Pharmacotherapeutics in Dentistry - Antimicrobials PDF

Pharmacotherapeutics in Dentistry – Antimicrobials Presented by Dr. JR Singh Department of Maxillofacial and Oral Surgery School of Oral Health Sciences Faculty of Health Sciences University of the Witwatersrand  ANTIM...

Pharmacotherapeutics in Dentistry – Antimicrobials Presented by Dr. JR Singh Department of Maxillofacial and Oral Surgery School of Oral Health Sciences Faculty of Health Sciences University of the Witwatersrand  ANTIMICROBIALS Antibiotics – against bacteria Antifungals – against fungal infections Antivirals – against viruses Antiparasitics – against parasites Antiseptics – surface nonspecific antimicrobial agents  Antimicrobial Overview Drug Class Sites of Action Selective toxicity Efficacy Those commonly used in Maxillofacial and Oral Surgery Empiric vs Definitive vs Prophylactic therapy Prophylaxis Mechanisms of resistance  ANTIBIOTICS - works against bacterial and not viruses or any other microbe. - Used only in an active infection unless there is a risk of developing a severe infection that could be life threatening. - It is more important to remove the cause of the infection. Use them to reduce the load so the immune system can cope with walling off and removing the infection. ***Immunocompromised – regime is reviewed Sites of action  Concept of selective toxicity 1. Highly effective enough against microbe 2. Minimal / no toxicity to humans 3. Find vulnerable targets in microbe that don’t exist in humans – surface receptors or proteins on cell walls or internal organelles  Concept of bacterial efficacy Ability to inhibit growth and replication of microbe under artificial conditions so the bodies immune system can cope with removing the foreign microbe Bacteriostatic vs Bacteriocidal  Cell wall synthesis inhibitors: Mechanism of action Bacteria in the growth and replication phase →penicillin is bactericidal Peptidoglycan (cell wall) synthesis in the bacterium is disrupted → transpeptidase enzyme is inhibited by penicillin Cell wall defects → swelling of the bacteria →rupturing of the cell membranes  Natural Penicillins Penicillin G (Benzylpenicillin) Penicillin V (Phenoxymethylpenicillin) Both have narrow spectrum β-Lactamase sensitive  Clinical Uses Prophylaxis Streptococcal infections Prevention of rheumatic fever recurrence – Surgical or dental procedures on patients with valvular heart disorders Penicillin G: initial therapy for serious infections (infective endocarditis).  Extended spectrum penicillins Aminopenicillins Extended-spectrum penicillins → many Gram +ve and Gram -ve bacteria (Gram -ve bacteria shows widespread resistance) β-lactamase sensitive strains – Amoxicillin (amoxycillin) – Ampicillin β-lactamase resistant strains – Augmentin® (amoxicillin + clavulanic acid)(coamoxiclav)  Amoxicillin Amoxicillin – Gram +ve spectrum similar to penicillin G, ↑ activity against enterococci and Listeria – Gram -ve spectrum: H. influenzae, E. coli, Proteus mirabilis, Salmonella & Shigella Amino side-chain is hydrophilic → penetration via porins in outer membrane of Gram -ve bacteria is easier  Amoxicillin Drug of choice for: oral infections, otitis media, sinusitis lower RTI Soft tissue infections Cholecystitis, GIT infections (incl. thyroid) – Urinary tract infections (possibility of resistance developing) Prophylaxis to prevent infective endocarditis  Amoxicillin 85% absorbed from GIT Oral/IV administration T1/2 60-80 min 20-30% metabolised in liver  Clavulanic Acid ± 80% of staphylococci produce β-lactamases (± 50 different types are known) Streptomyces-moulds produce a powerful β- lactamase inhibitor → use clavulanic acid Although it contains a β-lactam ring, it shows very little intrinsic antimicrobial activity Clavulanic acid binds covalently near or in the active site of the β-lactamase enzyme Most Gram -ve organisms are irreversibly inhibited by clavulanic acid  Adverse Effects -Penicillin Antibodies formed → hypersensitivity reactions (skin rashes → anaphylactic shock) → 5 – 10% occurrence Cross-hypersensitivity between all penicillin β-lactams allergy  Adverse Effects Extended-spectrum β-lactam antibiotics 1. Superinfections are possible especially by Candida and Clostridium difficile (Antibiotic associated colitis – especially ampicillin) 2. Rashes (toxin) rather than allergic reaction 3. GIT effects 4. Infectious mononucleosis /kissing disease – EBV - rash with amoxicillin – not an allergy  Adverse Effects Augmentin 1. Gastrointestinal discomfort, diarrhoea, nausea and vomiting → high dosages of Augmentin® 2. Hepatitis and cholestatic jaundice → clavulanic acid 3. Amoxicillin and clavulanic acid must also be used with caution during lactation → excreted in mother's milk  Exercise caution in: Elderly Neonates (extended dose intervals) C/I when allergic  Dental infections Penicillin V – Tooth abscess – Narrow spectrum – Lower probability of resistance – Doses → 4x daily Amoxicillin– Tooth abscess – Broad spectrum – Doses → 3x daily Augmentin → when resistance is suspected in tooth abscess ➔ 3x daily or 2x daily if 1g is prescribed  Vancomycin (oral) Gastrointestinal tract infections (pseudomembranous colitis) → Clostridium difficile No cross-resistance with other antibiotics  Vancomycin IV formulation generally for other indications Mechanism of action: – Bactericidal – Inhibits cell wall synthesis → attaching to the D-alanine-D-alanine end of a peptidoglycan pentapeptide of growing a growing cell – Transglycosylation is inhibited → peptidoglycan cross- linkages do not form – Result → weakened bacterial cell wall → lyses of the bacterium  Vancomycin Poorly absorbed during oral administration IM administration is painful The drug is only administered by IV infusion (slow) ➔ ‘red man's syndrome’ if fast Orally for pseudomembranous colitis Therapeutic drug monitoring essential (elderly, children, impaired renal function) Interacts with other ototoxic and nephrotoxic drugs ➔ aminoglycosides  Adverse Effects Fever and skin rashes Administered too rapidly → release of histamine → blushing of the neck and face known as “red-man-syndrome” Ototoxic and nephrotoxic (rare) Nephrotoxic in geriatric patients  Adverse Effects Renal Impairment Elderly patients Neonates/young infants Hearing abnormalities Pregnancy  DNA synthesis Inhibits Metronidazole – Powerful antibacterial action against anaerobic organisms (bacteria growing in the absence of O2) (excl. actinomycosis) – Bactericidal – Antiprotozoal action – Helicobacter pylori → peptic ulcers – Giardiasis – intestinal parasite in poor sanitation areas – Acute necrotising ulcerative gingivitis – Pseudomembranous colitis Clostridium difficile  Metronidazole - MOA Selectively toxic against anaerobic organisms because Diffuses into the organism, inhibits protein synthesis by interacting with DNA, and causes the loss of helical DNA structure and causes the strands to break. Blocks nucleic acid synthesis and thus replication  Metronidazole Administered orally → nearly totally absorbed Rectal, IV and topical preparations Wide distribution into body fluids including the CSF Plasma clearance decreased with impaired liver function Dose adjustment with severe liver and renal disease  Adverse Effects Nausea, headache, dry mouth Metallic taste Mild GIT discomfort Inhibits alcohol metabolism → acetaldehyde levels ↑ → disulfiram-like effect CNS effects  Drug Interactions Cimetidine (metronidazole metabolism ↓) Phenobarbitone (metronidazole metabolism ↑) Phenytoin (plasma levels ↑) Warfarin (anticoagulant effect ↑) Alcohol ➔ Disulfiram like reaction Lithium (plasma levels ↑)  Cautions/Contraindications C/I with alcohol use Caution in patients with epilepsy, porphyria Caution with CNS disease Impaired hepatic function Avoid if possible during 1st trimester of pregnancy and breastfeeding  Dental Infections Metronidazole – Tooth abscess & gum infections – Infections under the gum around the neck of the tooth or a dental implant infection – Anaerobic bacteria Amoxicillin/Metronidazole combination – Infections not responding to Amoxicillin  Clindamycin Lincosamide antibiotic NOT Macrolide Bacteriostatic BUT Bactericidal at high []’S Protein synthesis inhibitor Susceptible Gram pos. infections in patients allergic to penicillin Sensitive staphylococcal & anaerobic infections Used for severe soft tissue infections Lung abscesses Quinsy (not responding to penicillin) Inactive against enterococci  Mechanism of Action Similar mechanism of action to macrolides Inhibits protein synthesis: – Bind to the 50S subunit of the bacterial ribosome (binding site identical to macrolides) – Interferes with the formation of the initiation complex – Inhibits translocation  Adverse Effects 1. Common: diarrhoea, nausea (oral, IV & IM), skin reactions 2. Transient ↑ liver enzymes & bilirubin 3. Transient leucopenia, thrombocytopenia, agranulocytosis, eosinophilia 4. Pseudomembranous colitis is a serious and potentially i. fatal complication ii. Toxin produced by Clostridium difficile  Cautions/Contraindications GIT disease Severe hepatic impairment Porphyria Elderly Pregnancy/Lactation  Role in Dentistry Infections within the bone e.g. tooth extraction infection – Tooth abscess – Good penetration into bone – Used when patient is allergic to penicillin – Risk of pseudomembranous colitis – Use when absolutely needed  Empiric vs Definitive vs Prophylactic therapy Empiric – Pathogen not