ANTIBACTERIAL AGENTS

Dr R . Jaya prada

• Antibiotics - antibacterial substances produced by various species of microorganisms (bacteria, fungi, and actinomycetes) - suppress the growth of other microorganisms.

Drugs that destroy microbes, prevent their multiplication or growth or prevent their pathogenic action.

Differ in their physical, chemical, and pharmacological properties.

Differ in their antibacterial spectrum of activity and their mechanism of action.

Antibiotics = “against life”Antibiotics can be either natural products or man-

made synthetic chemicals.Old : An antibiotic is a chemical substance

produced by various species of microorganisms that is capable of inhibiting the growth of other microorganisms in small concentrations.

New: An antibiotic is a product produced by a microorganism or a similar substance produced wholly or partially by chemical synthesis, which in low concentrations, inhibits the growth of other microorganisms.

• Antibiotics (i.e., anti-infective or antimicrobial drugs) may be directed at one of several disease-producing organisms including bacteria, viruses, fungi, helminthes, etc.

• The vast majority of antibiotics are bacteria fighters; although there are millions of viruses, there are only about half a dozen antiviral drugs.

• Bacteria are more complex than viruses (while viruses must “live” in a host (us), bacteria can live independently, and so are easier to kill.

Where do antibiotics come from?

• Several species of fungi including Penicillium and Cephalosporium

• E.g. penicillin, cephalosporin

– Species of actinomycetes, Gram positive filamentous bacteria• Many from species of Streptomyces

– Also from Bacillus, Gram positive spore formers– A few from myxobacteria, Gram negative bacteria– New sources explored: plants, herbs, fish

Microbes in History

• Date Event• 300Bc Aristotle, Greek philosopher and scientist, studied and

wrote about living organisms.• 1675 Antony van Leeuwenhoek discovered bacteria.• 1796 Edward Jenner laid the foundation for developing vaccines.• 1848 Ignác Fülöp Semmelweis discovered simple handwashing

could prevent passage of infection from one patient to another.• 1857 Louis Pasteur introduced the germ theory of disease.• 1867 Joseph Lister showed evidence that microbes caused disease

and pioneered the use of antiseptics during surgery to kill germs.• 1876 Robert Koch, by studying anthrax, showed the role of

bacteria in disease.• 1928 Alexander Fleming is credited with discovering penicillin.

History of Antimicrobial Therapy• 1909 Paul Ehrlich– Differential staining of tissue, bacteria– Search for magic bullet that would attack bacterial

structures, not ours.– Developed salvarsan, used against syphilis ultimately

proved to be too toxic for human use.

• Arsphenamine was the opening event in the chemotherapeutic revolution for the treatment of human infections.

Ehrlich’s Magic Bullets (arsenicals)

• In 1891, the Russian Romanovsky – suggested that usage of quinine to cure malaria.

• Ehrlich (1854–1915) coined the term chemotherapy.

• Ehrlich defined chemotherapy as “the use of drugs to injure an invading organism without injury to the host.”

Fleming and Penicillin

Alexander Fleming was first to characterize penicillin’s activity. He found mold contaminating his culture plates, with clearing of staphylococcal colonies all around the mold. Fleming then isolated penicillin from the mold.

Staphylococcusaureus(bacterium)

Penicilliumchrysogenum(fungus)

Zone wherebacterial growthis inhibited

Thanks to work by Alexander Fleming (1881-1955), Howard Florey ( 1898-1968) and Ernst Chain (1906-

1979), penicillin was first produced on a large scale for human use in 1943.

• E. Chain • H. Florey• A. Fleming

• Florey developed penicillin during WWII when it was much needed; tons of mold was grown to produce it, and was even collected from the urine of people that had first been treated with it (because it is eliminated unchanged by the kidneys).

• 1935- Sulfa drugs discovered.• 1943 -Streptomycin discovered.• Gerhard Domagk– Discovered sulfanilamide

• Selman Waksman– Antibiotics

• Antimicrobial agents produced naturally by organisms

• 1905 Atoxyl Trypanosomiasis

• 1909 Arsphenamine Syphilis

• 1912 Neoarsphenamine Syphilis

• 1912 Tartar emetic Leishmaniasis

• 1917 Tartar emetic Schistosomiasis

• 1919 Tryparsamide Trypanosomiasis

Selective toxicity means safer for host• Antibiotics generally have a low MIC– Minimum inhibitory concentration– Effective at lower doses

• Good therapeutic index ( Ti)– Safer; larger quantity must be administered before

harmful side effects occur.

