ANTIBIOTICS
Dr. Nusrum Iqbal
Department of Medicine
Lahore Medical & Dental College
Lahore
Overview
Antimicrobial drugs are effective in the treatment of infections because of their
selective toxicity – the ability to kill an invading microorganism without harming the
cells of the host
Selection of Antimicrobial Agents
Selection of the most appropriate antimicrobial agent requires knowledge of:
The organism’s identity and its sensitivity to a particular agent
The site of the infection
The safety of the agent
Patient factors
The cost of therapy
Empiric therapy prior to organism identification
In the critically ill patient, immediate empiric therapy is indicated
Therapy is initiated after specimens for laboratory analysis have been obtained but
before the results of the culture are available
Selecting a Drug
The choice of drug in the absence of sensitivity data is influenced by site of infection
and patient history, for example, hospital- or community-acquired patient is
immunocompromised patient’s travel record and age
Status of the Patient
Renal dysfunction:
Poor kidney function (10% or less of normal) causes accumulation of antibiotics
Direct monitoring of serum levels of some antibiotics is preferred to
Hepatic dysfunction
Poor perfusion
The effect of the site of infection on therapy
Adequate levels of an antibiotic must reach the site of infection in order for the
invading microorganism to be effectively eradicated
Natural barriers cause inadequate penetration of the drug into certain tissues such as
the brain, prostate and bone
Status of the Patient
Pregnancy
Tooth dysplasia and inhibition of bone growth encountered with the tetracyclines
Aminoglycosides should be avoided in pregnancy because of their ototoxic effect in the
fetus
Status of the Patient
Lactation
Even though the concentration of an antibiotic in breast milk is usually low, the total
dose to the infant may be enough to cause problems
Age
Renal hepatic elimination processes are often poorly developed in newborns, making
neonates particularly vulnerable
Young children should not be treated with tetracyclines fluoroquinolones which
interfere with cartilage growth
Safety of the Agent
Penicillins, are among the least toxic of all drugs
Chloramphenicol are less specific and are reserved for life-threatening
Bacteriostatic Versus 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.
Bactericidal agent kills bacteria and the total number of viable organisms decreases.
Complications of Antibiotic Therapy
Hypersensitivity
Direct toxicity
Superinfections
Folate Antagonists
Folic acid coenzymes are required for the synthesis of purines and pyrimidines
(precursors of RNA and DNA)
Sulfa drugs are inhibitors of folic acid synthesis
Sulfonamides
All sulfonamides in clinical use are structural analogs of p-aminobenzoic acid (PABA)
The sulfonamides compete with this substrate for the enzyme dihydropteroate
synthetase, thus preventing the synthesis of bacterial folic acid
Antibacterial Spectrum
The sulfas, including co-trimoxazole are bacteriostatic. Active against enterobacteria,
chlamydia, Pneumocystis, nocardia and gram positive organisms
Suladiazine in combination with the dihydrofolate reductase inhibitor pyrimethamine
is the only effective form of chemotherapy for toxoplasmosis
Pharmacokinetics
Silver sulfadiazine have been effective in reducing burn sepsis
Penetrate well into cerebrospinal fluid,prostatic fluid and in the vaginal fluid. They
can also pass the placental barrier and into breast milk
Adverse Effects
Crystalluria
Adequate hydration and alkalinization of urine prevent the problem
Hypersensitivity
Rashes, angioedema, and Stevens-Johnson syndrome
Adverse Effects
Hemopoietic Disturbances
Hemolytic anemia is encountered in patients with glucose 6-phosphate dehydrogenase
deficiency. Granulocytopenia, thrombocytopenia
Kernicterus
Disorder may occur in newborns
Contraindications
Sulfas should be avoided in newborns and infants less than 2 months old as well as
pregnant women at term, due to the danger of kernicterus
Co-trimoxazole
Trimethoprim is most often compounded with the sulfa drug, sulfamethoxazole.
Greater antimicrobial activity than equivalent quantitites of either drug used alone
Mechanism of Action
Sulfamethoxazole inhibits the incorporation of PABA into folic acid, and trimethoprim
prevents reduction of dihydrofolate to tetrahydrofolate.
