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
Identification and Sensitivity of the Organism

It is essential to obtain a sample culture of the organism prior to initiating treatment if possible, making a public health impact in identification of the source of an outbreak of infectious diseases
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

Immune system
 Alcoholism, diabetes, HIV, malnutrition, advanced age can affect a patient’s immunocompetency

Higher than usual doses of bactericidal agents or longer treatment are required to eliminate the infective organisms in these individuals
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
Status of the Patient

Pregnancy

Tooth dysplasia and inhibition of bone growth encountered with the tetracyclines

Some anthelminitics are embryotoxic and teratogenic

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
Cost of Therapy

Several drugs may show similar efficacy in treating an infection, but vary widely in cost
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.
Drug Resistance

Bacteria are said to be resistant if their growth is not halted by the maximal level of an antibiotic that is tolerated by the host

The emergence of these resistant strains has been ascribed to the imprudent and inappropriate use of antibiotics
Drug Resistance

Genetic alterations leading to drug resistance

Spontaneous mutations of DNA

DNA transfer of drug resistance

Altered expression of proteins in drug-resistant organisms

Modification of target sites

Decreased accumulation

Enzymic inactivation
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

Synergistic combination of sulfamethoxazole is effective in treating conditions such as
Pneumocystis carinii pneumonia, salmonella infections
Sulfonamides

All sulfonamides in clinical use are synthesis structural analogs of p-aminobenzoic acid (PABA)

The sulfonamides complete with this substrate for the enzyme dihydroteroate synthetase, thus preventing the synthesis of bacterial folic acid
Antibacterial Spectrum

The sulfas, including co-trimoxazole are bacteriostatic. Active against enterobacteria, chlaydia, Pneumocystis and nocardia

Suladiazine in combination with the dihydrofolate reductase inhibitor pyrimethamine is the only effective form of chemotherapy for toxoplasmosis
Resistance

Bacterial resistance to the sulfas can arise from plasmid transfers or random mutations
Pharmacokinetics

Sulfasalazine whne administered orally or as a suppository, is reserved for treatment of chronic inflammatory bowel disease, because it is not absorbed

Silver sulfadiazine have been effective in reducing burn sepsis

Penetrate well into cerebrospinal fluid. They can also pass the placental barrier and into breast milk

Elimination of sulfas is by glomerular filtration
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
Resistance

Resistance to the trimethoprim-sulfamethoxazole combination is less frequently encountered than resistance to either of the drugs alone
Pharmacokinetics

Co-trimoxazole is generally administered orally. Intravenous administration to patients with severe pneumonia caused by Pneumocystis carinii

Fate

Trimethoprim concentrates in the relatively acidic milieu of prostatic and vaginal fluids and accounts for the use in infections at these sites
Adverse Effects

Hematologic: Megaloblastic anemia, leukopenia, and thrombocytopenia in patients with glucose-6-phosphate deficiency

HIV patients: drug-induced fever, rashes, diarrhea and/or pancytopenia

Drug Interactions: Prolonged prothrombin times in patients receiving warfarin
Inhibitors of Cell Wall Synthesis

Selectivity interfere with the synthesis of the bacterial cell wall

These agents require actively proliferating microorganims; 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 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

Antistaphlococcal penicillins: Methicillin nafcillin, oxacillin, cloxacillin, dicloxacillin are penicillinase resistant. Methicillin-resistant strains of Staphlococcus aureus (MRSA),

currently a serious source of nosocomial (hospital-acquired) infections, are usually susceptible to vanocomycin
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 be dentists for pateitns with abnormal heart valves undergo extensive oral srugery
Antibacterial Spectrum

Antipseudomona penicillins: Carbenicillin piperacillin

Penicillins and aminoglycosides: synergistic with the aminoglycosides. Penicillin alter permeability of the bacterial cell can facilitate entry of antibiotics that might not ordinarily gain access to larges sites
Resistance

Natural resistance penicillins occurs in organisms that either lack a peptidogycan cell wall. Acquired resistance to the penicillins by palasmid transfer

Excretion: The primary route of excretion is through the organic acid (tubular) secretory system of the kidney as by glomerular filtration. Patients with impaired renal function must have dosage regimens adjusted

Nafcillin is primarily eliminated through the biliary route
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 have been classified
 First generation have activity against Proteus mirabilis, Escherichia coli and klebsiella pneumobiae
 Second generation activity against three additional gram-negative organisms, haemophilus influenzae, enterobacter aerogenese, 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 in the treatment of meningitis.
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

Antreonam only commercially available. Axtreonam is resistant to the action of βlactamases

Antibacterial spectrum anterobacteria. Aerobic gram-negative rods. Lakcs activity against gram-positive organisms and anaerobes
Adverse Effects

Phelbitis, skin rahs, abnormal liver function tests

Azteronam 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 are the drug of choice
Tetracyclines

Tetracyclines concentrate in the liver, kidney, spleen, and skin and bind to tissues undergoing calcification (for example, teeth and bones), or to tumors have a high calcium content (gastric carcinoma)

Minocycline: useful in eradicating the meningococcal carrier state

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 by the mechanism determined for streptomycin

Antibiotic then binds to the separated 30S ribosomal subunit
Aminoglycosides

Antibacterial spectrum

All aminoglycosides are bactericidal. Effective only against aerobic organisms, since anaerobes lack the oxygen-requiring transport system. Streptomycin is used to treat tuberculosis, plague, tularemia and combination with penicillin, endocarditis viridans group streptococci
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. It is the drug of choice.

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. Eitherbactericidal 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
 The drug is excreted into the bile or urine by glomerular filtration
 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

Hot routinely recommended for use in patients under 18 years of age

Since fluoroquinolones are excreted in breast milk, contraindicated for nursing mothers.