Drug-pathogen-patient• Selective toxicity- kills harmful microbes without• damaging the host• • Resistance- intrinsic versus acquired• • host defense -Immune response• • Pharmacokinetics- absorption, distribution,• metabolism, elimination• • Pharmacodynamics-adverse effects, dose-

related,• allergy, idiosyncratic

• What is the ideal antimicrobial drug ?• Have highly selective toxicity to the

pathogenic microorganisms in host body• Have no or less toxicity to the host.• Low propensity for development of resistance.• Not induce hypersensitivies in the host.• Have rapid and extensive tissue distribution• Be free of interactions with other drugs.• Be relatively inexpensive

• Antimicrobial drugs are chemotherapeutic drugs.• Two categories:• – Antibiotics : Antimicrobial drugs produced by microorganisms.• – Synthetic drugs : Antimicrobial drugs synthesized in the lab.• Antibacterial synthetic drugs• Antifungal synthetic drugs• Antiviral agents

Definitions• Chemotherapeutic Index (CI): the ratio of median lethal dose (LD50) to median effective dose (ED50) of infective animals.LD50/ED50 or LD5/ ED95• Generally the bigger the CI of a drug is, the lower its toxicity, the better its curative effect and the greater its value of clinical application.However, a drug with big CI does not mean that it is definitely safety.• Penicillin G has almost no toxicity and its CI is big, can cause anaphylactic shock and lead to death.

Definitions• Antimicrobial spectrum : the scope that a drug kills or suppresses the growth of

microorganisms.• Narrow-spectrum: The drugs that only act on one kind or one strain of bacteria. (isoniazid )• Broad-spectrum: The drugs that have a wide antimicrobial scope.

(tetracycline,chloramphenicol )

Definitions

• Antimicrobial activity: the ability that a drug kills or suppresses the growth of microorganisms.• Potency- AMA activity per mg/µg. • Expressed as MIC, MBC, MAC

• The minimal inhibitory concentration (MIC) the minimum amount of a drug required to

inhibit the growth of bacteria in vitro.• The minimal bactericidal concentration (MBC)• the minimum amount of a drug required to kill

bacteria in vitro.

• MIC 90- inhibit 90 % m/o tested• MBC- to kill m/o• MAC- Conc of AMA, reduces the growth of m/o in

vitro by a factor of 10. It may be 1 quarter or 1/10th of the MIC depends on the drug and organism.

• PAE – persistence of AMA for longer period

( few hrs) after brief exposure to or in absence of detectable conc of AMA.

• Biphasic (Eagle’s) effect- phenomenon , Low dose-cidal whereas High dose - No effect

• Common in BLA because of differential sensitivity of the PBPs to high doses of BLA.

• The molecular basis of chemotherapy• The biochemical reactions that are potential targets for

antibacterial drugs• • There are three groups.• Class I: Utilization of glucose / carbon source for the

generation of energy (ATP) and synthesis of simple carbon compounds used as precursors in the next class of reactions.

• Class II: Utilization of these precursors in an energy-dependent synthesis of all the amino acids, nucleotides, phospholipids, amino sugars, carbohydrates and growth factors required by the cell for survival and growth.

• Class III: Assembly of small molecules into macromolecules- proteins, RNA, DNA, polysaccharides and peptidoglycon.

• Other potential targets are the formed structures

e.g., cell membrane

microtubules

other specific tissues muscle tissue in helminths).

Bacterial StructuresFlagella PiliCapsulePlasma MembraneCytoplasmCell WallLipopolysaccharidesTeichoic AcidsInclusionsSpores

Antimicrobial Agents• Effect on microbes:

• Cidal (killing) effect• Static (inhibitory) effect

• Spectrum of action • Broad Spectrum – effective against procaryotes which kill or inhibit a

wide range of Gram+ and Gram- bacteria• Narrow spectrum – effective against mainly Gram+ or Gram- bacteria• Limited spectrum – effective against a single organism or disease

