CHEMOTHERAPY

BY; SEYOUM GIZACHEW (B.Pharm., MSc)

2

Introduction

• Antimicrobial drugs have caused a dramatic change not only of the treatment of infectious diseases but of a fate of mankind.

• Microorganisms were found to be responsible for a variety of infectious diseases that had been plaguing humanity from ancient days.

• Accordingly, chemotherapy aimed at the causative organisms was developed as the main therapeutic strategy.

• The first antimicrobial agent in the world was salvarsan, – a remedy for syphilis that was synthesized by Ehrlich in

1910. • In 1935, sulfonamides were developed by Domagk and other

researchers.

3

Introduction cont…

• In 1928, Fleming discovered penicillin. – came into clinical use in the 1940s.

• Penicillin,– an outstanding agent in terms of safety and efficacy, – led in the era of antimicrobial chemotherapy by saving

the lives of many wounded solders during World War II.

4

Introduction cont…

• Antimicrobial therapy takes advantage of the biochemical differences that exist between microorganisms and human beings.

• Their selective toxicity; i.e., they have the ability to injure or kill an invading microorganism without harming the cells of the host.

• In most instances, the selective toxicity is relative rather than absolute.

• The more closely related the undesirable cells are to normal human cells, – the more difficult the task of finding a drug to that cell. – E.g., it is easier to cure malaria than cancer.

5

Definition of terms• Chemotherapy:

– is the use of chemicals against invading organisms (i.e. bacteria).The term is used for both treatment of cancer and treatment of infection.

• Antibiotic:– is a chemical that is produced by one microorganism and

has the ability to harm other microbes, also include synthetic agents (eg. Sulfa drugs).

• Selective toxicity:– is the ability of a drug to injure a target cell or organism

without injuring other cells or organisms that are in intimate contact.

6

Definition of terms cont…

• Narrow spectrum anti-infectives: – affect only a few bacterial types.– E.g., The early penicillin drugs.

• Broad-spectrum anti-infectives: – affect many bacteria.– E.g., Imipenem.

• Bactericidal Drugs: – Antibiotics that can aggressively cause bacterial death.– Penicillins, Cephalosphorins, Metronidazole,

Aminoglycosides, Vancomycin.• Bacteriostatic drugs:

– Anti-infectives that interfere with the ability of the cell to reproduce/replicate without killing them.

– E.g., Tetracyclines, chloramphenicol.

7

Definition of terms cont…

• Empiric therapy:– treatment of an infection before specific culture

information has been reported or obtained.• Superinfection:

– An infection occurring during antimicrobial treatment for another infection, resulting from overgrowth of an organism not susceptible to the antibiotic used.

– A secondary infection that occurs due weakening of the patients immune system by the first infection.

8

Managing Chemotherapy• Initial therapy is usually empirical,

– the regimen is adjusted according to the results of culture and sensitivity testing.

• Drug and its regimen may be changed several times during therapy.

• For example, – severe nausea and high severity of illness may necessitate

initial parenteral antibiotic administration. – when the patient is clinically stable, may be switched to

oral chemotherapy.

9

Managing Chemotherapy cont…

• Treatment must be continued for several days after objective signs and symptoms of infection have resolved.

• Patients should be instructed to continue antibiotics for the full duration indicated, even if they feel better.

• If delayed recovery from what is reasonably expectable, the diagnosis should be reconsidered.

10

Misuse of Antibiotics

Antibiotics are misused in the following conditions;• Treatment of untreatable infections

– Treatment of common cold/flu– Take rest, but not antibiotic– Viral infections don't respond to antibiotics and are self

limited.• upper respiratory tract infection

• Therapy of fever of unknown origin– Most instances of pyrexia of short duration are due to

virus.• Improper dosage - suboptimal dose.

11

Types of Antimicrobial Resistance

• Generally there are tow types of resistance as a defense mechanism for bacteria against the action of antibiotics:

1. Natural Resistance• Some microorganisms are naturally resistant to the action of

antibiotics.• Cells without peptidoglycan are naturally resistant to

penicillins– Mycoplasma

• Mycobacterium • Viruses, fungi, human cells are naturally resistant to

penicillins.

