Microbes & Antibiotics PDF

MICROBES & ANTIBIOTICS ANTIBIOTICS FOR MASTITIS & NIPPLE PAIN Readings: Ch 15, 18, & 19 in Pharmacology Revealed 2 AGENDA • • • • Introduction to the Midwifery Drug List (884/93) Selecting Antibiotic Treatment Antibiotics and How They Work Antibiotics for the Treatment of Mastitis • All Purpos...

MICROBES & ANTIBIOTICS ANTIBIOTICS FOR MASTITIS & NIPPLE PAIN Readings: Ch 15, 18, & 19 in Pharmacology Revealed 2 AGENDA • • • • Introduction to the Midwifery Drug List (884/93) Selecting Antibiotic Treatment Antibiotics and How They Work Antibiotics for the Treatment of Mastitis • All Purpose Nipple Ointment 3 MIDWIVES MAY PRESCRIBE DRUGS FOR: • • • • • • • • • • • • • • Nausea and Vomiting of Pregnancy Urinary tract infections (UTIs) Mastitis Bacterial Vaginosis Postpartum Hemorrhage Post Partum Pain Group B Streptococcus Prophylaxis Lactation Breast & Nipple Pain Local Anesthesia for Perineal Repair or Episiotomy Vaccination (some) Yeast Infection Hemorrhoids Vitamin K Deficiency Bleeding See Midwifery Drug Legislation 884/93 Image Sourced From: www.natural-health-news.com Image Sourced From: www.2minutemedicine.com Slide Modified From: Dr. C. Beites, Laurentian University 4 WHAT DO YOU HAVE TO KNOW TO SELECT THE CORRECT TREATMENT? 1. Identity of the organism 2. Susceptibility of the organism to a given microbial agent 3. Client factors 4. Safety of the agent 5. Cost of the therapy Slide Modified From: Dr. C. Beites, Laurentian University 5 ANATOMY OF BACTERIA Gram Negative • Thin layer of peptidoglycan • Has outer lipid layer that has LPS: harder for antibiotics to penetrate LPS layer • Stain pink in Gram stain Gram Positive • Thick layer of peptidoglycan • No outer lipid layer (so more susceptible to certain antibiotics e.g. penicillin) • Stain purple in Gram stain 6 GRAM VARIABLE BACTERIA • Not clearly purple or pink after Gram staining, but a combination of both • Not many Gram variable species • The Mobiluncus spp. and Gardnerella vaginalis which are typically associated with bacterial vaginosis are Gramvariable • Mobiluncus is truly a Gram-negative organism with a thin peptidoglycan cell wall and a outer membrane • Gardnerella is Gram-positive based on the thick cell wall and absence of the external membrane FIG 15-4 Gram-stain of a vaginal swab in a case of bacterial vaginosis. Gardnerella indicated by g 7 SUSCEPTIBILITY TO ANTIMICROBIAL AGENTS • Antibiotic resistance is rapidly increasing • “Superbugs” • E.g., MRSA How Do You Avoid Antibiotic Resistance (what is your responsibility)? 1. Use antibiotics appropriately – avoid where possible 2. Start with a narrow-spectrum antibiotic (vs. medium or broad spectrum • Narrow treats a single group of microbes • Extended or medium treats more globally • Broad spectrum affects a wide range 3. Culture and Sensitivity Tests 4. Counsel Clients Appropriately • Complete entire course of treatment Slide Modified From: Dr. C. Beites, Laurentian University 8 CULTURE & SENSITIVITY TESTING Image Sourced From: www.allnurses.com 9 ANTIBIOTIC RESISTANCE MECHANISMS • Occurs when antibiotics that have historically killed a given strain of bacteria no longer work • Arises due to alterations in bacterial DNA • Mutation • Takes on DNA from another strain 10 ANTIBIOTIC RESISTANCE MECHANISMS • Microbes can become antibiotic resistance by taking on DNA from another, drug-resistant strain (horizontal gene transfer) • Drug resistance genes often coded on plasmid DNA • Horizontal gene transfer occurs in 3 ways: 1. Transformation Pieces of DNA are taken up from the external environment 2. Conjugation Transfer of plasmid DNA via direct cell-to-cell contact (via a pilus) 3. Transduction A bacteriophage (virus that infects bacteria) performs the gene transfer 11 ANTIBIOTIC RESISTANCE MECHANISMS Image Sourced From: http://textbookofbacteriology.net 12 ANTIBIOTIC RESISTANCE - TYPES 1. Enzymatic Inactivation of Antibiotic • Most common mechanism • Bacteria make enzymes that metabolize antibiotics • E.g., β-lactamases 2. Decreased Antibiotic Uptake • Gram-negative organisms can be resistant to some antibiotics