VI. Antibacterial Agents

• A. Inhibitors of cell wall synthesis• 1. Penicillins • 2. Cephalosporins • 3. Other antibacterial agents that act on cell walls• B. Disrupters of cell membranes• 1. Polymyxins• 2. Tyrocidins• C. Inhibitors of protein synthesis• 1. Aminoglycosides• 2. Tetracyclines • 3. Chloramphenicol• 4. Other antibacterial agents that affect protein synthesis• a. Macrolides• b. Lincosamides• D. Inhibitors of nucleic acid synthesis• 1. Rifampin• 2. Quinolones• E. Antimetabolites and other antibacterial agents• 1. Sulfonamides• 2. Isoniazid• 3. Ethambutol• 4. Nitrofurans

Inhibition of pathogen’sattachment to, orrecognition of, hostArildonePleconaril

Inhibition of DNAor RNA synthesisActinomycinNucleotide analogsQuinolonesRifampin

Inhibition of generalmetabolic pathwaySulfonamidesTrimethoprimDapsone

Disruption ofcytoplasmic membranePolymyxinsPolyenes (antifungal)

Inhibition ofprotein synthesisAminoglycosidesTetracyclinesChloramphenicolMacrolides

Inhibition of cellwall synthesisPenicillinsCephalosporinsVancomycinBacitracinIsoniazidEthambutolEchinocandins(antifungal)

Inhibitors of Cell Wall Synthesis

Penicillin G (benzylpenicillin)

Cephalosporin

Cell wall structure

Mechanisms of antimicrobial agents• Inhibition of cell wall synthesis• – Penicillins and cephalosporins stop synthesis of

wall by preventing cross linking of peptidoglycan units.

• – Bacitracin and vancomycin also interfere here.• – Excellent selective toxicity

Vancomycin also inhibits cell wall synthesis but it is not a β lactam AMA. It does by interfering with the production of Peptidoglycan.It binds to D-Ala-D-Ala terminals of peptido glycan precursors on the outer surface membrane. As a result precursors cannot incorporate into the peptidoglycan.

Bacitracin inhibits secretion of NAG and NAM subunits

STRUCTURE OF -LACTAM ANTIBIOTICS

“Penicillin Home”• Looks like a house with a new room added to

the side• Think of the R-group as of a funky antenna• Changing “antennae” and or finishing the

“basement” will create better “homes” (penicillins)

[Penicillin] Home Improvement Project

• Adding a new antenna creates broad spectrum penicillins – Example: Ampicillin

• Adding additional antennae and finishing the basement creates cephalosporins– Example: 1st, 2nd, 3rd, & 4th generation

cephalosporins

Penicillins• Penicillins contain a b-lactam ring which inhibits the

formation of peptidoglycan crosslinks in bacterial cell walls (especially in Gram-positive organisms)

• Penicillins are bactericidal but can act only on dividing cells

• They are not toxic to animal cells which have no cell wall

Synthesis of Penicillin· b-Lactams produced by fungi, some

ascomycetes, and several actinomycete bacteria· b-Lactams are synthesized from amino acids

valine and cysteine

Penicillins (cont.) Clinical Pharmacokinetics

• Penicillins are poorly lipid soluble and do not cross the blood-brain barrier in appreciable concentrations unless it is inflamed (so they are effective in meningitis)

• They are actively excreted unchanged by the kidney, but the dose should be reduced in severe renal failure

Penicillins (cont.)Resistance

• This is the result of production of b-lactamase in the bacteria which destroys the b-lactam ring

• It occurs in e.g. Staphylococcus aureus, Haemophilus influenzae and Neisseria gonorrhoea

Penicillins (cont.)Examples

• There are now a wide variety of penicillins, which may be acid labile (i.e. broken down by the stomach acid and so inactive when given orally) or acid stable, or may be narrow or broad spectrum in action

Penicillins (cont.)Examples

• It is the most potent penicillin but has a relatively narrow spectrum covering Strepptococcus pyogenes, S. pneumoniae, Neisseria meningitis or N. gonorrhoeae, treponemes, Listeria, Actinomycetes, Clostridia

• Benzylpenicillin (Penicillin G) is acid labile and b-lactamase sensitive and is given only parenterally

Penicillins (cont.)Examples

• Phenoxymethylpenicillin (Penicillin V) is acid stable and is given orally for minor infections

• it is otherwise similar to benzylpenicillin

• Ampicillin is less active than benzylpenicillin against Gram-possitive bacteria but has a wider spectrum including (in addition in those above) Strept. faecalis, Haemophilus influenza, and some E. coli, Klebsiella and Proteus strains

