through cell wall) and in part by an energydependent process (active transport through cell
membrane). Susceptible cells concentrate the
drug intracellularly.
-Once inside the cell, tetracyclines bind reversibly to
the 30S subunit of the bacterial ribosome, blocking the
binding of aminoacyl-tRNA to the acceptor site on the
mRNA-ribosome complex. This prevents addition of
amino acids to the growing peptide.
-Tetracyclines are broad-spectrum bacteriostatic
antibiotics that inhibit protein synthesis.
Mechanisms of resistance
(1) 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
Any organism resistant to one tetracycline is
resistant to all.
Pharmacokinetics
-Substitutions on these rings are responsible for variation in the
drugs'individual pharmacokinetics, which cause small differences in their
clinical efficacy.
-Absorption after oral administration is approximately 60–70% for tetracycline,
oxytetracycline, and methacycline; and 95–100% for doxycycline and
minocycline.
-Absorption occurs mainly in the upper small intestine
and is impaired by food (except doxycycline and minocycline); by divalent
cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which
contain multivalent cations.
-Tetracyclines are 40–80% bound by plasma proteins.Tetracyclines are
distributed widely to tissues and body fluids except for CSF, where
concentrations are 10–25% of those in serum.
(Minocycline reaches very high concentrations in tears and saliva, which
makes it useful for eradication of the meningococcalcarrier state).
-Tetracyclines cross the placenta to reachthe fetus and are also excreted
in milk. As a result of chelation with calcium, tetracyclines are bound to
and damage growing bones and teeth.
-Tetracyclines are excreted mainly in bile and urine. Some of the drug
excreted in bile is reabsorbed from the intestine (enterohepatic circulation)
and may contribute to maintenance of serum levels .
Excretion into the urine, mainly by glomerular Filtration . Small % of the
these drugs are excreted in feces.
-Minocycline and mostly Doxycycline, in contrast to other tetracyclines, is
eliminated nonrenaly , do not require dosage adjustment in renal failure.
Thus it is one of the safest TET for the treatment of extrarenal infections
Spectrum & Clinical Uses
-Tetracyclines are active against many Gram-positive and Gram-negative bacteria,
including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and against some
protozoa, as amebas.
-Minocycline is usually the most active followed by doxycycline.
-Tetracyclines remain effective in most chlamydial infections, including sexually
transmitted diseases.
-Tetracyclines are effective in treatment of Rocky Mountain spotted fever by
rickettsia rickettsii.
-Other uses include treatment of acne, exacerbations of bronchitis & communityacquired pneumonia
-They are used in combination regimens to treat gastric and duodenal ulcer
disease caused by H. pylori.
- Although all tetracyclines enter the (CSF), levels are insufficient for therapeutic
efficacy, except for minocycline enters the brain in the absence of inflammation
and also appears in tears and saliva so it is useful in
eradicating the meningococcal carrier state, but not effective for central nervous
system infections.
Adverse Reactions
TET can produce a variety of adverse effects ranging from minor
inconvenience to life-threatening.
-Hypersensitivity reactions (drug fever, skin rashes) to
tetracyclines are not very common.
-Nausea, vomiting, and diarrhea are the most common
reasons for discontinuing tetracycline medication.
These effects are attributable to direct local irritation of
the intestinal tract. These effects can usually be controlled by administering the drug with carboxymethylcellulose, reducing drug dosage, or discontinuing the drug.
-TET like other antimicrobial agents administered orally may
lead to development superinfections, as Tetracyclines
modify the normal flora, with suppression of susceptible
organisms and overgrowth of pseudomonas, proteus,
staphylococci, , clostridia (causing Pseudo membranous
colitis ), and candida. This can result in intestinal functional
disturbances, anal pruritus, vaginal or oral candidiasis
Diarrhea must be distinguished either:
A. Normal -loose stools do not contain blood or leukocytes
B. Pseudo membranous colitis -severe diarrhea, fever, stools
containing shreds of mucous membrane and large number of
neutrophils. As CI. difficile produces a toxin which is
cytotoxic to mucosal cells.
--Tetracyclines are readily bound to calcium deposited
in newly formed bone or teeth in young children.