2. Acquired resistance• Make lots of trouble to human kind.• Bacteria become resistant after some modifications.

12

Classification Of Antimicrobial Drugs By Susceptible Organisms

• Antibacterials• Antifungals• Antiprotozoals• Antihelminthics• Antivirals • Antimycobacterial

13

Classification By Mechanism Of Action

• Drugs that inhibit bacterial wall synthesis or activate

enzymes that disrupt the cell wall.

• Drugs that increase cell membrane permeability (causing

leakage of intracellular material).

• Drugs that inhibit bacterial protein synthesis.

• Drugs that inhibit bacterial synthesis of nucleic acids.

• Antimetabolites (disruption of specific biochemichal

reactions--> decrease in the synthesis of essential cell

constituents).

14

Inhibitors of Bacterial Cell Wall Synthesis

• Also called Cell wall active agents.• Include;

– Bacitracin – Vancomycin – Β-lactams

• Penicillins• Cephalosporins • Monobactams• Carbapenems

15

β-Lactam Antibiotics: Mechanism of Action

• β-Lactam Antibiotics contain the β-lactam ring essential for the antibacterial activity.

• Cross-linking of adjacent peptidoglycan (murein) strands, – A transpeptidation reaction.

• Catalyzed by enzyme transpeptidase (also called Penicillin Binding Proteins, PBPs)

• β-lactam antibiotics;– Covalently bind the enzyme at the active site, – Inhibit cell wall synthesis.

16

Penicillins

• A large group of bactericidal compounds. • The antimicrobial activity of penicillin resides in the β-

lactam ring. • Splitting of the β-lactam ring by either acid hydrolysis or β-

lactamases results in the formation of penicilloic acid, – a product without antibiotic activity.

• Addition of various side chains (R) to the basic penicillin molecule,– Gives compounds with the same mechanism of action but

with different chemical and biological properties.

17

Penicillins cont…

• Penicillins may be classified into four groups: – Natural penicillins (G and V) (narrow spectrum), – Antistaphylococcal (penicillinase-resistant) penicillins

(very narrow spectrum), – Aminopenicillins (extended spectrum), and – Antipseudomonal penicillins (very extended spectrum).

18

Natural Penicillins

Penicillin G (benzylpenicillin) • an acid-labile compound, poor absorption from GIT. • Most appropriate for IM or IV therapy. • Distributes to most tissues.• Excreted by the kidneys,

– 90% via tubular secretion, 10% by glomerular filtration. • Half-life = 30 minutes.

19

Clinical uses of penicillin G

Include; • Endocarditis caused by S. viridans (or Streptococcus bovis), • pharyngitis (group A β-hemolytic streptococci), • Cat bite cellulitis (Pasteurella multocida), and • Syphilis (Treponema pallidum).

PENICILLIN UNITS:• The activity of penicillin G was originally defined in units. • Crystalline sodium penicillin G contains approximately 1600

units per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g).

20

Penicillin G cont…

• Depot intramuscular formulations of penicillin G, – procaine penicillin and benzathine penicillin, – decreased solubility, delayed absorption, and a prolonged

half-life. • Procaine penicillin:

– Drug is detectable 24 hours after injection, and • Benzathine penicillin:

– low levels (0.003 units/mL) are detectable 4 weeks after injection.

21

Penicillin G cont…

• Intravenous penicillin G– first choice for therapy of meningitis caused by

susceptible S. pneumoniae. • Depot formulation of benzathine penicillin G

– for rheumatic fever prophylaxis. • Penicillin V

– orally administered phenoxymethyl congener of penicillin G

– have an antibacterial spectrum of activity that is similar to that of penicillin G.

– used to treat streptococcal infections when oral therapy is appropriate and desirable.

22

Antistaphylococcal (penicillinase-resistant) Penicillins

• Methicillin, Nafcillin, oxacillin, cloxacillin, and dicloxacillin

• More resistant to bacterial β-lactamases than is penicillin G.