as drug cannot penetrate outer cell membrane • Decrease number of porins • E.g., cephalosporins 3. Increased Antibiotic Efflux • Energy-dependent pumps transport the drug out of cells • E.g., quinolones 4. Modification of Antibiotic Targets • Receptors for drugs, target molecules, enzymes are modified • E.g., S. aureus became resistant to methicillin because the penicillinbinding protein changed shape 13 ANTIBIOTIC RESISTANCE - TYPES 14 ANTIBIOTICS • “Anti-Life” • General principle: to inhibit the growth of bacteria without harming the host Bacteriocidal • Kill bacteria directly • E.g., penicillins make holes in bacteria, bacteria die, immune system clears up the cellular fragments Bacteriostatic • Stop the growth or division of bacteria • Need an actively fighting immune system to resolve the infection 15 MODES OF ANTIBIOTIC ACTION 16 CELL WALL SYNTHESIS INHIBITORS • Peptidoglycan cell wall in bacteria is made up of a carbohydrate backbone linked together by amino acid side chains and cross bridges • The beta-lactam antibiotics (e.g., the penicillins and cephalosporins) inhibit the formation of the peptide cross-bridges • The peptidoglycan cell wall is thus incomplete and weakened, and the cell may undergo autolysis 17 CELL WALL SYNTHESIS INHIBITORS • Beta-lactam antibiotics: • Penicillin Class • • • Penicillin G Amoxicillin Cloxacillin • Cephalosporin Class • • Cephalexin Cefazolin • Vancomycin (not on the midwifery drug list): • Does not have the beta-lactam ring, but is also a cell wall synthesis inhibitor • Can work when anti-biotic resistance has been developed to other antibiotics • Penicillin G is intermediate spectrum: • Best for Gram+ cocci (Streptococcus, Staphylococcus spp), then Gram- like N. gonorrheae, then others like Treponema pallidum • Amoxicillin in intermediate spectrum • Similar to PenG, but also good for some Gram- (like bacilli) • Cephalosporins: similar activity to PenG, plus E. coli and Klebsiella pneumoniae, and some others Slide Modified From: Dr. C. Beites, Laurentian University 18 PROTEIN SYNTHESIS INHIBITORS • Clindamycin and erythromycin bind at the 50s ribosomal subunit and will inhibit the growth of peptides by preventing the translocation of amino acids • Mupirocin blocks protein synthesis by blocking tRNA synthesis • At present, there are no drugs on the 884/93 that block protein synthesis at the 30S ribosomal subunit • E.g., the tetracyclines, streptomycin 19 DNA SYNTHESIS INHIBITORS • Fluoroquinolones inhibit DNA synthesis • Most common is ciprofloxacin • Gets inside bacteria via porins and inhibits DNA gyrase • DNA gyrase is the enzyme responsible for relaxing/uncoiling DNA so it can be replicated • Nitrofurantoin is a prodrug • Activated by susceptible bacteria when excreted into the urine • Reactive intermediates have many functions, including inhibit bacterial DNA synthesis • Also: • • • • Inhibit protein synthesis Inhibit aerobic energy metabolism Inhibit RNA synthesis Inhibit cell wall synthesis 20 BACTERIAL DNA SYNTHESIS Image sourced from: www.proquest.com 21 Image sourced from: http://biology.kenyon.edu/courses/biol114/Chap01/cell.html FOLATE SYNTHESIS INHIBITORS Why do we care about folic acid? • In Humans: • Need dietary folic acid to make bases for DNA (we don’t make our own folic acid) • Without proper bases, DNA can’t divide • If DNA can’t divide, cells can’t divide • Since the neural tube is formed very early in development and requires tons of cell division, deficiency in folic acid leads to neural tube defects (aren’t enough cells to close the neural tube properly) • In Bacteria: Image Sourced From: https://openi.nlm.nih.gov • The principle is the same, but bacteria make their own • Use p-aminobenzoic acid (PABA) for de novo synthesis 22 STOP HERE!! When studying for Term Test #2 24 MASTITIS • Inflammation of the breast caused by: • Blocked milk ducts in the lactating person AND • Bacterial breast infection • Almost always caused by Staphylococcus aureus (or other Gram+ organism such as Streptococcus) • Untreated – may lead to abscess that needs to be surgically drained • Infections that don’t resolve with antibiotics within 24h may be Candida albicans (Thrush, not mastitis) Image Sourced From: www.women-info.com Slide Modified From: Dr. C. Beites, Laurentian University 25 MASTITIS • Can have varied etiologies: • untreated or unresolved engorgement or plugged duct • milk stasis (from improper latching or problems with suckling) • breast or nipple trauma like cracked nipples (entry for bacteria) • compromised immune status (or through extreme fatigue) ducts Glandular tissue Green liquid is infected breast milk associated with Mastitis Slide Modified From: Dr. C. Beites, Laurentian University 26 dDX OF BREAST SYMPTOMS Engorgement Plugged Ducts Mastitis Onset of Symptoms Gradual – usually from d3-d5 postpartum, or if BF is not done on a regular schedule Gradual Sudden – from 7d to several weeks postpartum Location Bilateral Usually unilateral Usually unilateral Inflammation/Heat Generalized Palpable mass, no heat or mild heat Affected area is hot, red, and swollen Pain Generalized Mild, but localized Intense but often diffuse (some will be able to pinpoint a defined area of pain) Temp <38.3C <38.3C >38.3C (101F) Overall Feeling Tired, but fine Tired, but fine Tired, run down, achy, chills, flu-like Sx, potentially cracked nipples Slide Modified From: Dr. C. Beites, Laurentian University 27 MASTITIS • Mastitis occurs in up to 10% of breastfeeding persons • Most common in the first 3 months of breastfeeding • Infective mastitis is a usually a bacterial disease, like a UTI, that is likely to be treated empirically with oral antibiotics • Culture and sensitivity test can be done but not very common (unless symptoms don’t get better with antibiotics) 28 MASTITIS Treating mastitis is much like treating engorgement only more urgent “Heat, Massage, Rest, Empty Breast” 1. Rest, rest, rest: replenishes immune system 2. Alternate warm and cold compresses on your breasts: cold compresses relieve pain, warm increases circulation to mobilize infection fighters 3. Gently massage the area of tenderness: increases circulation, helps to loosen plugged ducts and mobilizes immune factors 4. Breastfeed frequently on the affected side or pump : lessens milk stasis 5. Try and vary the baby's position at the breast: ensure all ducts are emptied 6. Take analgesics for fever and pain (acetaminophen safe while breastfeeding) 7. Drink lots of fluids: like when you have the flu 8. Boost your immune system: with good nutrition 9. Sleep without a bra or wear loose fitting bra : to decrease pressure on affected area 10. Baby may refuse to nurse on the affected breast: inflammation increases sodium content of your milk, salty 11. ANTIBIOTICS Slide Modified From: Dr. C. Beites, Laurentian University 29 Staphylococcus aureus • Almost always the causative agent of mastitis • Ubiquitous, normal flora of humans and other animals • Part of the normal flora of the nasopharynx in 30% of the population (usually transiently) • Part of the normal flora of the skin of 20% of the population • Higher for hospitalized persons, or hospital employees S. aureus in culture Gram+ cocci, occur in clusters Clusters under electron microscope Slide Modified From: Dr. C. Beites, Laurentian University 30 ANTIBIOTICS FOR MASTITIS Cell Wall Inhibitors • Beta-lactam antibiotics • Amoxicillin-clavulanic acid • Cloxacillin • Cephalexin DNA Synthesis Inhibitor • Ciprofloxacin Protein Synthesis Inhibitor • Clindamycin Image Sourced From: www.micobiologypressesses.blogspot.ca 31 CELL WALL SYNTHESIS INHIBITORS FOR MASTITIS • In pregnancy: no studies showing risks in humans but may pose potential toxicity in animals • The penicillin class is the most widely used, in general, in pregnancy AMOXICILLIN-CLAVULANIC ACID • Beta-lactam antibiotic, penicillin class • Lactation Category L1 – no infant concerns reported via milk • Extended-spectrum penicillin, treats Gram+ and Gram• Potential problems with wider spectrum antibiotics? • Amoxicillin is sensitive to beta-lactamase (secreted by S. aureus), so it’s given with clavulanic acid (which inactivates beta-lactamases) • Very small amounts are secreted in breastmilk (0.9%mg/L = less than 0.5% of a typical infant dose of amoxicillin) Slide Modified From: Dr. C. Beites, Laurentian University 32 AMOXICILLINCLAVULANIC ACID t1/2 1.7h • t1/2 = half-life in the adult • PHL = pediatric half-life PHL • Tmax = time to peak plasma level Tmax 1.5h MW 365 Vd 0.3 • M:P = Milk:Plasma ratio M:P 0.014-0.043 • PB = % protein bound PB 18% • Oral = oral bioavailability (adult) Oral 89% pKa 9.48 RID 0.9% • MW = Molecular Weight • Vd = Volume of distribution (L/kg) • RID = relative infant dose Thomas W. Hale: Medications & Mothers’ Milk, 16th Ed. 33 CELL WALL SYNTHESIS INHIBITORS FOR MASTITIS CLOXACILLIN • Beta-lactam antibiotic, penicillin class • Lactation Category L2 – limited data, probably compatible • No pediatric concerns but for GI Sx such as diarrhea • Has good oral bioavailability • Narrow spectrum: treats only treats Staphylococcus, so less GI upset • (Amoxicillin-clavulanic acid may be a better choice if you want to kill both Staph and Strep infections) Slide Modified From: Dr. C. Beites, Laurentian University 34 CLOXACILLIN t1/2 0.7-3h • PHL = pediatric half-life PHL Tmax 0.5-2h MW 436 Vd • t1/2 = half-life in the adult 6.6-10.8 M:P • Tmax = time to peak plasma level • MW = Molecular Weight • Vd = Volume of distribution (L/kg) • M:P = Milk:Plasma ratio • PB = % protein bound PB 90-96% Oral 37-60% pKa 13.65 RID 0.4-0.8% • Oral = oral bioavailability (adult) • RID = relative infant dose Thomas W. Hale: Medications & Mothers’ Milk, 16th Ed. Image Sourced From: www.chemistry-about.com 35 CELL WALL SYNTHESIS INHIBITORS FOR MASTITIS CEPHALEXIN • Beta-lactam antibiotic, cephalosporin class • Lactation Category L1 – limited data, probably compatible • No pediatric concerns but for GI Sx such as diarrhea • Structurally similar to the penicillin class, but has a 6member ring and a large group stuck to the beta-lactam ring • Same antimicrobial activity as penicillin • Gram+ and good coverage of Gram- • Advantages: • Resistant to beta-lactamase • Acceptable for clients with query/mild allergy to penicillin • 20% may have cross-reactivity but only clinically relevant for 1% Slide Modified From: Dr. C. Beites, Laurentian University 36 CEPHALEXIN t1/2 50-80min • t1/2 = half-life in the adult • PHL = pediatric half-life PHL • Tmax = time to peak plasma level Tmax 1h MW 347 Vd 0.25 • M:P = Milk:Plasma ratio M:P 0.008-0.14 • PB = % protein bound PB 10% • Oral = oral bioavailability (adult) Oral complete pKa 11.91 RID 0.5-1.5% • MW = Molecular Weight • Vd = Volume of distribution (L/kg) • RID = relative infant dose Thomas W. Hale: Medications & Mothers’ Milk, 16th Ed. Image Sourced From: www.medicodrugs.com 37 DNA SYNTHESIS INHIBITORS FOR MASTITIS CIPROFLOXACIN • Fluoroquinalone • Most commonly used quinolone, and the only one on the midwifery drug list • Lactation Category L3 – limited data, probably compatible • Pseudomembranous colitis in one infant, observe for diarrhea, tooth discoloration in several infants reported • Moderately safe, category due to lack of controlled studies in BF population • Approved by the AAP for the breastfeeding population • Broad spectrum: all Gram-, some Gram+ • Has poor activity against S. aureus and streptococci • More expensive than penicillins • Unrelated to penicillins, so safe to use in a penicillin allergic client Slide Modified From: Dr. C. Beites, Laurentian University 38 CIPROFLOXACIN Adverse Effects of Ciprofloxacin • A rash in about 1% • A host of GI symptoms including N/V/D • With prolonged use there is a concern about pseudomembranous colitis (also true of clindamycin and penicillin antibiotics) in the infant • A side-effect which is not likely to be seen but is well known is that inflammation/rupture of tendons may occur • drug should be discontinued at the first sign of tendon inflammation Drug Interactions with Ciprocloxacin • Ciprofloxacin absorption is inhibited by cations consumed orally such as magnesium (e.g., TUMS, MAALOX), aluminum (MAALOX, GAVISCON), iron (oral iron supplements), and calcium • will decrease absorption • There are no drugs in the midwifery drug list which interact significantly with ciprofloxacin Slide Modified From: Dr. C. Beites, Laurentian University 39 CIPROFLOXACIN t1/2 4.1h • t1/2 = half-life in the adult • PHL = pediatric half-life PHL • Tmax = time to peak plasma level Tmax 0.5-2.3h MW 331 Vd 1.4 • M:P = Milk:Plasma ratio M:P >1 • PB = % protein bound PB 40% • Oral = oral bioavailability (adult) Oral 50-85% pKa 7.1 RID 0.012-39.7% • MW = Molecular Weight • Vd = Volume of distribution (L/kg) • RID = relative infant dose Thomas W. Hale: Medications & Mothers’ Milk, 16th Ed. Image Sourced From: www.Sigma-Aldtich.com 40 PROTEIN SYNTHESIS INHIBITORS FOR MASTITIS CLINDAMYCIN (oral) • Macrolide • Lactation Category L2 – limited data, probably compatible • Pseudomembranous colitis in one infant, commonly used in pediatric infections, levels in breastmilk likely not significant • Safe for BF people • More GI side-effects compared to penicillins • Do not administer with erythromycin due to possible antagonism • Use only in persons with severe hypersensitivity to penicillins because of side-effects • Less wide spectrum than cephalexin • Kills mostly Gram+ aerobes and anaerobes Slide Modified From: Dr. C. Beites, Laurentian University 41 CLINDAMYCIN t1/2 2.4h • t1/2 = half-life in the adult • PHL = pediatric half-life PHL Tmax 45-60min MW 425 • Tmax = time to peak plasma level • MW = Molecular Weight • Vd = Volume of distribution (L/kg) Vd 2 • M:P = Milk:Plasma ratio M:P 0.47 • PB = % protein bound PB 94% • Oral = oral bioavailability (adult) Oral 90% pKa 7.45 RID 0.9-1.8% • RID = relative infant dose Thomas W. Hale: Medications & Mothers’ Milk, 16th Ed. Image Sourced From: www.antibiotics-info.org 42 BREAST AND NIPPLE PAIN (APNO) • All Purpose Nipple Ointment (APNO) • Mupirocin-betamethasone valerate-miconazole • Mupirocin • A topical antibiotic • Betamethasone valerate • A steroidal anti-inflammatory • Miconazole • Fungicide, effective against yeasts and also some Gram+ bacteria • Ibuprofen can be added for pain relief prn • Made at a compounding pharmacy 43 APNO 44 MUPIROCIN (topical) • Mupirocin inhibits protein production in the cell • Inhibits the production of tRNA • Can be absorbed by the infant PO but: • The majority of it sticks to the nipple • Very little is ingested by the infant • Often suspended in polyethylene glycol (PEG) • Some people have allergies to PEG 45 BETAMETHASONE VALERATE (topical) • High potency steroidal anti-inflammatory • Purpose in APNO is to decrease pain caused by tissue inflammation • Side Effects: • The listed side effects for betamethasone refer to long-term systemic use of the drug • Not anticipated to be relevant with relatively short-term use of a topical ointment 46 MICONAZOLE • Antimycotic: inhibits the formation of ergosterol which is necessary for fungal cell walls • Decrease inflammation and pain associated with fungal infections of the skin very rapidly • Effective against some Gram+ bacteria • This is useful since the Staphylococcus aureus may lead to mastitis in an inflamed, cracked areola/nipple • Side effects • Less than 1% of the drug is absorbed into maternal circulation so side-effects are unlikely, but it is unclear how much reaches the baby during breastfeeding • On the skin stinging, erythema and local irritation are possible but contact (allergic) dermatitis is very rare 47 SELF-STUDY • Remember to check your syllabus for studies related to today’s lecture: • #8 – Mary’s Mastitis • #12 – Samir’s Sore Nipples • #13 – Thomas’s Thrush 48 TEST #2 • • • • • Next week during class time We will start promptly at 0830 – be on time! 90 minutes – no class afterwards 20% of your final grade MDCL 2232 & 2233 • Same rooms as last time – Lists posted to Teams are the same. • Multiple choice (scantron) & short answer • Scantron must be completed in pencil and short answer in PEN • Short answer papers completed in pencil will not be marked • Not cumulative – from after Test #1 to today. • All formulas will be provided, bring a calculator if you want one. • Mobile phones may NOT be used as calculators • Help each other study and remember to use our public discussion spaces to ask questions! 49