Antimicrobial TherapyAntimicrobial Therapy
Dr. Yahya Ibn Ilias
Are effective in the treatment of infections
because of their selective toxicity i.e the ability
to kill an invading micro organism without
harming the cells of the host.
Antibiotic is the term used to describe any
compound ( Synthetic / Natural) that inhibit of
or kills micro organism.
Antimicrobial TherapyAntimicrobial Therapy
• Selective destruction of the microorganism.
• No or rare side effects on the host.
• Antimicrobial substances should have a specific
action against molecules or enzymes or
metabolism of the microorganism only.
Criteria that determine the effectivenessCriteria that determine the effectiveness
of antimicrobial agents:of antimicrobial agents:
Antibiotic Sensitivity TestAntibiotic Sensitivity Test
During recent years, many bacteria have shown drug
resistance against single or multiple drugs.
Once the organism is isolated from clinical sample, it
is necessary to identify them and to test them against
various antibiotics so as to choose the most effective
one and in turn, to treat the patient in most rational
Main purpose of Antibiotic Sensitivity Test:
To guide clinician in selecting the best antimicrobial
agent in order to treat the patient.
Bacteriostatic Vs Bactericidal drugs
Bacteriostatic drugs arrest the growth and replication
of bacteria at serum levels achievable in the patient ,thus
limiting the spread of infection while the body’s immune
system attacks, immobilizes and eliminates the pathogens.
Bacteriocidal drugs kill bacteria and decreases the
total number of viable organism.
Eg: Chloramphenicol is static against gram-ve rods and
cidal against pnemococci.
Antimicrobial spectra of a particular drug refers to the
species of organisms affected by that drug.
1. Narrow spectrum: Antimicrobial agents acting
only on a single or a limited group of micro
Eg: isoniazid is active only against mycobacteria.
Glycopeptides and bacitracin are only effective against Gram-positive bacteria,
whereas polymixins are usually only effective against Gram negative bacteria.
Aminoglycosides and sulfonamides are only effective against aerobic organisms,
while nitroimidazoles are generally only effective for anaerobes.
2. Broad Spectrum: Drugs that affect a wide variety of species .
Eg: Tetracycline and chloramphenicol, fluoroquinolones, “third-
generation” and “fourth-generation” cephalosporins.
Administration of broad spectrum antibiotics can drastically alter
the nature of the normal bacteria flora and can precipitate a
super infection of an organism.
Extended expectrum: Applied to antibiotics
that are effective against gram +ve
organisms and also against a significant
number of gram -ve bacteria.
Eg: Ampicillin as it acts gram +ve and
some gram-ve bacteria.
Combinations of Antimicrobial drugs
It is therapeutically advisable to treat with the
single agent that is most specific for the infecting
This strategy reduces the possibility of super
infection, decreases the emergence of resistant
organisms and minimizes toxicity.
However situations in which combinations of drugs
are employed do exist. Eg: Rx of tuberculosis
benefits from drug combinations.
Advantages of drug combinations:
Certain combinations of antibiotics such as b-lactams and
aminogycosides show synergism i.e. combination is
more effective than either of the drugs used separately.
Disadvantages of drug combinations:
A number of antibiotics act only when organisms are
growing. Thus concomitant administration of a second
agent that results in bacteriostatic may interfere with the
action of the first drug that is bactericidal.
Bacteria is said to be resistant if their growth is not halted by
the maximal level of an antibiotic that is tolerated by the host.
Some organisms are inherently resistant to an antibiotic. Eg:
gram – (ve) bacilli are resistant to Penicillin or M. Tuberculosis
is insensitive to Tetracyclines.
However, microbial species normally responsive to a particular
drug may develop resistant strains.