• Effective against streptococci and penicillinase-producing staphylococci.

– used mostly for skin and soft-tissue infections or documented methicillin-sensitive S. aureus infections.

• Lack activity against Gram-negative bacteria,

– Unable to pass through G-negative bacterial porins due to size.

23

Antistaphylococcal Penicillins cont…

• Nafcillin (IM, IV)– T1/2 = 0.8 to 1.2 hrs– Primarily cleared by biliary excretion.

• Oxacillin (IM, IV)– T1/2 = 0.4 to 0.7 hrs.– Eliminated by both the kidney and biliary excretion.

• Indications for nafcillin or oxacillin include, – severe staphylococcal infections like cellulitis, empyema,

endocarditis, osteomyelitis, pneumonia, septic arthritis.

24

Antistaphylococcal Penicillins cont…

• Cloxacillin and dicloxacillin:– Comparable alternatives for oral therapy.– Eliminated by both the kidney and biliary excretion.

• No dosage adjustment is required for these drugs in renal failure.

• T1/2 = 0.5 to 0.8 hrs• Indications for cloxacillin or dicloxacillin include,

– clinically mild staphylococcal infections like impetigo.

25

Aminopenicillins (extended spectrum)• Include, Ampicillin and Amoxicillin.• Effective against a variety of Gram-positive cocci, Gram-

negative cocci such as Neisseria gonorrhoeae and N. meningitidis , and Gram-negative rods such as E. coli and Haemophilus influenzae, but their spectrum is limited by sensitivity to most β-lactamases.

• Have similar pharmacokinetics . • Both have good oral bioavailability• Concomitant ingestion of food decreases the bioavailability of

ampicillin but not amoxicillin.• T1/2; ampicillin= 1.1 to 1.5 hrs, amoxicillin = 1.4 to 2.0 hrs. • Ampicillin achieves therapeutic concentrations in the CSF only

during inflammation. – Effective treatment for meningitis caused by Listeria

monocytogenes.

26

Aminopenicillins cont…

• Amoxicillin does not reach adequate concentrations in the CNS,– not appropriate for meningitis therapy.

• Other indications for ampicillin include serious infections like enterococcal endocarditis and pneumonia caused by β-lactamase-negative H. influenzae.

• Amoxicillin oral therapy:– appropriate for clinically acute nonserious bacterial

infections like otitis media and sinusitis. • Amoxicillin also has use in multidrug regimens for the

eradication of Helicobacter pylori in duodenal and gastric ulcers.

27

Antipseudomonal Penicillins (very extended spectrum)

• Mezlocillin, piperacillin, Carbenicillin, azlocillin and ticarcillin • Achieve only low concentrations in the CSF,

– not among the drugs of first choice for meningitis therapy.• Undergo renal elimination.• Have comparable spectra of activity against many gram-

positive and gram-negative pathogens, including most anaerobes.

• Mezlocillin, piperacillin, and ticarcillin; – have similar clinical outcomes in patients with known or

suspected P. aeruginosa infections. • Inactivated by β-lactamase (may be combined with β-lactamase

inhibitors)

28

β-Lactamase Inhibitor Combinations• β-Lactamase Inhibitors;

– Clavulanic acid, sulbactam, and tazobactam.• Several formulations combine a β-lactam antibiotic with a

β-lactamase inhibitor (ampicillin-sulbactam [Unasyn], ticarcillin-clavulanic acid [Timentin], amoxicillin–clavulanic acid [Augmentin]).

• Combination significantly broadens the spectrum of antibacterial activity against β-lactamase-producing organisms.

• These drugs have clinical use in treating infections with known or suspected mixed bacterial flora, such as biliary infections, diabetic foot ulcers, endomyometritis, and peritonitis.

29

β-Lactam Antibiotics in Pregnancy

• All of the penicillin antibiotics are classified by FDA in pregnancy category B.

• Obstetricians frequently prescribe,– ampicillin, penicillin G, and penicillin V – because they are effective against the infections most

frequently encountered in caring for pregnant women (e.g., upper respiratory and lower urinary tract infections).

