Lecture 10 - Principles Of Antimicrobial Therapy

Antimicrobial Chemotherapy Dr. Eiman Mokaddas MD, FRCPath Associate Professor Microbiology Department Faculty of Medicine

Aims and Objectives • Explain the terms MIC/MBC, sensitive/resistant, bacteriocidal/bacteriostatic, synergy/antagonism • Describe the mechanism of action of the major groups of antibiotics • Describe the spectrum of action of commonly used drugs • Describe the mechanism of clinically significant resistant mechanism for particular groups of drugs • Factors affecting choice of antibiotic • Side effects commonly associated with antibiotics • Explain the role of the laboratory and clinical microbiologists in influencing antimicrobial usage in clinical practice

Introduction History of Antibiotics • 2500 years ago: anti-invective substances were known: – Chineese used moldy soya been for carbuncles & boils – Greek( hypocrates) used wine to treat wounds – 1900’s: syphilis treated with arsenic – 1936: Sulphonamides discovered – 1940’s: Penicillin & Streptomycin – 1950’s: Golden age of antimicrobial

Definitions • Antimicrobial agents: – Anti-bacterial – Anti-viral – Anti-fungal – Anti-protozoal • Antibiotics: – Naturally occurring compound • Chemotherapy: – Synthetic chemical compounds • Semi-synthetic antibiotics – Naturally occurring compound manipulated chemically

Laboratory Terms

• Susceptible: – The organism is killed or inhibited by given levels of antibitoics • Resistant: – The organism not killed or inhibited by given level of antibiotics • Minimal Inhibitory Concentration(MIC): – Minimum concentration of antibiotics needed to inhibit visual growth of the organism : the lower the better

Laboratory Terms • Minimal Bacteriocidal Concentration (MBC): – Minimum concentration of antibitoics needed to kill the organism ( the lower the MBC the more effective is the antibiotic) • Tolerent: ⇓ MIC & ⇑ MBC

Common Groups of Antimicrobial Agents • Beta-lactams: – Penicillins • • • • • •

Penicillin G Ampicillin/amoxicillin Co-amoxiclav Flucloxacillin/cloxacillin: Resistant to staphylococcal B-lactamases Piperacillin: broad spectrum penicillin Carbapenems: imipenem, meropenem: very broad spectrum ( Gram-positive, Gram-negative and anaerobes)

– Cephalosporins: • • • •

First generation: cepharadine Second generation: cefuroxime Third generation: ceftazidime Fourth generation

S R1

CH3

NH

CH3 C

N

COOH

O

B-LACTAMASE ACTION

Basic penicillin structure ( R side chain varies)

S R1

NH

C

N

CH2

R2

O COOH B-LACTAMASE ACTION

Basic cephalosporin Structure ( R side chain varies)

Common Groups of Antimicrobial Agents • Aminoglycosides: – Gentamicin, amikacin

• Glycopeptides: – Vancomycin, teicoplanin

• Macrolides: – Erythromycin, clarithromycin

• Quinolones: – ciprofloxacin

• Mescellaneous: – – – –

Metronidazole Fusidic acidTrimethoprim and sulphamethoxazole Chloramphenicol Tetracyclins

Principles of antibiotics • Selective toxicity: – Ability of the antibiotic to inhibit the growth or kill the pathogen without harming the host cell

• Cidal: Antimicrobials that kill a microbe ( penicillin) • Static: Antimicrobial that only inhibit the growth ( sulphonamides)

• Administration: – Oral – Systemic: IV, IM – Topical

Mechanism of action of antibiotics

Inhibition of nucleic acid synthesis e.g. Trimethoprim& quinolones

Inhibition of protein synthesis e.g gentamicin & erythromycin

Inhibition of cell wall synthesis e.g. penicillin, cephalosporins (B-lactams) & glycopeptides

Inhibition of cell wall synthesis – Most bacteria have rigid cell walls not found in host (selective toxicity) – Act on the formation of peptidoglycan – Disruption of cell wall killing the cell (cidal)

Inhibition of cell wall synthesis • • • • • • • •

B-lactams: All share B-lactam ring Penicillin & cephalosporins All bound to proteins at cell membrane involved in cell wall synthesis known as penicillin binding proteins (PBP) Penicillins and cephalosporines disturb peptydoglycan synthesis by inhibiting the enzymes which are responsible for cross-linking the carbohydrate chains The enzymes are called penicillin binding proteins ( PBP’s) Once the cell wall synthesis is dirupted the organism is finally killed by autolytic enzymes Resistance : – B-lactamase enzyme – Alteration of PBP