The emergence of these resistant strains has been ascribed to the
inappropriate use of antibiotics in conditions that might resolve
without treatment or which are amenable to antibiotic therapy. eg:
Mechanism of Resistance
Susceptible bacteria can acquire resistance
to AMAs by either Genetic mutation
or by accepting Antimicrobial
resistance gene from other
A. Genetic alteration leading to drug resistant:
Resistance develops due to ability of DNA to:
1.Undergo spontaneous mutation
2.Move from one organism to another (resistance develop due to DNA
transfer from one organism to another)
B. Altered expression of proteins in drug resistant
1.Alteration of the target site through mutation can confer resistance as
occurs with the penicillin binding proteins in methicillin-resistant S.aureus.
2. Efflux systems : That pumps out the drugs (tetracycline)
3. The ability to destroy or inactivate the antimicrobial agent
also can confer resistance on microorganisms. Eg:b-lactamase
destroy many penicillins and cephalosporins, acetyltransferase can
convert chloramphenicol to an inactive compound.
C. Decreased penetrability of an agent can protect organisms
against that antibiotic because it is unable to gain access to the
site of action due to the presence of lipopolysaccharide layer
Complications of Antibiotic Therapy
1.Hypersensitivity: Hypersensitivity reactions to
antimicrobial drugs or their metabolic products frequently
Eg: Penicillins despite their almost absolute selective microbial
toxicity can cause serious hypersensitivity problems, ranging
from urticaria to anaphylactic shock.
2.Direct Toxicity: High serum levels of certain antibiotics
may cause toxicity by affecting cellular processes in the host
Eg: Aminoglycosides can cause ototoxicity by interfering with
membrane function in the hair cells of the organ of corti.
Drug therapy, particularly with broad spectrum
antimicrobials or combinations of agents, can lead to
alterations of the normal 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
An additional infection occurring during the course of an existing infection,
usually caused by opportunistic microorganisms resistant to the antimicrobial
agents used in treating the first infection
Misuses of Antibiotics
TREATMENT OF NONRESPONSIVE INFECTIONS
Most viral diseases are self-limited and do not respond to any of the currently
available anti-infective compounds. Thus, antibiotic therapy of at least 90% of
infections of the upper respiratory tract and many GI infections is ineffective.
THERAPY OF FEVER OF UNKNOWN ORIGIN
Fever of short duration in the absence of localizing signs usually is associated with
undefined viral infections. Antimicrobial therapy is unnecessary, and resolution of
fever usually occurs spontaneously within a week.
Fever persisting for 2 or more weeks, commonly referred to as fever of unknown
origin, has a variety of causes; only about one quarter of these are infections.
Moreover, some of these infections (e.g., tuberculosis,disseminated fungal
infections) may require antibiotics that are not typically used for
Inappropriately administered antibiotics may mask an underlying infection, delay
the diagnosis, and prevent the identification of the infectious pathogen by culture.
Dosing errors with antibiotics are common. Excessive dosing can result
in significant toxicities, while too low a dose may result in treatment
failure and is most likely to select for antibiotic resistance.
INAPPROPRIATE RELIANCE ON CHEMOTHERAPY ALONE
Infections complicated by abscess formation or the presence of necrotic
tissue or a foreign body often cannot be cured by antibiotic therapy
Drainage, debridement, and removal of the foreign body are at least as
important as the choice of antibiotic agent.
As a general rule, when an appreciable quantity of pus, necrotic tissue,
or a foreign body is present, the most effective therapy is an
antimicrobial agent given in adequate dose plus a properly performed
CLASSIFICATION AND MECHANISM
Antimicrobial agents are classified based on proposed
mechanism of action as follows:
(1) Agents that inhibit synthesis of bacterial cell
walls, including the b-lactam class and other agents
such as Vancomycin;
(2) Agents that act directly on the cell membrane to
increase permeability and cause leakage of intracellular
(3) Agents that disrupt function of ribosomal
subunits to reversibly inhibit protein synthesis (e.g.,
chloramphenicol, the tetracyclines, erythromycin, and
(4) Agents that bind to the 30S ribosomal subunit
and alter protein synthesis (e.g., the
(5) Agents that affect bacterial nucleic acid
metabolism by inhibiting RNA polymerase (e.g.,
rifampin) or Topoisomerase / DNA gyrase (e.g., the
(6) The antimetabolites, including trimethoprim and the
sulfonamides, which block essential enzymes (PABA)
of folate metabolism.
C. Carbapenems: Imipenem, Meropenem,
D. Monobactams: Aztreonam
Other Antibiotics: Vancomycin, Bacitracin
B-Lactamase Inhibitors: Clavulanic acid, sulbactam
Most widely effective antibiotics and are among the least
toxic drugs known.
Mechanism of action (MOA):
Bacterial cell wall is cross linked polymer of polysaccharides and
Penicillin interact with penicillin binding protein(PBP) on
cytoplasmic membrane to inhibit transpeptidation reactions
involved in cross linking of peptidoglycan chains, the final step
in cell wall synthesis.
Penicillins are only effective against rapidly
growing organisms that synthesize a
peptidoglycan cell wall.
Consequently they are inactive against
organisms devoid of this structure, such as
mycobacteria, protozoa, fungi and viruses.
Activation of autolytic enzymes(autolysins) that
destroy the existing cell wall.
B-lactam ring is present in penicillin. B-lactamase is the
enzyme that hydrolyzes the cyclic amide bond of the B-
lactam ring, which results in loss of bactericidal activity.
Subgroups and Antimicrobial
Narrow spectrum, B-lactamase sensitive:
1. Penicillin G (natural penicillins) Acid labile
2. Penicillin V (acid stable )
Streptococcal infection ( Pharyngitis, Otitis media,
Pneumococcal infection :
Meningococcal infection : like meningitis,
Gram + (ve) bacilli : B. Antharcis, C. Diphtheriae
All clostridia are highly sensitive, so are Spirochetes.
Mechanisms of Resistance:
1. Production of beta- lactamase by the organism:
Penicillin -- beta-lactamase ---------- penicillonic
acid (no antibacterial activity)
---- break lactam ring structure. eg: staphylococcal
2. Structural change in PBPs: methicillin resistant s.
aureus, penicillin resistant pneumococci.
3. Reduction in the permeability of the outer
membrane of the bacteria to penicillins.
RESISTANCE TO ANTIBIOTICS-
Administration: oral (amoxycillin), iv (methicillin,
ticarcillin, carbenicillin, piperacillin) or im route
(procaine penicillin and benzathine penicillin).
Absorption: most of the penicillins are incompletely
absorbed after oral administration and reach the
intestine in sufficient amount to affect the
composition of the intestinal flora.
Distribution: distribution of the drug throught the
body is good.
Metabolism: metabolism of these drugs by the
host is usually insignificant, but some
metabolism of penicillin G has been shown to
occur in patients with impaired renal function.
Excretion: most are eliminated through active
tubular secretion. Nafcillin and oxacillin
eliminated largely in bile.
Plasma half life : usually < 2 hours
Narrow spectrum Penicillins
Benzylpenicillin (penicillin G)
Bactericidal in action and very high activity
Destroyed by gastric HCL
Destroyed by beta – lactamase
Short duration of action
Highly water soluble
Pneumococcal, streptococcal (infective endocarditis),
meningococcal meningitis, tetanus, gas gangrene, syphillis,
Penicillin V (acid resistant)
Same as penicillin G but
Less potent activity
Acid resistant (orally active)
Short duration of action
Destroyed by beta – lactamase
Prophylaxis before and after surgery
Beta – lactamase resistant penicillins
The penicillins that are resistant to hydrolysis by beta
lactamase (penicillinase) are called beta – lactamase resistant
Narrow spectrum of activity, but less potent then benzylpenicillin
Acid resistant (except methicillin)
Food interferes absorption of drugs (administered 1 hour before or
Indication is infections caused by penicillinase producing
Staphylococci, for which they are the drug of choice except in area
where methcillin resistant Staph. aureus (MRSA)
Narrow spectrum beta-lactam antibiotic
Used to treat infections caused by susceptible Gram-
Mode of action
Acts by inhibiting the synthesis of bacterial cell walls.
It inhibits cross-linkage between the peptidoglycan polymer
chains that make up a major component of the cell wall
of Gram-positive bacteria.
1. Staphylococcal skin infections and cellulitis including
Impetigo, Otitis externa, folliculitis, boils, carbuncles, and mastitis
2. Osteomyelitis, septic arthritis
4. Empirical treatment for endocarditis
5. Surgical prophylaxis
Previous history of allergy
to penicillins, cephalosporins or carbapenems
Should also not be used in the eye
Used with caution in the elderly, patients with renal
impairment, where a reduced dose is required; and
those with hepatic impairment, due to the risk of
An allergic reaction (shortness of breath; swelling of
lips, face, or tongue; rash; or fainting);
Severe watery diarrhea and abdominal cramps; or
Unusual bleeding or bruising.
aureus (MRSA) has developed resistance to
flucloxacillin and other penicillins by having
an altered penicillin binding protein
Note : Oxacillin, Nafcillin, Cloxacillin and Dicloxacillin
are similar to Flucloxacillin.
Taken in empty stomach
Plasma protein binding > 90%
Elimination : kidney, partially by liver
Plasma half life : about 1 hour
Broad spectrum penicillins
Ampicillin, Amoxicillin, Carbenicillin, ticarcillin, azlocillin.
These are semisynthetic penicillin
Acid resistant (not destroyed by HCL)
Destroyed by beta – lactamase
Less potent than benzylpenicillin
Short duration of action (4 – 6 hours) and plasma t1/2 I hour
Usually given with beta lactamase inhibitors
Adverse effects : Superinfection, hypersensitivity, GI upset (loose
Beta – lactamase inhibitors
Are family of enzymes produced by many gram + and gram
– bacteria that inactivates beta – lactam antibiotics by
opening the beta – lactam ring .
Clavulanic acid :
Inhibits a wide variety of beta lactamase produce by both
gram + and gram – bacteria
It is a progressive inhibitor: binding with beta –
lactamase is reversible initially, but becomes covalent later –
inhibition increasing with time and called sucide inhibitor.
Rapid oral absorption
Bioavailability 60 %
t1/2 1 hour
Eliminated through kidney but not affected by probenecid.
ADR : same as amoxicillin
Uses : addition of clavulanic acid re- establishes the activity of
amoxicillin against beta lactamase producing resistant Staph.
Aureus, H. influenza, N. gonorrhoea, E. coli, proteus, Klebsiella,
Salmonella, and shigella
Penicillin + Probenecid
Probenecid inhibit the tubular secretion of penicillin, so
probenecid causes :
Raises the plasma concentration of penicillin
Prolongation of the action of penicillin
Penicillin is excreted through kidney by tubular secretion,
when aspirin is administered with penicillin, it inhibits the
tubular secretion of penicillin, so prolonged the action
Adverse Reactions of penicillin
1. Hypersensitivity: most important adverse effect of
the penicillins; ranges from maculopapular rash to
angioedema and anaphylaxis.
2. GI Distress: nausea, vomitting and diarrhoea
B-lactams antibiotics that are closely related both
structurally and functionally to penicillins.
Like the penicillins, cephalosporins have a beta-
lactam ring structure that interferes with
synthesis of the bacterial cell wall and so are
To be continued……
Mechanism of action (MOA):
Cephalosporins are bactericidal agents and have the
same mode of action as other beta-lactam antibiotics
All bacterial cells have a cell wall that protects them.
Cephalosporins disrupt the synthesis of the
peptidoglycan layer of bacterial cell walls, which causes
the walls to break down and eventually the bacteria die.
I Generation: Predominantly active
against gram positive pathogens
II Generation: Moderate activity against
gram positive & gram negative
III Generation: Predominantly active
against gram negative pathogens
IV Generation: wider spectrum
First Generation Cephalosporins
Active against gram + cocci, pneumococci,
streptococci and staphylococci.
The first generation cephalosporins are:
Pharmacokinetics and dosage
A. Oral :
Cephalexin, cephradine, cefadroxil (500mg)
Excretion by kidney and tubular secretion into the urine.
Probenecid block the tubular secretion (increase the serum
B. Parenteral :
Cefazolin : only first generation parenteral
Oral drugs : UTI, cellulitis or soft tissue abscess
Cefazolin penetrates the most tissues.
Drug of choice for surgical prophylaxis.
Streptococcal or staphylococcal infections who have
history of penicillin allergy.
Does not penetrate the CNS
Second generation cephalosporins
Are active against organism inhibited by 1st
generation drugs and extended gram negative
The second generation cephalosporins are:
Cefmetazole, and cefotetan active against anaerobes.
Cefaclor, Cefuroxime, cefamandole, cefonicid,
and ceforanide ------- active against H.
Cefoxitin and ----- active against B fragilis.
Pharmacokinetics and dosage :
A . Oral : - Cefaclor, Cefuroxime, cefprozil,.
Adult (10-15mg/kg/d x 4 x divided dose;
Children (20-40mg/kg/d up ot 1 g/d)
Cefuroxime (not active against penicillin-resistant
Cefaclor (susecptible to beta- lactamase hydrolysis)
B. Parenteral : excreted by kidney
I.M is very painful so I.V is used.
Clinical uses :
Oral : beta-lactamase producing H influenzae,
Moraxella catarrhalis. Tx of sinusitis, otitis or lower
respiratory tract infections.
Cefuroxime for community- acquired pneumonia.
Third generation cephalosporins
Third generation cephalosporins have a broad spectrum of activity
and expanded gram-negative coverage, and some are able to cross
Effective against beta – lactamase producing strains of haemophilus
Most enter CNS and are important in emperic management of
meningitis and sepsis.
Cefoperazone, ceftadizime are only two
drugs with activity against P aeruginosa.
Ceftizoxime and moxalactam (B.
Penetrate body fluids and tissues well .
Half life :
Ceftriaxone 15-50mg/kg/d (t1/2 : 7-8 hrs) x od
1g dose is sufficient for most serious infections
4g x od for meningitis
Cefoperazone 25-100mg/kg/d (t1/2:2 hrs) x8-12hrs.
Remaining drugs (t1/2 : 1-1.7hrs)
Cefixime x p/o x 200mg (bd) or 400mg (od) for RTI or UTI.
Excretion : renal except cefoperazone and ceftriaxone through biliary
tract (no dose adjustment in renal disease)
Ceftriaxone and cefotaxime (meningitis)- caused by
pneumococci, meningococci, H influenzae and
suspected gram negative rods, but not by L
Sepsis of unknown cause.
Ceftriaxone and cefotaxime for meningitis (cross the
Fourth generation cephalosporins are extended spectrum
agents with similar activity against gram-positive organisms
as first generation cephalosporins.
Many can cross blood brain barrier and are effective in
Highly active against haemophilus and neisseria.
Plasma half life (2 hrs) and excreted by kiney.
The fourth generation cephalosporins are:
Ceftobiprole, Ceftaroline has been described as
"fifth-generation" cephalosporin, though
acceptance for this terminology is not universal.
Ceftobiprole has powerful anti pseudomonal
characteristics and appears to be less susceptible to
development of resistance.
Ceftaroline has also been described as "fifth-generation"
cephalosporin, but does not have the anti-pseudomonal
coverage as Ceftobiprole .
Hypersensitivity reactions (anaphylaxis, fever, skin rashes,
nephritis and hemolytic anemia)
Patients with history of anaphylaxis to penicillins should not
Thrombophlebitis after IV and local irritation after IM
Renal toxicity; interstitial nephritis
common side effects involve mainly the digestive system: mild
stomach cramps or upset, nausea, vomiting, and diarrhea.
Incidence of resistance is lower than penicillins
Some common uses of cephalosporins
Hospital-acquired pneumonias - Cefotaxime
Meningitis - Cefotaxime, Ceftriaxone
Sepsis (initial Tx) - 3rd
Acute urinary tract infections (UTI)
Used as IV every 8 hrly, 1-2 g
Half life (1- 2 hrs)
Narrow spectrum – Gram(-) rods
Highly resistant to β-lactamases
Penicillin – allergic patients tolerate aztreonam.
ADR: - May causes skin rashes.
Alternative to aminoglycosides and 3rd generation cephalosporins
Imipenem, Meropenem, Ertapenem
Imipenem, like other b-lactam antibiotics, binds to PBPs, disrupts bacterial cell
wall synthesis, and causes death of susceptible microorganisms.
It is very resistant to hydrolysis by most b-lactamases.
The activity of imipenem is excellent for a wide variety of aerobic and
anaerobic microorganisms. Streptococci (including penicillin-resistant S.
pneumoniae), staphylococci (including penicillinase-producing strains), and
Listeria are all susceptible.
Although some strains of methicillin-resistant staphylococci are susceptible,
many are not. Activity is excellent against the Enterobacteriaceae, including
organisms that are cephalosporin-resistant.
Imipenem is inactivated by dehydropeptidases in renal
tubules, resulting in low urinary concentrations. Consequently,
it is administered together with an inhibitor of renal
dehydropeptidase, Cilastatin, for clinical use.
Imipenem–cilastatin is effective for a wide variety of
infections, including urinary tract and lower respiratory
infections; intra-abdominal and gynecological infections; and
skin, soft tissue, bone, and joint infections.
The combination appears to be especially useful for the
treatment of serious infections caused by cephalosporin-
resistant nosocomial bacteria, as may be seen in hospitalized
patients who have recently received other b-lactam antibiotics.
Meropenem has slightly greater activity against gram-negative
aerobes and slightly less activity against gram-positives. It is not
significantly degraded by renal dehydropeptidase and does not
require an inhibitor.
Its toxicity and clinical efficacy are similar to imipenem,
except that it may be less likely to cause seizures.
Ertapenem is less active than meropenem or imipenem and it is
not degraded by renal dehydropeptidase.
Carbapenems penetrate body tissues and fluids well,
including the cerebrospinal fluid.
Cleared renally, and the dose must be reduced in patients
with renal insufficiency.
Imipenem Dose : 0.25–0.5 g given intravenously every 6–8
hours (half-life 1 hour).
Meropenem Dose : 1 g intravenously every 8 hours.
Ertapenem Dose : 1 g intravenously or intramuscularly ,half-
life (4 hours) and is administered as a once-daily.
Most common adverse effects :
- Imipenem—nausea, vomiting, diarrhea, skin
rashes, and reactions at the infusion sites.
Excessive levels of imipenem in patients with renal
failure may lead to seizures.
- Meropenem and Ertapenem are less likely to cause
seizures than imipenem.
- Patients allergic to penicillins may be allergic to
carbapenems as well.
Is an antibiotic produced by Streptococcus
With the single exception of flavobacterium,
it is active only against gram-positive
bacteria, particularly staphylococci.
water-soluble and quite stable.
Mechanisms of Action
Inhibits the transglycosylase, preventing further
elongation of peptidoglycan and cross-linking. The
peptidoglycan is thus weakened and the cell becomes
susceptible to lysis. The cell membrane is also
damaged, which contributes to the antibacterial
Antibacterial Activity :
Vancomycin is bactericidal for gram-positive bacteria.
Synergistic with Gentamicin and Streptomycin
Poorly absorbed from the intestinal tract and is
administered orally only for the treatment of
antibiotic-associated enterocolitis caused by
90% of the drug is excreted by kidney.
Half-life of vancomycin is 6–10 days.
Parenteral doses must be administered
Indication for parenteral vancomycin is sepsis or
endocarditis caused by methicillin resistant staphylococci
Combination with gentamicin is an alternative regimen for
treatment of enterococcal endocarditis in a patient with
serious penicillin allergy
dosage is 30 mg/kg/d in two or three divided doses
Children is 40 mg/kg/d in three or four divided doses.
Oral vancomycin, 0.125–0.25 g every 6 hours, is used to treat
antibiotic-associated enterocolitis caused by Clostridium difficile.
In about 10% of cases
Phlebitis at the site of injection
Chills and fever
Ototoxicity is rare and nephrotoxicity uncommon
"red man" or "red neck’’ syndrome (infusion-related
flushing is caused by release of histamine) - prevented
by prolonging the infusion period to 1–2 hours or
increasing the dosing interval
Active against gram-positive microorganisms
Inhibits cell wall formation by interfering with dephosphorylation in cycling of
the lipid carrier that transfers peptidoglycan subunits to the growing cell wall.
Markedly nephrotoxic if administered systemically, producing proteinuria,
hematuria, and nitrogen retention
Because of its marked toxicity when used systemically, it is limited to topical
Poorly absorbed and local antibacterial activity without significant systemic
Use :- irrigation of joints, wounds, or the pleural cavity.
Protein synthesis inhibitors
The bacterial ribosome is composed of 30s
and 50s subunits.
30s ribosomal subunit inhibitors:
aminoglycosides and tetracyclines
50s ribosomal subunit inhibitors:
Macrolides, chloramphenicol, clindamycin
Inhibit protein synthesis ( 30 s subunit ) by
interfering with the initiation complex of peptide formation
induce misreading of mRNA, resulting in nonfuctional
Eg: Streptomycin, Neomycin, Kanamycin,
Amikacin, Gentamicin, Tobramycin,
1. Produce enzyme that inactivate the
2. Impaired entry of aminoglycoside into the
3. Alteration of drug binding site (30s ribosomes) by
Common properties of aminoglycosides
Water soluble and more active at alkaline pH
Extracellular distribution only, cannot cross the BBB
Can cross the placenta (teratogenicity)
Narrow therapeutic index
All show common toxicities (ototoxicity, nephrotoxicity,
Gram negative bacillary infections:
1. Septicaemia (gentamycin, amikacin)
2. Abdominal and pelvic sepsis
Bacterial endocarditis (gentamycin + penicillin)
Tuberculosis, plague, brucellosis
Topical uses (Neomycin)
1. Conjunctival infection
2. Infection of external ear
3. Prior to bowel surgery (to reduce the intestinal flora)
1. Ototoxicity : Damage of 8th
CN (vestibular and
auditory damage) by toxic effects on sensory hair
cells of cochlea and vestibular organ.
a) Vestibular damage : comes earlier, usually
reversible, headache (first), nausea, vomiting,
dizziness, nystagmus, vertigo
b) Auditory disturbance : comes lately; usually
irreversible, tinnitus, deafness, headache
2. Nephrotoxicity : excreted unchanged mainly by
glomerular filtration; so attain high concentration in
urine and accumulate in renal tubule :
a) - damage to renal tubules (reversible)
b) - proteinuria and haematuria
c) - rising serum creatinin level
3. Neurotoxicity : Prevent release of acetylcholine.
Bactericidal (high dose)
Bacterostatic (low dose)
Second or third line drugs of tuberculosis
Serious form of tuberculosis
Subacute bacterial endocarditis
Urinary and respiratory tract infections
Sensitive strains : bactericidal against pseudomonas, proteus, klebsiella,
More potent than streptomycin
Spectrum: broad spectrum then streptomycin
Indications : septicaemia, bacterimia, abdominal and pelvic abscess,
bacterial endocarditis, infected burns, pneumonia, peritonitis
Route of administration : IV, IM and topical (creams, ointments)
Broad spectrum antibiotic
Susecptible : E. coli, enterobacter, klebsiella
pneuminiae, Staph. aureus, M. tuberculosis
Poorly absorbed from the gut and excreted by
Topical : infected burn, wound, ulcers
Oral : preparation of the bowel for surgery
Mechanism of action
Tetracyclines enter microorganisms ( by passive
diffusion and active transport)------ 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
Absorption after oral administration :
30% - chlortetracycline;
60–70% - tetracycline, oxytetracycline, demeclocycline, and
95–100% - 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+) ; by dairy products and
antacids, which contain multivalent cations; and by alkaline pH
Distributed widely to tissues and body fluids .
Minocycline reaches very high concentrations in tears and
Tetracyclines cross the placenta and excreted in milk. As a
result of chelation with calcium, tetracyclines are bound to—
and damage—growing bones and teeth.
Carbamazepine, phenytoin, barbiturates, and chronic alcohol
ingestion may shorten the half-life of doxycycline 50% by
induction of hepatic enzymes that metabolize the drug.
Excreted mainly in bile, feces and urine
Some of the drug excreted in bile is reabsorbed from the intestine
(enterohepatic circulation) and contributes to maintenance of serum
Ten to 50 percent of various tetracyclines is excreted into the urine,
mainly by glomerular filtration.
Ten to 40 percent of the drug in the body is excreted in feces.
Doxycycline, in contrast to other tetracyclines, is eliminated by
nonrenal mechanisms, does not accumulate significantly in renal
failure, and requires no dosage adjustment, making it the tetracycline
of choice for use in the setting of renal insufficiency.
Hypersensitivity reactions (drug fever, skin
Gastrointestinal: - Nausea, vomiting, and
diarrhea are the most common, direct local
irritation of the intestinal tract,
- Nausea, anorexia, and diarrhea can usually be
controlled by administering the drug with food
Bony Structures and Teeth
Tetracyclines are readily bound to calcium deposited in
newly formed bone or teeth in young children.
When the drug is given during pregnancy, it can be deposited
in the fetal teeth, leading to discoloration, and enamel
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.
Especially during pregnancy, in patients with preexisting
hepatic insufficiency and when high doses are given
Hepatic necrosis has been reported with daily doses of 4 g or
Kidney Toxicity :Renal tubular acidosis and Fanconic
syndrome (patient ingesting outdated and degraded
tetracycline) resulting in nitrogen retention (except
Local Tissue Toxicity: IV lead to venous thrombosis. IM
painful local irritation
Systemic tetracycline administration, demeclocycline,
can induce sensitivity to sunlight or ultraviolet light
Vestibular Reactions :Dizziness, vertigo, nausea, and
vomiting (doxycycline at doses above 100 mg).
Superinfection : caused by Candida (angular
stomatitis, sore throat; Proteus (UTI)
Drug of first choice
Drug of second
Respiratory tract infection
Children below 8 years of age
Pregnancy : early (teratogenicity) ; late (fetal bone
deformity, discoloration of teeth of offspring)
Renal failure (except doxycycline)
Antacids : decrease effectiveness by
Iron : decrease absorption of
Comparative study between
2. Irregularly absorbed
3. Plasma half life : 12
4. Excretion : renal route
5. Renal failure :
2. Completely absorbed
3. Plasma half life : 16
4. Excretion : non renal
5. Renal failure :
Mechanism of action
Inhibit protein synthesis by binding to the 50 s subunit
Bactericidal or bacteriostatic, depending on the concentration
and type of bacteria
Example : Erythromycin, Azithromycin and
Clarithromycin and azithromycin are semisynthetic
derivatives of erythromycin.
Drug of choice in corynebacterial infections (diphtheria, corynebacterial
sepsis); in respiratory, neonatal, ocular, or genital chlamydial infections;
and in treatment of community-acquired pneumonia
Gram +ve cocci
Atypical organisms (chlamydia, mycoplasma, ureaplasma species)
Azithromycin: similar spectrum but more active in respiratory
infections including mycobacterium avium
Clarithromycin: has more activity against M.avium and H.pylori.