30

Adverse Effects to Penicillins

• Penicillins are considered among the safest antibiotics.• Anaphylaxis

– a serious, rare allergic response with an occurrence rate between 0.004% and 0.015% of penicillin courses.

• Allergic cross-reactivity between β-lactam antibiotics is significant.

• Diarrhea: common with extended spectrum.• Neurotoxicity• Nephritis

31

Cephalosporins

• Semisynthetic antibiotics derived from products of various microorganisms, including Cephalosporium and Streptomyces.

• β-lactam ring.– associated with antibacterial activity.

• The different pharmacological, pharmacokinetic, and antibacterial properties of individual cephalosporins – Variation in substitution (R).

• More resistant to β-lactamase than penicillins.• cephalosporinases (β-lactamases specific for the

cephalosporins). – Inactivate cephalosporins

32

Antibacterial Spectrum• Cephalosporins are classified into generations according to

their antibacterial spectrum and stability to β-lactamases. • The first-generation cephalosporins:

– active against streptococci, methicillin-sensitive S. aureus, and a few gram-negative bacilli.

– Broad spectrum especially against Gm+ve organisms.– Not effective against pseudomonas.– Resistant to β-lactamase enzyme.– Do not cross the meninges so not effective in meningitis.

Figure: The structure of cephalosporins.

33

Antibacterial Spectrum cont…

• The second-generation cephalosporins: – have greater stability against β-lactamase inactivation– possess a broader spectrum of activity to include gram-

positive cocci, gram-ve organisms, and anaerobes.– Do not penetrate meninges

• The extended-spectrum, or third-generation, cephalosporins – high degree of potency and β-lactamase stability– broader spectrum of action against many common gram-ve

bacteria and anaerobes while retaining good activity against streptococci.

– Less active against staph. than the earlier generations.– greatest activity against P. aeruginosa.– Cross BBB (most agents)

34

Antibacterial Spectrum cont…

Figure:

Summary of therapeutic

applications of

cephalosporins

35

Pharmacokinetics

• Distribute in satisfactory concentrations to most tissues except the CNS.

• Cefotaxime and ceftriaxone– antibiotics of first choice for the empirical treatment of

brain abscess and meningitis.• Urinary excretion:

– the major elimination path for most cephalosporins. – Dose adjustment in patients with renal failure.

• Biliary elimination is important for some cephalosporins.– Cefoperazone, cefoxitin, and ceftriaxone.

36

Table: Pharmacokinetic Parameters of Selected Cephalosporins

37

Clinical Uses of Cephalosporins

• The first-generation cephalosporins have activity against most of the bacterial pathogens that colonize skin and infect wounds. – useful in antimicrobial prophylaxis before surgery.

• Second-generation cephalosporins– cefoxitin and cefotetan have good anaerobic activity,

• prophylaxis of lower abdominal and gynecological infection.

• Third-generation cephalosporins– broad spectrum, used in wide range of infections

including,• Lyme disease (Borrelia sp.), pneumonia, peritonitis,

and sepsis syndrome.

38

Adverse Effects of Cephalosporins• The cephalosporins have good safety profiles.• Hypersensitivity reactions. • Local irritation: severe pain after IM injection and

thrombophlebitis after IV injection.• Nephrotoxicity especially when used with aminoglycosides.• Superinfections with Clostridium difficile, enterococci,

MRSA, P. aeruginosa, and Candida albicans. • Bleeding

– inhibits production of active vitamin K.– Antiplatelet effects.

39

Protein Synthesis Inhibitors

• Aminoglycosides• Macrolides, • Tetracyclines,• Chloramphenicol.

40

Protein Synthesis Inhibitors• Are divided into two groups: bacteriostatic and bactericidal.

– Chloramphenicol, Macrolides, and Tetracyclines are bacteriostatic,

– Aminoglycosides are bactericidal. • Mechanisms of action: Inhibit protein synthesis by binding

at different sites of manufacturing process.

41

Aminoglycosides

• Include: amikacin, gentamicin, kanamycin, netilmicin, neomycin, streptomycin, paromomycin and tobramycin.