When a tetracycline is given during pregnancy, it can
be deposited in the fetal teeth, leading to fluorescence,
discoloration, and enamel dysplasia; it can also be
deposited in bone, where it may cause deformity or
growth inhibition. If the drug is given for long periods to
children under 8 years of age, similar changes can
result.
4-Chloramphenicol
An antibiotic produced by Streptomyces venezuelae, an
organism first isolated from a soil sample in Venezuela.
Chloramphenicol
inhibits protein synthesis in bacteria and, to a lesser
extent, in eukaryotic cells
The drug is either bacteriostatic, or bactericidal
depending on the organism.
Mechanism of Action
-It readily penetrates bacterial cells, by
facilitated diffusion.
-It acts primarily by binding reversibly to the 50S
ribosomal subunit. The drug prevent the
interaction between peptidyltransferase and
its amino acid substrate, and peptide bond
formation is inhibited .
Because of the similarity of mammalian
mitochondrial ribosomes to those of
bacteria,protein synthesis in these organelles
may be inhibited at high circulating
chloramphenicol levels, producing bone
marrow toxicity.
Resistance
Resistance is conferred by the presence of an acetyl coenzyme A transferase.
This enzyme inactivates chloramphenicol
.
Adverse effects
1-Nausea, vomiting, unpleasant taste, and diarrhea may follow the oral
administration of chloramphenicol. Among the rare toxic effects
produced by this antibiotic are blurring of vision and paresthesias.
2-Hematologic Toxicity
The most important adverse effect of chloramphenicol is on the bone
marrow cells. Chloramphenicol affects the hematopoietic system in two
ways:
by an non-dose-related idiosyncratic response manifested by aplastic anemia,
leading in many cases to death of the patient.
-by a dose-related toxic effect that presents as anemia, It seems to occur more
commonly in individuals who undergo prolonged therapy.
3-Gray baby syndrome
Fatal chloramphenicol toxicity may develop in neonates,
especially premature babies, when they are exposed to
excessive doses of the drug.
The gray baby syndrome, usually begins 2 to 9 days after
treatment is started.
The manifestations in the first 24 hours are vomiting, refusal to
suck, irregular and rapid respiration, abdominal distention,
periods of cyanosis, and passage of loose, green stools. Soon
they become flaccid, turn an ashen-gray color, and become
hypothermic
Two mechanisms are apparently responsible for chloramphenicol
toxicity in neonates
(1) failure of the drug to be conjugated with glucuronic acid, owing
to inadequate activity of glucuronyl transferase in the liver of the
infant , which is characteristic of the first 3 to 4 weeks of life.
(2) inadequate renal excretion of unconjugated drug in the
newborn.
-Exchange transfusion and charcoal hemoperfusion have been used
to treat overdose with chloramphenicol in infants
4-Although relatively uncommon skin rashes occur as a result of
hypersensitivity to chloramphenicol.
Therapeutic Uses
Chloramphenicol has a wide range activity that includes gram+,
gram-, aerobic and anaerobic bacteria
But because of potential toxicity, bacterial resistance, and the availability of many
other effective alternatives, chloramphenicol is rarely used.
-It may be considered for treatment of :
-Typhoid Fever
-Bacterial Meningitis (alternative to a beta-lactams for treatment of
meningococcal meningitis
occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis
caused by penicillin-resistant strains of pneumococci)
-Rickettsial Diseases (alternative to tetracycline especially in children <8 years old )
5-Clindamycin
Clindamycin has a mechanism of action that is the same as that of
erythromycin. (i.e) Inhibiting the translocation steps of protein
synthesis. They may also interfere at other steps, such as
transpeptidation
Clindamycin is employed primarily in the treatment of
infections caused by anaerobic bacteria, such that
causes abdominal infections associated with trauma.
However, it is also significantly active against gram
-positive cocci.
Resistance
1)The inability of the organism to take up the antibiotic
or the presence of an efflux pump.
2) Decreased affinity of the 50S ribosomal subunit for the antibiotic,
resulting from the methylation of bacterial ribosomal RNA
..
Adverse effect
-Skin rashes.
-The most serious adverse effect is potentially fat
pseudomembranous colitis caused by overgrowth of
Clostridium. difficile, which elaborates necrotizing
toxins. Oraladministration of either metronidazole or
vancomycin is usually effective in controlling this
serious problem. [Note: Vancomycin should be
reserved for a condition that does not respond to
metronidazole.]