Inhibition of cell wall synthesis Glycopeptides: • Vancomycin & teicoplanin • Large molecule • Act on cell wall synthesis at a stage prior to Blactams inhibiting assembly of a peptidoglycan precursor and not inhibited by B-lactamases • Act only on Gram-positive bacteria • Not act on PBP, not inactivated by B-lactamase enzymes

2. Glycopeptides: • • • • •

Vancomycin & teicoplanin Large molecule Act on early stages of cell wall synthesis Act only on Gram-positive bacteria Not act on PBP, not inactivated by Blactamase enzymes

Mechanism of action • Inhibition of protein synthesis: – Protein synthesis involves translation of messenger RNA at the ribosome and differences between the bacterial ribosome and the mammalian ribosome allow selective action on bacterial protein synthesis – Examples: • Aminoglycoside ( toxicity is the major problem) • Others: Macrolides, Tetracyclin& Chloramphenicol

Mechanism of action • Inhibition of nucleic acid synthesis: – Inhibit DNA synthesis directly or indirectly – Quinolones directly inhibit DNA gyrase

• Inhibition of Metabolism: – Trimethoprim and sulphamethoxasole • Inhibition of folate synthesis

• Inhibition of cell membrane: – Polymyxin – Isoniazid

Factors affecting choice of the antibitoic • Possible infecting organism: Spectrum of activity • Type of infection: site ( meningitis, osteomylitis, endocarditis) • Susceptibility pattern: Lab results • Host factors: Age, other medications, Renal and liver status

Spectrum of commonly used agents • Broad spectrum • Narrow spectrum

B-lactams A. Penicillins •

Penicillin G (benzyle penicillin): – Naturally-occuring substance – Act against Gram-positives e.g. Group A streptococci pharyngitis

•

Semisynthetic derivatives: – Ampicillin/amoxicillin: better absorption, and better Gram-negative activity – Co-amoxiclav: combines amoxicillin with B-lactamase enzyme inhibitor clavulanic acid extending the spectrum to cover B-lactamase producing bacteria – Flucloxacillin, Cloxacillin, methicillin: resistant to staphylococcal Blactamase. First choice in staphylococcal infections. Methicillin is a similar agent used in the lab only to test the sensitivity and resistant strain are called methicillin resistant Staphylococcus aureus ( MRSA) – Piperacillin: Broad spectrum against Gram- negatives( pseudomonas) – Carbapenems ( imipenem, meropenem): very broad spectrum Grampositive, Gram-negative and anaerobes

Beta lactams II. Cephalosporines • Divided into generations: 1st , 2nd, 3rd, 4th generation cephalosporins • Spectrum differs with the generations • Spectrum against Gram-negatives increases with ascending generations from first to second to third • Spectrum against Gram-positive decreases with ascending generations • Ceftazidime has activity against pseudomonas spp

B-lactams B. Cephalosporins • • • •

1st Genaration 2nd Genaration 3rd Genaration 4th Generation

More anti-Gram-positive activity

More anti-Gram-negative activity

Aminoglycosides • Active against Gram-negative organisms including pseudomonas • Staphylococci are often sensitive • Streptococci are intrinsically resistant • Only parentral preparation • Examples: • Amikacin • Gentamicin • Toxicity:

Glycopeptides • Very large molecules • Vancomycin & teicoplanin • Active only against Gram-positive organisms both aerobes and anaerobes • Only parentral • Toxicity

Macrolides • Anti-Gram-positive activity • Effective against agents causing atypical pneumonia such as Mycoplasma and Chlamydia • Examples: – Erythromycin: active against Gram-positive organisms and used as an alternative to penicillin in hypersensitive patients – New agents: clarithromycin

Quinolones • Broad spectrum mainly Gram-negatives including Pseudomonas • Available orally for Pseudomonas infections • Activity against Staphylococci and Streptococci is doubtful • Examples: • Ciprofloxacin • Newer agents: good anti Gram-positive cover

Miscellaneous • Metronidazole: Against Anaerobes both Grampositive and Gram-negative and Trichomonas vaginalis • Fusidic acid: – Used only as anti-staphylococcus agent – Staphylococci can develop resistance readily especially if used alone – Used in combination with other anti-staphylococcal antibiotics – Diffuses into bone and tissues – Good for treatment of osteomylitis anti staphylococcal activity

• Chloramphenicol: – Serious side effects: bone marrow toxicity – Little usage – Excellent penetration into blood brain barrier BBB

• Trimethoprim/sulfamethoxazole: – – – –

Co-trimoxazole Broad spectrum agent Treatment of UTI Treatment of RTI

• Tetracyclins: – Mainly against atypical pathogens – Genital tract infections ( Chlamydia, Mycoplasma)

Drug-related consideration 1. Spectrum • Effective against the likely infective organism • Lab results • Narrow or broad spectrum

Drug-related consideration 2. Monotherapy vs. combination • Indications: – mixed infections – Attain synergy( enhanced activity) e.g. – Avoid resistance : treatment of tuberculosis – To reduce toxicity

• Outcome: • Additive – Synergystic – Antagonistic

Drug-related consideration 3. Penetration to site of infection • Most important • Usually overlooked • E.g. – Meningitis – Endocarditis – Bone infection( osteomyelitis)

Drug-related consideration 4. Monitoring • Mainly for toxic agents: – Aminoglycosides – Vancomycin

Drug-related consideration 5. Dose and Duration of Therapy • Depend on type of infection: • Serious infections require high doses e.g meningitis, endocarditis • Also need prolonged duration: TB, endocarditis

Indication for Antimicrobials • Prophylaxis • Medical: – e.g.:Rheumatic heart diseases, endocarditis, meningococal meningitis contacts

• Surgical: – Clean contaminated & contaminated surgery: colorectal surgeries

Indication for Antimicrobials • Therapy: – Empirical: based on: • Site and type of infection • Likely causative agent • The common antimicrobial susceptibility pattern

– Directed therapy: • Based on culture and sensitivity

Drug-related Toxicity •

Allergic reactions: B-lactams –

Immediate or delayed hypersensitivity:

2. Immediate Hypersensitivity: • • •

Anaphylactic shock is extreme life-threatening form IgE mediated occurs within minutes of adminstration Charactrized by itching, urticaria, nausea, vomiting, wheezing and shock

3. Delayed Hypersensitivity: • •

May take hours or days to develop Drug rash, fever or serum sickeness

Drug-related Toxicity • GIT side effects: – Nausea, vomiting, diarrhoea, pseudomembranous colitis ( C.diffecile)

• • • • •

Thrush: Broad spectrum antibiotics Suppression of normal flora Overgrowth of resistant organisms Yeast infection: oral or vaginal (Candida infection)

Drug-related Toxicity • Liver toxicity: • Important organ for metabolism and excretion • Transient elevation of liver enzymes to severe hepatitis • More in pregnancy • Tetracyclins, isoniazid, rifampicin

Drug-related Toxicity • Renal toxicity: • Kidney is the most important route of excretion • Nephrotoxicity is dose-related and associated with prior renal disease • Aminoglycosides: gentamicin, amikacin • Glycopeptides: vancomycin • Monitoring blood levels needed • Usually reversible

Drug-related Toxicity • Neurological toxicity: – Ototoxicity: Aminoglycosides & vancomycin – Optic neuropathy: ethambutol – Encephalopathy & convulsions: high doses of penicillin – Peripheral neuropathy:Metronidazole, nitrofurantoin • Haematological toxicity: – Bone marrow suppression ( aplastic anemia) – Chloramphenicol: • Dose related ( reversible) • Non-dose related (Non reversible)

Quiz 1 • Answer T or F: 2. Pencillin G ( benzyl penicillin) interferes with peptidoglycan synthesis in the bacterial cell wall 3. Vancomycin and penicillin act on different stage of cell wall synthesis 4. Aminoglycosides act on DNA synthesis 5. Trimethoprim interferes with protein synthesis at the ribosomal level 6. The differing ribosomes of mammalian bacterial cells allow selective toxicity

Quiz 2 • For the B-lactam group of antibiotics which of the following statements are true? • All Staphylococcus aureus strains are susceptible to fluconazole • First generation cephalosporins are more active against Gram-negative bacteria than Grampositive • Penicillin allergic patients may be allergic also to cephalosporins • Piperacillin is active against Psudomonas aerugionosa

Quiz 3 • Answer T or F: 2. Vancomycin is only active against anaerobes 3. Vancomycin is only active against Grampositive organisms 4. Ceftazidime ( third generation cephalosporin have better anti staphylococcal activity than earlier cephalosporins 5. Gentamicin is associated with nephrotoxicity 6. Metronidazole is widely used to treat anaerobic infections 7. Vancomicin is associated with ototoxicity