• It is acid stable, is given orally or parenterally, but is b-laclamase sensitive

• Amoxycillin is similar but better absorbed orally • It is sometimes combined with clavulanic acid,

which is a b-lactam with little antibacterial effect but which binds strongly to b-lactamase and blocks the action of b-lactamase in this way

• It extends the spectrum of amoxycillin

• Flucloxacillin is acid stable and is given orally or parenterally

• It is b-lactamase resistant • It is used as a narrow spectrum drug for

Staphylococcus aureus infections

• Azlocillin is acid labile and is only used parenterally

• It is b-lactamase sensitive and has a broad spectrum, which includes Pseudomonas aeruginosa and Proteus species

• It is used intravenously for life-threatening infections,i.e. in immunocompromised patients together with an aminoglycoside

Penicillins (cont.)Adverse effects

• Allergy (in 0.7% to 1.0% patients). Patient should be always asked about a history of previous exposure and adverse effects

• Superinfections(e.g.caused by Candida )• Diarrhoea : especially with ampicillin, less

common with amoxycillin• Rare: haemolysis, nephritis

Penicillins (cont.)Drug interactions

• The use of ampicillin (or other broad-spectrum antibiotics) may decrease the effectiveness of oral conraceptives by diminishing enterohepatic circulation

Antistaphylococcus penicillins

• Oxacillin, cloxacillin– Resistant against staphylococcus penicillinases

Cephalosporins

• They also owe their activity to b-lactam ring and are bactericidal.

• Good alternatives to penicillins when a broad -spectrum drug is required

• should not be used as first choice unless the organism is known to be sensitive

Cephalosporins

• BACTERICIDAL- modify cell wall synthesis• CLASSIFICATION- first generation are early

compounds• Second generation- resistant to β-lactamases• Third generation- resistant to β-lactamases &

increased spectrum of activity• Fourth generation- increased spectrum of

activity

Cephalosporins

• FIRST GENERATION- eg cefadroxil, cefalexin, Cefadrine - most active vs gram +ve cocci. An alternative to penicillins for staph and strep infections; useful in UTIs

• SECOND GENERATION- eg: cefaclor and cefuroxime. Active vs Enterobacteriaceae eg E. Coli, Klebsiella spp, proteus spp. May be active vs H. influenzae and N. meningtidis

c• THIRD GENERATION- eg cefixime and other

I.V.s cefotaxime,ceftriaxone,ceftazidime. Very broad spectrum of activity inc gram -ve rods, less activity vs gram +ve organisms.

• FOURTH GENERATION- cefpirome better vs gram +ve than 3rd generation. Also better vs gram -ve esp enterobacteriaceae & pseudomonas aerugenosa. I.V. route only

Cephalosporins (cont.)Adverse effects

• Allergy (10-20% of patients with penicillin allergy are also allergic to cephalosporins)

• Nephritis and acute renal failure• Superinfections• Gastrointestinal upsets when given orally

Vancomycin

• This interferes with bacterial cell wall formation and is not absorbed after oral administration and must be given parenterally.

• It is excreted by the kidney. • It is used i.v. to treat serious or resistant Staph.

aureus infections and for prophylaxis of endocarditis in penicillin-allergic people.

Vancomycin Adverse effects

• Its toxicity is similar to aminoglycoside and likewise monitoring of plasma concentrations is essential.

• Nephrotoxicity• Allergy

Ribosomes: site of protein synthesis• Prokaryotic ribosome's are 70S; – Large subunit: 50 S • 33 polypeptides, 5S RNA, 23 S RNA

– Small subunit: 30 S • 21 polypeptides, 16S RNA

• Eukaryotic are 80SLarge subunit: 60 S

• 50 polypeptides, 5S, 5.8S, and 28S RNA

– Small subunit: 40S• 33 polypeptides, 18S RNA

Baseball player slides into home The ball is fielded by the catcher who makes a CLEan TAG The word CLEean lies over the base: these inhibit 50S The word TAG lies beneath the base: these inhibit 30S

Ribosome Home Plate

Antibiotics that Inhibit Protein Synthesis

• Inhibitors of initiation – complex formation and tRNA-ribosome interactions

Tetracyclines & Aminoglycosides

Antibiotics that Inhibit Protein Synthesis

• Inhibitors of peptide bond formation & translocation

• Chloramphenicol• Erythromycin A

Tetracyclines• Discovered in 1947

• Bacteriostatic (almost always)

• Enter via porins (G-) and by their lipophilicity in (G+).