• Are absorbed very poorly from the intact GIT due to their hydrophilicity.

Streptomycin and amikacin• effective in the treatment of tuberculosis.Gentamicin• It is a synergistic companion with beta-lactam antibiotics,

against;– Pseudomonas, Proteus, Enterobacter, Klebsiella, Serratia,

and other gram-negative rods that may be resistant to a multiple of other antibiotics.

– used concurrently with penicillin G for bactericidal activity in endocarditis due to streptococci viridans.

42

Aminoglycosides cont…

• Creams, ointments or solutions of gentamicin sulfate are used for the treatment of infected burns, wounds, or skin lesions.

Neomycin, • Very poorly absorbed when given orally.• Is used in preparation for elective bowel surgery. • In hepatic coma, it is used to suppress the coliform flora thus

reducing ammonia intoxication.Adverse effects: • Aminoglycosides cause ototoxicity and nephrotoxicity. • Losses of balance, vertigo are common manifests of

ototoxicity.

43

Tetracyclines• Include: tetracycline, chlortetracycline, oxytetracycline,

demeclocycline, methacycline, minocycline and doxycycline.• All tetracyclines have a similar mechanism of action,

– But have different chemical structures.• Structural analogues synthesized

– to improve pharmacokinetic properties and antimicrobial activity.

44

Tetracyclines cont…

• Are broad-spectrum antibiotics. • Active against many gram-positive and gram-negative

bacteria, including: anaerobes; rickettsiae; active against some protozoa.

Pharmacokinetics: • Partially absorbed from the stomach and upper GI tract. • Tetracyclines mainly differ in their absorption from GIT and

their elimination. • Doxycycline is better absorbed than tetracycline. • Absorption is impaired by preparations containing divalent

cations (Ca++, Mg++, Fe++ or Al+++).• Cross the placenta to reach the fetus and is also excreted in

milk.

45

Pharmacokinetics cont…

• Incompletely absorbed tetracyclines remaining in the intestine. – may inhibit sensitive intestinal microorganisms and alter

the normal intestinal flora.• Penetrate the uninflamed meninges• Doxycycline, minocycline, and chlortetracycline

– excreted primarily in the feces. – best for elderly patients.

• The other tetracyclines– eliminated primarily in the urine by glomerular filtration.

46

Clinical Uses• Little difference in clinical response among the various

tetracyclines. • Their use restricted in pregnancy and in patients under the

age of 8 years• Doxycycline,

– longer half-life and – lack of nephrotoxicity,

• choice for patients with preexisting renal disease or those who are at risk for developing renal insufficiency.

• Lack of nephrotoxicity – related mainly to biliary excretion.

47

Clinical Uses cont…

• Doxycycline– first-line agent in the prophylaxis of anthrax after

exposure.– choice for the primary stage of Lyme disease in adults and

children older than 8 years.• Tetracyclines are still the drugs of choice for treatment:

– cholera, – diseases caused by Rickettsia and Coxiella,– relapsing fever, – chlamydial diseases (trachoma, lymphogranuloma

venereum), and – nonspecific urethritis.

48

Adverse Effects

• Oral admin. - nausea, vomiting, epigastric burning, stomatitis, and glossitis

• IV injection- phlebitis.

• Hepatotoxicity

• Staining of both the deciduous and permanent teeth and retardation of bone growth can occur if tetracyclines are administered after the fourth month of gestation or if they are given to children less than 8 years of age.

• Superinfection:

– may result in oral, anogenital, and intestinal Candida albicans infections,

– Staphylococcus aureus or Clostridium difficile overgrowth may cause enterocolitis.

49

Chloramphenicol

• Bacteriostatic, broad-spectrum antibiotic.• Active against both aerobic and anaerobic gram-positive and

gram-negative organisms.• Active also against rickettsiae. • Haemophilus influenzae, N. meningitidis, and some strains of

Bacteroides are highly susceptible, and for them chloramphenicol may be bactericidal.

• Excretion– changed and unchanged drug excreted by urine. – A small amount of active drug is excreted into bile or

feces.• Inactivated in the liver by glucuronosyltransferase and is

rapidly excreted (80–90% of dose) in the urine.