Exhibits more potent antimicrobial activity than sulfamethoxazole or trimethoprim
Inhibitors of Cell Wall Synthesis
These agents require actively proliferating micro organisms; they have little or no
effect on bacteria that are not growing. Most important members of the group are the βlactam antibiotics, named after the β-lactam ring
Penicillins
Most widely effective antibiotics least toxic drugs known
Members of this family differ from one another in the R substituent attached to the 6aminopenicillanic acid residue
Mechanism of Action
Intefere with the last step of bacterial cell wall synthesis (transpeptidation or crosslinkage), exposing the osmotically less stable membrane. Cell lysis can then occur,
bactericidal
Only effective against rapidly growing organisms that synthesize a peptidoglycan
Penicillins inactivate proteins present on the bacterial cell membrane
Inhibition of transpeptidase
Degradative action of the autolysins proceeds in the absence of cell wall synthesis
Antibacterial Spectrum
Gram-positive microorganisms
Natural penicillin
Penicillin G (benzylpenicillin)
Penicillin V is more acid-stable than penicillin G
Antistaphylococcal penicillins: Methicillin nafcillin, oxacillin, cloxacillin, dicloxacillin
are penicillinase resistant.
Methicillin-resistant strains of Staphylococcus aureus (MRSA), currently a serious
source of nosocomial (hospital-acquired) infections, are usually susceptible to
vancomycin
Antibacterial Spectrum
Extended spectrum penicillins: Ampicillin, amoxicillin, antibacterial spectrum similar
to that of penicillin G, but are more effective against gram-negative bacilli.
Ampicillin, Listeria monocytogenes. Amoxicillin is employed prophylactically by
dentists for patients with abnormal heart valves undergo extensive oral surgery
Antibacterial Spectrum
Antipseudomonal penicillins: Carbenicillin, piperacillin
Penicillins and aminoglycosides: synergistic with the aminoglycosides. Penicillin alter
permeability of the bacterial cell wall can facilitate entry of antibiotics that might not
ordinarily gain access to larges sites
Adverse Reactions
Penicillins are among the safest drugs, and blood levels are not monitored
Hypersensitivity: ranging from maculopapular rash to angioedema, maculopapular rash
Diarrhea
Nephritis: acute interstitial nephritis
Neurotoxicity: provoke seizures. Epileptic patients are especially at risk
Platelet dysfunction
Cephalosporins
Cephalosporins are β-lactam antibiotics that are closely related both structurally and
functionally to the penicillins. Most cephalosporins are produced semi-synthetically by
the chemical attachment of side chains to 7-aminocephalosporanic acid
Tend to be more resistant than the penicillins to β-lactamases
Cephalosporins
First generation have activity against Proteus mirabilis, Escherichia coli and klebsiella
pneumoniae
Second generation activity against three additional gram-negative organisms,
haemophilus influenzae, enterobacter, neisseria activity against gram-positive organisms
is weaker
Third generation inferior to their activity against gram-positive cocci. Enhanced
activity against gram-negative bacilli. Ceftriaxone cefotaxime.
Pharmacokinetics
Must be administered intravenously because of their poor oral absorption
Adequate therapeutic levels in the cerebrospinal fluid (CSF), regardless of
inflammation, are achieved only with the third generation cephalosporins
Elimination occurs through tubular secretion and/or glomerular filtration.
Cefoperazone and ceftriaxone are excreted through the bile into the feces and are
frequently employed in patients with renal insufficiency
Adverse Effects
Allergic manifestations
Disulfiram-like effect
Bleeding: anti-vitamin K effects
Carbapenems
Imipenem is the only drug of this group currently available
Imipenem resists hydrolysis by most β-lactamases. Empiric therapy active against
penicillinase-producing gram-positive and gram-negative organisms, anaerobes.
Pseudomonas aeruginosa
High levels of this agent may provoke seizures
Monobactams
Aztreonam only commercially available. Aztreonam is resistant to the action of βlactamases
Antibacterial spectrum enterobacteria. Aerobic gram-negative rods. Lacks activity
against gram-positive organisms and anaerobes
Indications
may offer a safe alternative for treating patient allergic to penicillins and/or
cephalosporins
Vancomycin
Vancomycin is a tricyclic glycopeptide that has effectiveness against multiple drug
resistant organisms such as methicillin-resistant staphylococci
It is used for potentially life-threatening antibiotic-associated colitis due to
staphylococci
Used prophylactically in dental patients
Vancomycin
Vancomycin is used in individuals with prosthetic heart valves in patients being
implanted with prosthetic devices. Vancomycin acts synergistically with the
aminoglycosides and this combination can be used in the treatment of enterococcal
endocarditis
Dosage must be adjusted in renal failure since the drug will accumulate
Adverse Effects
Fever, chills, phlebitis. Shock as a result of rapid administration
Flushing (“red man syndrome”) and shock result due to histamine release caused by
rapid infusion. Dose-related hearing loss
Bacitracin
Active against a wide variety of gram-positive organisms
Its use is restricted to topical application because of its potential for nephrotoxicity
Protein Synthesis Inhibitors
These antibiotics exert their antimicrobial effects by targeting the bacterial ribosome,
which has components that differ structurally from those of the mammalian cytoplasmic
ribosome
Tetracyclines
Binding of the drug to the 30S subunit of the bacterial ribosome is believed to block
bacterial protein synthesis
Tetracyclines are also effective against organisms other than bacteria. Bacteriostatic
Tetracyclines
All tetracyclines cross the placental barrier and concentrate in fetal bones and dentition
Adverse Effects
Gastric discomfort
Deposition in the bone and primary dentition occurs during calcification in growing
children; discoloration and hypoplasia of the teeth and a temporary stunting of growth
Fetal hepatotoxicity: This side effect has been known to occur in pregnant women who
received high doses of tetracycliens, especially if they are experiencing pyelonephritis
Adverse Effects
Phototoxicity
Vestibular problems: dizziness, nausea, vomiting
Pseudotumor cerbri: Benign intracranial hypertension
Superinfections: Renally-impaired patients should not be treated with any of the
tetracyclines except doxycycline
The tetraccyclines should not be employed in pregnant or breast-feeding women, or in
children under 8 years of age
Aminoglycosides
Aminoglycosides antibiotics had been the mainstays of treatment of serious infections
due to aerobic gram-negative bacilli
Inhibit bacterial protein synthesis Antibiotic binds to the 30S ribosomal subunit
Aminoglycosides
Antibacterial spectrum
All aminoglycosides are bactericidal. Effective only against aerobic organisms, since
anaerobes lack the oxygen-requiring transport system.
Pharmacokinetics
All cross the placental barrier and may accumulate in fetal plasma and amniotic fluid
All are rapidly excreted into the urine, predominantly glomerular filtration.
Accumulation occurs in patients with renal failure
Adverse Effects
It is important to monitor peak and trough plasma levels of gentamicin
Ototoxicity: Deafness may be irreversible and has been known to affect fetuses in
utero
Nephrotoxicity: damage from mild renal impairment to severe acute tubular necrosis
which can be irreversible
Adverse Effects
Neuromuscular paralysis: decrease both the release of acetylcholine from prejunctional
nerve endings and the sensitivity of the postsynaptic site. Patients with myasthenia gravis
are particularly at risk. Neostigmine can reverse the block
Contact dermatitis
Macrolides
The macrolides are a group of antibiotics with macrocyclic lactone structure.
Erythromycin an alternative to penicillin in individuals who are allergic to β-lactam
antibiotics. Clarithromycin, azithromycin have some features in common
Macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus
inhibiting the translocation steps of protein synthesis. Bacteriostatic may be cidal at
higher doses
Antibacterial Spectrum
It is used in patients allergic to the penicillins.
Clarithromycin: similar to that or erythromycin is also effective agaisnt haemophilus
influenzae. Its activity against intracellular pathogens such as chlamydia, legionella and
ureaplasma is higher than that of erythromycin
Antibacterial Spectrum
Azithromycin more active against respiratory infections, Haemophilus influenzae and
moraxella catarrhalis. Preferred therapy for urethritis caused by chlamydia trachomatis.