• Low toxicity, broad spectrum for both Gram- and Gram+ bacteria

• Selectivity results from transfer into bacterial cells but not mammalian cells

• Primary binding site is 30s ribosomal subunit. Prevents the attachment of amino acyl-tRNA to the ribosome and protein synthesis is stopped

• Resistance associated with ability of compound to permeate membranes and alteration of the target of the antibiotic by the microbe

Aminoglycosides (bactericidal)streptomycin, kanamycin, gentamicin, tobramycin, amikacin,

netilmicin, neomycin (topical)

• Mode of action - The aminoglycosides irreversibly bind to the 60S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur. They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. By binding to the 16 S r-RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity. May also destabilize bacterial membranes.

• Spectrum of Activity -Many gram-negative and some gram-positive bacteria

• Resistance - Common• Synergy - The aminoglycosides synergize with β-lactam

antibiotics. The β-lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.

AminoglycosidesClinical pharmacokinetics

• These are poorly lipid soluble and, therefore, not absorbed orally

• Parenteral administration is required for systemic effect.

• They do not enter the CNS even when the meninges are inflamed.

• They are not metabolized.

Aminoglycosides Clinical pharmacokinetics

• They are excreted unchanged by the kidney (where high concentration may occur, perhaps causing toxic tubular demage) by glomerular filtration (no active secretion).

• Their clearance is markedly reduced in renal impairment and toxic concentrations are more likely.

Aminoglycosides Resistance

• Resistance results from bacterial enzymes which break down aminoglycosides or to their decreased transport into the cells.

Aminoglycosides Examples

• Gentamicin is the most commonly used, covering Gram-negative aerobes, e.g. Enteric organisms (E.coli, Klebsiella, S. faecalis, Pseudomonas and Proteus spp.)

• It is also used in antibiotic combination against Staphylococcus aureus.

• It is not active against aerobic Streptococci.

Aminoglycosides Examples

• Tobramycin: used for pseudomonas and for some gentamicin-resistant organisms.

• Some aminoglycosides,e.g. Gentamicin, may also be applied topically for local effect, e.g. In ear and eye ointments.

• Neomycin is used orally for decontamination of GI tract.

Aminoglycosides Adverse effects

• The main adverse effects are: NephrotoxicityToxic to the 8th cranial nerve (ototoxic), especially the vestibular division.

• Other adverse effects are not dose related, and are relatively rare, e.g. Allergies.

Macrolides (bacteriostatic)erythromycin, clarithromycin, azithromycin,

spiramycin• Mode of action - The macrolides inhibit

translocation by binding to 50 S ribosomal subunit

• Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella (intracellular bacterias)

• Resistance - Common

Macrolides Examples and clinical pharmacokinetics

• Erythromycin is acid labile but is given as an enterically coated tablet

• It is excreted unchanged in bile and is reabsorbed lower down the gastrointestinal tract.

• It may be given orally or parenterally

Macrolides Examples and clinical pharmacokinetics

• Macrolides are widely distributed in the body except to the brain and cerebrospinal fluid

• The spectrum includes Staphylococcus aureus, Streptococcuss pyogenes, S. pneumoniae, Mycoplasma pneumoniae and Chlamydia infections.

Macrolides – side effects

• Although effective, aminoglycosides are toxic, and this is plasma concentration related.

• It is essential to monitor plasma concentrations ( shortly before and after administration of a dose) to ensure adequate concentrations for bactericidal effects, while minimising adverse effects, every 2-3 days.

Macrolides – side effects

• Nauzea, vomiting• Allergy• Hepatitis, ototoxicity• Interaction with cytochrome P450 3A4

(inhibition)

Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic)

• Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity.

• Spectrum of activity - Chloramphenicol - Broad range;Lincomycin and clindamycin - Restricted range

• Resistance - Common

• Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis.

Clindamycin

• Clindamycin, although chemically distinct, is similar to erythromycin in mode of action and spectrum.

• It is rapidly absorbed and penetrates most tissues well, except CNS.

• It is particularly useful systematically for S. aureus (e.g.osteomyelitis as it penetrates bone well) and anaerobic infections.

ClindamycinAdverse effects

• Diarrhoea is common.• Superinfection with a strain of Clostridium

difficile which causes serious inflammation of the large bowel (Pseudomembranous colitis)

Chloramphenicol

• This inhibits bacterial protein synthesis. • It is well absorbed and widely distributed ,

including to the CNS.• It is metabolized by glucoronidation in the

liver.• Although an effective broad-spectrum

antibiotics, its uses are limited by its serious toxicity.

Chloramphenicol

• The major indication is to treat bacterial meningitis caused by Haemophilus influenzae, or to Neisseria menigitidis or if organism is unknown.It is also specially used for Rikettsia (typhus).

Chloramphenicol Adverse effects

• A rare anemia, probably immunological in origin but often fatal

• Reversible bone marrow depression caused by its effect on protein synthesis in humans

• Liver enzyme inhibition

Tetracyclines (bacteriostatic)tetracycline, minocycline and doxycycline

• Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome.

• Spectrum of activity - Broad spectrum; Useful against intracellular bacteria

• Resistance - Common• Adverse effects - Destruction of normal intestinal

flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth.

Tetracyclines Examples and clinical pharmacokinetics

• Tetracycline, oxytetracycline have short half-lives.• Doxycycline has a longer half-life and can be

given once per day.• These drugs are only partly absorbed.• They bind avidly to heavy metal ions and so

absorption is greatly reduced if taken with food, milk, antacids or iron tablets.

Tetracyclines Examples and clinical pharmacokinetics

• They should be taken at least half an hour before food.

• Tetracyclines concentrate in bones and teeth.• They are excreted mostly in urine, partly in bile.• They are broad spectrum antibiotics, active

against most bacteria except Proteus or Pseudomonas.

• Resistance is frequent

Tetracyclines Adverse effects

• Gastrointestinal upsets• Superinfection• Discolouration and deformity in growing teeth

and bones (contraindicated in pregnancy and in children < 12 years)

• Renal impairment (should be also avoided in renal disease)

3- Metabolic inhibitors

• Sulfonamides (sulfanilamide) are structural analogs of PABA, a molecule crucial for Nucleic acid synthesis

• humans do not synthesize dihydropteroic acid from PABA

• Trimethoprim interferes in next step DHF -> THF

Mechanism of Action ANTIMETABOLITE ACTION

Sulfonamides and trimethoprim• Sulfonamides are rarely used alone today.• Trimethoprim is not chemically related but is

considered here because their modes of action are complementary.

Sulfonamides, Sulfones (bacteriostatic)

• Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitively inhibit formation of dihydropteroic acid.

• Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.

• Resistance - Common

• Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.

Trimethoprim, Methotrexate, (bacteriostatic)

• Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid.

• Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.

• Resistance - Common• Combination therapy - These antimicrobials are

used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.

p-aminobenzoic acid + Pteridine

Dihydropteroic acid

Dihydrofolic acid

Tetrahydrofolic acid

Pteridine synthetase

Dihydrofolate synthetase

Dihydrofolate reductase

Thymidine

Purines

Methionine

Sulfonamides

Trimethoprim

Sulfonamides and trimethoprimMode of action

• Folate is metabolized by enzyme dihydrofolate reductase to the active tetrahydrofolic acid.

• Trimethoprim inhibits this enzyme in bacteria and to a lesser degree in animal s, as the animal enzyme is far less sensitive than that in bacteria.

Sulfonamides and trimethoprimClinical pharmacokinetics

• It is the drug of choice for the treatment and prevention of pneumonia caused by Pneumocystis carinii in immunosupressed patients.

• Trimethoprim is increasingly used alone for urinary tract and upper respiratory tract infections, as it is less toxic than the combination and equally effective.

Sulfonamides and trimethoprimAdverse effects

• Gastrointestinal upsets• Less common but more serious:

sulfonamides: allergy, rash, fever, renal toxicity trimethoprim:

anemia, thrombocytopenia

-cotrimoxazole: aplastic anemia

4-Interference with nucleic acid synthesis

• Bacterial DNA is negatively supercoiled– Supercoiling is maintained by gyrase, a type II

topoisomerase.– Inhibition of gyrase and type IV topoisomerase

interferes with DNA replication, causes cell death– Eukaryotic topoisomerases differ in structure

Quinolones (bactericidal)nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin,

levofloxacin, lomefloxacin, sparfloxacin

• Mode of action - These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis.

• Spectrum of activity - Gram-positive cocci and urinary tract infections

• Resistance - Common for nalidixic acid; developing for ciprofloxacin

Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS

Quinolones Examples and clinical pharmacokinetics

• Nalidixic acid, the first quinolone, is used as a urinary antiseptic and for lower urinary tract infections, as it has no systemic antibacterial effect.

• Ciprofloxacin is a fluoroquinolone with a broad spectrum against Gram-negative bacilli and Pseudomonas,

Quinolones Examples and clinical pharmacokinetics

• It can be given orally or i.v. to treat a wide range of infections, including respiratory and urinary tract infections as well as more serious infections, such Salmonella.

• Activity against anaerobic organism is poor and it should not be first choice for respiratory tract infections.

Quinolones Adverse effects

• Gastrointestinal upsets• Fluoroquinolones may block the inhibitory

neurotransmitter, and this may cause confusion in the elderly and lower the fitting threshold.

• Allergy and anaphylaxis

Quinolones Adverse effects

• Possibly damage to growing cartilage: not recommended for pregnant women and children

Metronidazole

• Metronidazole binds to DNA and blocks replication.

Pharmacokinetics• It is well absorbed after oral or rectal

administration and can be also given i.v.• It is widely distributed in the body (including

into abscess cavities) • It is metabolized by the liver.

Metronidazole Uses

• Metronidazole is active against anaerobic organisms (e.g. Bacteroides, Clostridia), which are encountered particularly in abdominal surgery.

• It is also used against Trichomonas, Giardia and Entamoeba infections

Metronidazole Uses

• Increasingly, it is used as part of treatment of Helicobacter pylori infection of the stomach and duodenum associated with peptic ulcer disease.

• It is used also to treat a variety of dental infections, particularly dental abscess.

Metronidazole Adverse effects

• Nausea, anorexia and metallic taste• Ataxia• In patients, who drink alcohol, may occur

unpleasant reactions. They should be advised not to drink alcohol during a treatment.

Nitrofurantoin

• This is used as a urinary antiseptic and to treat Gram-negative infections in the lower urinary tract. It is also used against Trypanosoma infections.

• It is taken orally and is well absorbed and is excreted unchanged in the urine.

Nitrofurantoin Adverse effects

• Gastrointestinal upsets• Allergy• Polyneuritis

Fucidin

• Fucidin is active only against Staphylococcus aureus (by inhibiting bacterial protein synthesis) and is not affected b-lactamase.

• It is usually only used with flucloxacillin to reduce the development of resistance.

• It is well absorbed and widely distributed, including to bone

• It can be given orally or parenterally.• It is metabolized in the liver.

Antibiotics for leprosy

• Leprosy is caused by infection with Mycobacteria leprae.

• A mixture of drugs are used to treat leprosy, depending on the type and severity of the infection and the local resistance patterns.

Antibiotics for leprosy

• Rifampicin is used, which is related to the sulphoamides.

• Rifampicin and Rifamycin block synthesis of m-RNA.

• Its adverse effects include haemolysis, gastrointestinal upsets and rashes.

5- Cell membranes as targets

• Bacterial cell membranes are essentially the same in structure as those of eukaryotes– Antibiotics also affect Gram neg. cell walls, ie.

Outer membrane together with cell membrane– Anti-membrane drugs are less selectively toxic

than other antibiotics.– Many antifungal drugs ( Polyenes as Amphotericin

B, Nystatin) make use of cell membrane differences.

Cell membrane disruptors

• Amphotericin B binds to ergosterol of cell membranes of fungi, causing lysis of cell

• Azoles (fluconazole) and allyamines (terbinafine) block ergosterol synthesis

• Polymixin disrupts bacterial cell membranes, but is toxic to people

Inhibition of the synthesis of the nucleotides

Alteration of the base-pairing properties of the template

Agents that intercalate in the DNA have this effect.e.g., Acridines (proflavine and acriflavine)- topically as antiseptics. The acridines double the distance between adjacent base pairs and cause a frame shift mutation , whereas some purine and pyrimidine analogues cause base mispairing.

Synergy and Antagonism• Synergy; If two antibiotics used in

combination have an antibacterial effect much greater than either drug alone–Ex.; beta-lactams and aminoglycosides

• Antagonism; When two drugs in combination have activity less than the better of the two–Ex.; bactericidal and bacteriostatic

Antibiotic Susceptibility Testing

• Dilution Method

• Disc Diffusion Method

• E-test

• High-Tech Methods