50

Clinical Uses of Chloramphenicol• Potentially fatal nature of chloramphenicol-induced bone

marrow suppression: – restricts its use to a few life-threatening infections in

which the benefits outweigh the risks. • No longer recognized as the treatment of choice for any

bacterial infection. • Since effective CSF levels are obtained,

– a choice for treatment of specific bacterial causes of meningitis: • Haemophilus influenzae, Neisseria meningitidis, and S.

pneumoniae. • Effective against H. influenzae–related arthritis,

osteomyelitis, and epiglottitis.

51

Clinical Uses cont…

• A major treatment of typhoid and paratyphoid fever in developing countries.

• Alternative to tetracycline for rickettsial diseases, – especially in children younger than 8 years.

52

Adverse Effects

Gray baby syndrome:• Newborn infants(less than a week old and premature infants)

cannot adequately conjugate chloramphenicol to form the glucuronide;

• High levels of free chloramphenicol may accumulate and cause a potentially fatal toxic reaction.

• This syndrome is characterized by:– abdominal distention, vomiting, flaccidity, hypothermia,

gray color, shock, and collapse. • The mortality rate is high.

Bone marrow depression.• The most publicized adverse affects. • anemia, sometimes leukopenia or thrombocytopenia.

53

Drugs that inhibit bacterial synthesis of nucleic acids

• Quinolones: Nalidixic Acid and Fluoroquinolones.• Rifamycins: Anti-TB drugs.

54

Quinolones: Nalidixic Acid and Fluoroquinolones.

• Synthetic fluorinated analogs of nalidixic acid.• Block bacterial DNA synthesis by inhibiting bacterial

topoisomerase II (DNA gyrase) and topoisomerase IV. • Inhibition of DNA gyrase,

– prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication.

• Inhibition of topoisomerase IV – interferes with separation of replicated chromosomal

DNA into the respective daughter cells during cell division.

• Bactericidal at therapeutic doses. • The quinolones are now often classified into generations,

much like the cephalosporins (table below).

55

Quinolones cont…

• Selectivity of action results from differences in structure b/n the bacterial and eukaryotic forms of these enzymes.

The first-generation and oldest quinolones – exhibit limited gram-negative activity.

• Nalidixic acid and cinoxacin – do not achieve systemic antibacterial levels.– restricted to therapy of bladder infections caused by

urinary pathogens, such as E. coli, Klebsiella and Proteus spp.

• Their use is restricted by resistance.

Generation Drug Names Spectrum

1stnalidixic acid cinoxacin

Gram -ve

2nd

norfloxacinciprofloxacin enoxacin ofloxacin

Gram -ve (including Pseudomonas species), some Gram+ve (S. aureus) and some atypicals

3rd

levofloxacin sparfloxacin gemifloxacin

Same as 2nd generation with extended Gram+ and atypical coverageSome anerobes

4th

trovafloxacinMoxifloxacin

Same as 3rd generation with broad anaerobic coverage

56

57

Antibacterial SpectrumThe second-generation drugs • most reliable activity against gram-negative, including

Enterobacteriaceae. • Haemophilus spp. and sexually transmitted disease agents,

such as Neisseria gonorrhoeae, Chlamydia trachomatis, • Possess antipseudomonal activity.

Third and fourth generations,• Greater activity against gram +ve, such as S. pneumoniae. • MRSA and Enterococcus faecium are resistant.

Fourth-generation quinolones,• Also possess activity against anaerobes.

58

Pharmacokinetics • Quinolones are rapidly and almost completely absorbed

orally.• Half-life for most quinolones is 3 to 4 hours.• Elimination through glomerular filtration and tubular

secretion. • Moderate to severe renal insufficiency,

– quinolone dosages should be modified. • Metabolized by hepatic conjugation and glucuronidation. • All quinolones interact with multivalent cations,

– Form chelation complexes resulting in reduced absorption.

• Inhibit CYP1A2 (enoxacin, ciprofloxacin)– elevated theophylline concentrations cause toxicity.