known – Broad spectrum Definitive – Pathogen identified – Narrow spectrum Prophylactic – No evidence of infection – Site expected to be exposed to pathogens – Single dose  Antibiotic prophylaxis before dental procedures 2017 AHA* and ACC** Guidelines – Use of preventive antibiotics before dental procedures for the prevention of Infective Endocarditis in patients with: – Prosthetic cardiac valves – Prosthetic material used for cardiac valve repair – History of infective endocarditis – Cardiac transplant with valve regurgitation due to structurally abnormal valve – Unrepaired cyanotic congenital heart disease – Repaired congenital heart defect with residual shunts or valvular regurgitation at or adjacent to site of prosthetic patch or device *AHA – American Heart Association **ACC – American College of Cardiology ***ADA – American Dental Association  Antibiotic prophylaxis before dental procedures 2015 ADA*** Guidelines – Use of preventive antibiotics before dental procedures in patients with prosthetic joints – Prophylactic antibiotics not recommended prior to dental procedures *AHA – American Heart Association **ACC – American College of Cardiology ***ADA – American Dental Association  Antibiotic prophylaxis before dental procedures What to prescribe? – Amoxil 2g 1 hour before treatment – Patient with penicillin allergy Clindamycin 600mg 1 hour before treatment Antibiotic resistance Mechanisms of resistance  How does resistance arise? Intrinsic Mutation (Vertical evolution) Transferable DNA (Horizontal gene transfer) o Results in acquiring new genes from other strains / species  Antifungals Overview Drug class Sites of action Selective toxicity Antifungals commonly used in Maxillofacial and Oral Surgery Mechanisms of antifungal resistance  INHIBIT CLASSIFICATION ANTIFUNGALS Increase cell membrane Amphotericin B Polyenes permeability to proteins and Nystatin monovalent and divalent cations Hamycin Blocks the synthesis of major Antibiotics Echinocandins Caspofungin cell wall components Micafungin Anidulafungin Inhibits fungal mitosis Heterocyclic benzofuran Griseofulvin Inhibits fungal protein synthesis and Antimetabolites Flucytosine interferes with fungal DNA synthesis Inhibits cytochrome P450 14α Clotrimazole Imidazoles (Topical) - demethylase Econazole Miconazole Oxiconazole Imidazoles (Systemic) Ketoconazole Azoles Fluconazole Triazoles (Systemic) Itraconazole Voriconazole Posaconazole Inhibits ergosterol synthesis Allyamines Terbinafine Tolnaftate Cyclopirox olamine Undecylenic acid Other topical agents Sites of action  Concept of selective toxicity Ergosterol unique to fungal cell membranes Host cells lack cytosine deaminase which converts Flucytosine to 5-Fluorouracil Fungistatic vs Fungicidal Increase cell membrane permeability: Mechanism of action Bind to sterols (Ergosterol) in cell membrane Depolarization of membrane and formation of pores permeability cell death  Polyenes Amphotericin B Nystatin  Clinical uses Superficial fungal infections (Candidiasis) Deep fungal infections (Apergillosis, Blastomycosis, Coccidioidomycosis, Cryptococcosis, Histoplasmosis, Mucomycosis, Paracoccidioidomycosis)  Amphotericin B Drug of choice for severe systemic fungal infections Not absorbed orally IV administration – Wide distribution T1/2 – 24 hours Eliminated in urine Use with caution in patients with renal disease  Drug interactions Other nephrotoxic agents Corticosteroids Agents causing hypokalaemia  Adverse effects Fever Headache Myalgia Nausea and vomiting Phlebitis Haematological toxicity Cardiovascular toxicity Hepatotoxicity Anaphylaxis  Nystatin Topical treatment of candidiasis Systemic absorption from intact mucous membranes negligible  Disruption of cell wall synthesis: Mechanism of action Inhibition of glucan sysnthesis  Echinocandins Caspofungin  Clinical uses Deep fungal infections (Aspergillosis)  Inhibition of RNA and DNA synthesis: Mechanism of action Replace uracil with 5-Fluorouracil in RNA Inhibit thymidilate synthetase interferes with DNA synthesis  Antimetabolites Flucytosine  Clinical uses Deep fungal infections (Cryptococcosis)  Flucytosine Use with caution in patients undergoing chemotherapy and drugs causing bone marrow suppression Adverse effects: Bone marrow depression Cytochrome P450 14α – demethylase inhibitors: Mechanism of action Enzyme in sterol biosynthesis pathway Inhibition Production of ergosterol inhibited  Azoles Imidazoles (Topical) – Clotrimazole Imidazoles (Systemic) – Ketoconazole Triazoles (Systemic) – Fluconazole – Itraconazole – Voriconazole – Posaconazole  Clinical uses Superficial fungal infections (Candidiasis) Deep fungal infections (Aspergillosis, Blastomycosis, Coccidomycosis, Cryptococcosis, