ANTIBIOTICS - Nusrum



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 β-lactam 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 6-aminopenicillanic acid residue

Mechanism of Action

Intefere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), 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 β-lactamases

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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GOOD LUCK FOR EXAMINATION!!!!!!!

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