59

Clinical Uses

• Therapeutic uses of the quinolones include:– urinary and respiratory tract infections, – GI and abdominal infections, STDs, and – bone, joint, and soft tissue infections.

• Nalidixic acid– effective for urinary tract infections.

60

Adverse Effects• In general, they are well tolerated. • Most frequently reported side effects

– nausea, vomiting, diarrhea, and abdominal pain. • CNS effects,

– drowsiness, weakness, headache, dizziness, and in severe cases, convulsions and toxic psychosis.

• Sparfloxacin, moxifloxacin– can cause QT prolongations.

• Trovafloxacin – Fulminant hepatotoxicity result in acute liver failure, – Use limited to life-threatening infections.

• Damage growing cartilage and cause an arthropathy. – Contraindicated in patients under 18 years of age.

61

Antimetabolites

• Called Folate Pathway Inhibitors.• Include: Sulfonamides, Trimethoprim

62

Sulfonamides

• Structural analogues of p-aminobenzoic acid (PABA). • Include: Sulfisoxazole, sulfamethoxazole, Sulfadiazine,

Sulfadoxine, Sulfasalazine, Sodium sulfacetamide, • Mechanism of action:

– Competitively inhibit dihydropteroate synthase, the enzyme responsible for the production of dihydrofolic acid.

63

Sulfonamides cont…

64

Antibacterial Spectrum

• Sulfonamides are broad-spectrum antimicrobials • effective against gram-positive and some gram-negative

organisms of the Enterobacteriaceae. – E. coli, Klebsiella, Salmonella, Shigella.

• Not active against Pseudomonas aeruginosa and Serratia spp. • Also effective against Chlamydia spp. • Used in treating infections caused by Toxoplasma gondii and

occasionally chloroquine-resistant Plasmodium falciparum.

65

Pharmacokinetic Properties• Sulfonamides are usually given orally, • Except for compounds designed for local gut effects, the

sulfonamides are rapidly absorbed from the intestinal tract, primarily from the small intestine.

• pass the placental barrier and enter CSF even in the absence of inflammation.

• Readily distribute throughout body fluids.• Half-lives range from 2.5 to 17 hours.• Metabolized by acetylation and oxidation (slow acetylators

are liable to toxicity).• The parent compound and the metabolites are excreted in the

urine.

66

Clinical Uses• Sulfonamides are infrequently used as single agents.

– meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant.

• The fixed-drug combination of Trimethoprim–Sulfamethoxazole (TMP-SMX) – the drug of choice for infections such as Pneumocystis

jiroveci pneumonia, toxoplasmosis, nocardiosis, genitourinary, GI, and respiratory tract infections caused by susceptible bacteria.

• Current indications are more limited, – especially to the treatment of urinary tract and ear

infections, because of frequently encountered resistance and the availability of better and safer agents.

67

Clinical Uses cont…

• Sulfadiazine, in combination with pyrimethamine,– Treatment choice for symptomatic toxoplasmosis. – Patients should be well hydrated to prevent crystalluria.

• Topically active sulfonamides are useful in preventing infections in burn patients.

68

Adverse Effects and Drug Interactions

• At high concentrations, – the free drug or its metabolites may form crystals and

cause bleeding or complete obstruction of the kidneys.• Hypersensitivity reactions (e.g., rashes, eosinophilia, and

drug fever). • Other rare allergic reactions include,

– Vasculitis, photosensitivity, agranulocytosis, and thrombocytopenia, hemolytic or aplastic anemia.

• Stevens-Johnson syndrome– fever, malaise, erythema multiforme, and ulceration of the

mucous membranes of the mouth and genitalia.

69

Adverse Effects and Drug Interactions cont…

• Sulfonamides compete for sites on plasma proteins that are responsible for the binding of bilirubin.– less bilirubin is bound, and – in the newborn the unbound bilirubin can be deposited in

the basal ganglia and subthalamic nuclei, • causing kernicterus, a toxic encephalopathy.

– Should not be given to newborns or to women during the last 2 months of pregnancy.