Antimicrobial Chemotherapy Lecture Notes PDF

Dr. D. Wynter-Adams Definitions Antimicrobials o Chemicals produced for restricting the growth or for killing microorganisms What are antibiotics? Antibiotics are substances produced by various species of non pathogenic microorganisms (bacteria, fungi) that suppress the...

Dr. D. Wynter-Adams Definitions Antimicrobials o Chemicals produced for restricting the growth or for killing microorganisms What are antibiotics? Antibiotics are substances produced by various species of non pathogenic microorganisms (bacteria, fungi) that suppress the growth of other microorganisms or kill them without effecting the host cell. Antibiotics may differ in physical, chemical and pharmacological properties: i.e. antibacterial spectrum and mechanism of action. Guidelines to studying Objectives o Chemical classification of drugs o Mechanism of action o Side effects o Target microorganisms o Indications o Drug Interactions o Special note Factors in Drug Selection Identify organism through Gram’s stain or from culture Drug safety profile Infection site Patient’s medical history…immune status, renal/hepatic function, pregnant state, lactation Common Bacterial Normal Flora Bacterial Characteristics Infection o The invasion or colonization of other parts of the body by normal flora or an imbalance in the host-pathogen interaction. May be asymptomatic. Ex woman with chlamydia infection with no signs of the disease Disease o Change from state of health that can result from an infection resulting in overt manifestations. E coli normally inhibits GI tract can colonize urinary tract to cause cystitis Diseases, conditions and drugs that decrease resistance to infection Addison’s disease Immunosuppressive AIDS/HIV drugs Alcoholism – Azathioprine – Cyclophosphamide Cancer – Cyclosorin Cirrhosis of the liver – Methotrexate Diabetes mellitus – Glucocorticoids Down syndrome Malnutrition Revision Name & explain six patient factors that can affect choice of antibiotics ✓ ✓ ✓ ✓ ✓ ✓ Revision 1. Name four disease states that can decrease resistance to infection? 2. Distinguish between infection and disease 3. Differentiate between empiric and definitive therapy. Include in your explanation, the scenario each is more likely to be used. Selection of an Antibacterial Agent 1. Patient Factors Age of patient o Liver enzyme maturity o Newborns: Gray baby syndrome with chloramphenicol; kernicterus with sulphonamides o Elderly: ototoxicity with aminoglycosides; effect of reduced renal function from age-related decrease in functioning nephrons (clinical response: ???) Host defence status o In impairment….higher doses, more powerful antibiotics o Bactericidal vs bacteriostatic Patient Factors cont’d Site of infection o Main factor to determine antibiotic choice o Normal flora, historical invading organisms o Presence of pus, necrotic tissue, clots, anaerobic environment o Infection in brain…..BBB Hepatic Function o Impairment can lead to toxic drug levels Renal Function o Impairment….higher plasma levels leading to toxicity o In renal impairment avoid AGs, cephalothin, tetracyclines except doxycycline; o Dose adjustments for: Amoxicillin; piperacillin/tazobactam (Zosyn) Cephalexin; cefuroxime, ciprofloxacin (Cipro); levofloxacin; clarithromycin (Klaricid); trimethoprim/sulfamethoxazole (Bactrim) Allergy 2. Microbe Factors If possible culture report should guide choice of therapy Empiric therapy: to cover all likely pathogens with combination therapy or broad spectrum Treatment with anti microbial therapy without specific knowledge of the organism involved. Done based on site of infection, known organisms at that site Definitive therapy 3. Drug Factors Efficacy against particular organism Narrow spectrum Bactericidal if host defence weak MIC vs MBC Dose, duration Safety…..side effects & compliance Route of administration Cost Definitions MIC o Minimum inhibitory concentration: lowest concentration that prevents growth of micro-organism. o Antibiotic concentrations in therapeutics are above the MIC to achieve 99.9% reduction of the microbes. MBC o Minimal bactericidal concentration: lowest in vitro concentration that kills organism o Often MBC is 2-8 times the MIC  Examples Bactericidal o Action of drug results in death of cells (normally have blood concentrations above the MBC) Penicillins Aminoglycosides Quinolones/Fluoroquinolones Cycloserine Vancomycin Bacteriostatic (blood concentrations above MIC but above