Its activity against mycobacterium avium intracellulare complex in AIDS patients with
disseminated infections
Pharmacokinetics
It is one of the few antibiotics that diffuses into prostatic fluid
Erythromycin is extensively metabolized and is known to inhibit the oxidation of a
number of drugs through its interaction with the cytochrome P-450 system. Azitrhomycin
does not undergo metabolism
Erythromycin and azitrhomycin are primarily concentrated and excreted in an active
form in the bile. Claritrhomycin and its metabolites are eliminated by the kidney
Adverse Effects
Epigastric distress
Cholestatic jaundice
Ototoxicity
Patients with hepatic dysfunction should not be treated with erythromycin, since the
drug accumulates in the liver
Erythromycin and claritrhomycin inhibit the hepatic metabolism of theophylline,
warfarin, terfenadine, astemizole, carbamazepine and cycloporine. Interaction with
digoxin may occur
Chloramphenicol
Chloramphenicol is active against a wide range of gram-positive and gram-negative
organisms, its use is restricted to life-threatening infections
Drug binds to the bacterial 50S ribosomal subunit and inhibits protein synthesis.
Similarly 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
Chloramphenicol
A broad spectrum antibiotic. Also against other microorganisms, such as richettsiae.
Excellent activity against anaerobes. Bactericidal or bacteriostatic, depending on the
organism
Adverse Effects
Anaemias: hemolytic anemia occurs in patients with low level of glucose 6-phosphate
deydrogenease. Reversible anaemia which is apparently dose-related and occurs aplastic
anaemia, which is idiosyncratic and usually fatal
Adverse Effects
Gray baby syndrome
In neonates if the dosage regimen of chloramphenicol is not properly adjusted. Low
capacity to glucuronidate the antibiotic and underdeveloped renal function.
Poor feeding, depressed breathing, cardiovascular collapse, cyanosis and death
Clindamycin
Clindamycin is employed primarily in the treatment of infections caused by anaerobic
bacteria, such as bacteroides fragilis non-enterococcal gram-positive cocci
Clostridium difficile is always resistant to clindamycin
Most serious adverse effect is potentially fatal pseudomembranous colitis caused by
overgrowth of clostridium difficile which elaborates necrotizing toxins. Oral
administration of either metronidazole or vancomycin is usually effective in controlling
this serious problem
DNA GYRASE INHIBITORS
Fluoroquinolones
The important quinolones are synthetic fluorinated analogs of nalidixic acid. They are
active against a variety of gram-positive and gram-negative bacteria.
Quinolones block bacterial DNA synthesis by inhibiting bacterial topoiosomerase II
(DNA gyrase) and topoisomerase IV
Fluoroquinolones
Earlier quinolones (nalidixic acid, oxolinic acid, cinoxacin) useful only for treatment
of lower urinary tract infections
Fluorinated derivatives (ciprofloxacin, levofloxacin, and others; have greatly improved
antibacterial activity compared with nalidixic acid and achieve bactericidal levels in
blood and tissues
Antibacterial Activity
Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin and pefloxacin
comprise a second group of similar agents possessing excellent gram-negative activity
and moderate to good activity against gram-positive bacteria
Antibacterial Activity
Levofloxacin, the L-isomer of ofloxacin twice as potent, has superior activity against
gram-positive organisms, including S pneumoniae
Clinafloxacin, gatifloxacin, and sparfloxacin comprise a third group of fluroquinolones
with improved activity against gram-positive organisms, particularly S pneumoniae and
to some extent staphylococci
Antibacterial Activity
Moxifloxacin and trovafloxacin make up a fourth group of fluoroquinolones that have
enhanced gram-positive activity. Also have good activity
Anaerobic bacteria
Fluoroquinolones also are active against agents of atypical pneumonia (mycoplasmas
and chlamydiae) intracellular pathgoens such as legionella, mycobacteria, mycobacterium
tuberculosis and M avium complex
Clinical Uses
Effective for bacterial diarrhea caused by shigella, salmonella, toxigenic E coli, or
campylobacter. Employed in infections of soft tisues, bones, joints and intra-abdominal
and respiratory tract infections
Ciprofloxacin and ofloxacin is effective for chlamydial urethritis or cervicitis
Eradication of menongococci from carriers or for prophylaxis of infection in
neutropenic patients
Adverse Effects
Photosensitivity
Concomitant adminstration of theophylline and quinolones can lead to elevated levels
of theophylline with the risk of toxic effects, seizures, damage growing cartilage cause an
arthropahty
Not routinely recommended for use in patients under 18 years of age
Since fluoroquinolones are excreted in breast milk, contraindicated for nursing
mothers.
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