MBC) o Stop growth & replication of bacteria Clindamycin Tetracycline Erythromycin Lincomycin Limitations to this system of classification as it also depends on the drug/microbe relationship. o E.g. Penicllin is bactericidal against Streptococci but bacteriostatic for Entercocci; Chloramphenicol is generally against most Enterobacteriaceae but is bactericidal against Haemophilus influenzae Adverse effects Dose dependent Concentration of antibiotic in the body Nature of drug Nature of host’s flora Other Factors in microbial therapy Concentration dependent or time dependent killing by antibiotic o Concentration dependent bactericidal action with aminoglycosides and fluoroquinolones o Time dependent action with beta lactams & glycopeptides, bactericidal action depends on maintaining antibiotic concentration above MBC over the dosing period Post-antibiotic Effect (PAE) o No return of normal bacterial replication for a variable period of time (hrs) after removal of antibiotic o PAE normally concentration dependent Aminoglycosides & fluoroquinolones show PAE against gram – ve bacteria Combination of Antimicrobials: Rationale Synergism o Two bactericidal drugs o Based on disease o Bacterial endocarditis: penicillin + streptomycin/gentamicin o Pseudomonas infections: carbenicillin + gentamicin o Beta lactamase producing organisms e.g. Haemophilus influenzae: amoxicillin + clavulanic acid Treatment of mixed infections to increase coverage o Anaerobic & aerobic organisms…orodental, intra-abdominal infections, traumatic wound infections o Adding metronidazole to amoxicillin for H. pylori infections, chronic sinusitis Combination therapy: Advantages Initial treatment of severe infections o Cover gram +ve & -ve: penicillin & aminoglycoside, add metronidazole if anaerobic organism also involved To prevent resistance o Treatment of tuberculosis & leprosy To reduce adverse effects o Lower doses to reduce possibility of adverse effects with each drug o In cryptococcal meningitis use amphotericin B & flucytosine Disadvantages of Antimicrobial Combination Risk of toxicity from each agent o Overlapping, enhancing Selection of resistant mutant strains Multiple drug resistance Cost of therapy Antibiotic Resistance Defined as antibiotic resistance by bacteria even at maximal tolerated dose Can be innate or acquired resistance. Innate resistance where drug does not work in the organism based on how the drug acts. For example, anaerobic bacteria lack oxygen- dependent transporter required for uptake of aminoglycosides; gram –ve bacteria naturally resistant to vancomycin, a cell wall inhibitor Acquired resistance refers to acquisition of resistance via plasmids, DNA spontaneous resistance, change in receptor sites, reduced bacterial permeability, production of hydrolytic enzymes E.g. beta lactamase production by staphylococcus bacteria leads to resistance to Amoxicillin Antibiotic Resistance Create a table summarizing the mechanisms of drug resistance across the main antibiotic classes Microorganisms that cause Disease in Humans Organism Description Examples of Treatment infection Bacteria Single cell, cell Pneumonia, otitis antibiotics wall to survive media, cystitis wide range of conditions Viruses Very small non- AIDS, flu, hepatitis antivirals cellular micro- organisms that require a host to line & reproduce Fungi Well-defined with Ringworm, antifungals true nucleus e.g. athlete’s foot, molds, yeasts vaginitis Parasites Protozoans Single-celled Amoebic Limited agents dysentery Helminths Multiple-celled Schistosomiasis Anti-helminthics Bacterial Classification Stain Shape Oxygen requirements Growth requirements Production of certain enzymes Disease producing o Virulence Bacterial Identification Gram Stain Violet colour followed by iodine then decolorize with alcohol or acetone. Counterstain with safranin Gram negative Gram positive Bacteroides fragilis Bacillus anthracis Brucella abortus Clostridium Escherichia coli Staphylococcus aureus Haemophilus influenzae Streptococcus pneumoniae Klebsiella pneumoniae Enterococci Neisseria gonorrhoea Stain Classification Gram +ve usually susceptible to cell wall Gram –ve bacteria have outer layer of inhibitors e.g. penicillin, cephalosporins lipoproteins, lipopolysaccharides (toxic) & and also some protein Inhibitors eg phospholipids…negative charge erythromycin (a macrolide). Gram –ve Periplasmic space contains beta lactamase usually resistant to these antibiotics. & other enzymes. Bacterial Identification Shape o Bacilli Rod-shaped: Haemaphilus bacilli o Cocci Spherical: Streptococci, Staphylococci o Spirochetes Spiral-like: Treponema pallidium Bacterial Identification Oxygen requirement o Aerobes Obligate o Anaerobes Obligate Facultative Differentiation with stain & oxygen requirements Gram Positive Gram Negative (Additional Aerobes outer membrane containing – Streptococcus pneumoniae lipopolysaccharide, that increases the virulence) – Streptococcus pyogenes – Staphylococcus aureus Aerobes – Coagulase –ve Staphylococci – Haemophilus influenza – Enterococci – Escherichia coli – Pseudomonas aeruginosa – Neisseria gonorrheae Anaerobes – Moraxella catarrhalis – Peptostreptococcus – Clostridium Anaerobes – Bacteroides – Fusobacterium Intracellular pathogens Live within host’s cell; protected from host’s immune system o Chlamydiae o Mycoplasmas o Legionella pneumophila o Mycobacterium tuberculosis Enzyme production Catalase o Produces O2 bubbles with hydrogen peroxide Coagulase o Clotting of plasma Beta lactamase* Protective Barriers in the Body Physical Barriers Chemical Barriers – Skin & mucous membranes – Gastric Acid – Nose hairs – Lysozyme (tears & saliva) – Airway mucus – Cilia on cells Medically important bacteria Gram +ve cocci: Staphylococci o Forms pus o Infections Boils, skin abscesses S. aureus…bone & joint infections Skin & wound infections Staph food poisoning Many hospital-acquired infections & infections with implanted devices Toxic shock syndrome Antibiotic resistance due to beta lactamase production S epidermidis (usually non-pathogenic) can cause bacteremia  Medically Important Bacteria Streptococci (gram +ve) Part of flora of mouth & intestine Key Streptococcal Species Species Diseases Streptococcus pyogenes Pharyngitis; Scarlet fever; Skin infections; Bacteremia; (group A ) Pneumonia Streptococcus agalactiae Neonatal infections (group B) Streptococcus Pneumonia; sinusitis; otitis media; meningitis; pneumoniae bacteremia Enterococcus spp Urinary tract infections; endocarditis; intra-abdominal infections; osteomyelitis Medically important bacteria Aerobic Gram –ve Neiserria meningitidis; N gonorrhoeae Pseudomonas aeruginosa Cells of Immune System Produced in bone marrow Mostly leukocytes o Neutrophils o Increase with infection o Ingest & digest bacteria Immune Response Summary of Antibiotic Mechanisms of Action Cell membrane inhibition Daptomycin; Polymixib B Respiratory Tract infections Pathogens associated with sinusitis Common Rare – Streptococcus pneumoniae – Pseudomonas aeruginosa – Haemophilus influenza – Staphylococcus aureus – Moraxella catarrhalis (esp in – Anaerobes (dental disease) children) Chronic Bronchitis Inflammation of bronchi Irritation, mucus secretion Colonization o Staphylococcus pneumoniae o H. influenza Up to 50% o M. catarrhalis o Staphylococcus. aureus o Rare: Mycoplasma pneumoniae o Viruses Community Acquired Pneumonia Causes o Streptococcus pneumoniae (16-60%) o Haemophilus influenza (4-15%) o Staphylococcus aureus (2-10%...esp in elderly) o Gram –ves: Legionella pneumophila; Moraxella catarrhalis o Viruses, fungi, protozoa Skin & Soft Tissue Infections Superficial layers of Infection of Dermis skin – Complicated – Acne – Impetigo Common Skin & Soft Tissue Infections Impetigo o Crusty eruptions on face, blisters Cellulitis o Secondary to trauma: pain, tenderness, local abscesses, fever, chills, necrosis Folliculitis o Infection of follicles Furuncle o Neck, buttocks, thighs Otitis media Middle ear infection Causes o Streptococcus pnuemoniae (10yrs & older) o Haemophilus influenza (2mths-10yrs) o Escherichia coli (neonates) o Moraxella catarrhalis Pharyngitis Causes Clinical Signs & Symptoms – Streptococcus pyogenes – Dysphagia – Gonococci – Sudden onset of sore – Corynebacterium diphtheria throat – Fever Treatment – Penicillin – Headache – Erythromycin – Malaise – Clindamycin  Categories of Antibiotics & Fetal Risk Category Description Drug A No human fetal risk or rare risk of fetal harm B No controlled studies show B-Lactams human risk B-Lactams with inhibitors Cephalosporins; Aztreonam; Clindamycin; Erythromycin; Azithromycin; Metronidazole; Sulfonamides C Animal toxicity seen; human risk Chloramphenicol; Fluoroquinolones; undefined Clarithromycin; Trimethoprim; Vancomycin, Trimethoprim- sulfamethoxazole; Gentamicin?; D Human fetal risk seen, but Tetracyclines; Aminoglycosides (except benefits overweight the risks gentamicin) X Human fetal risk present;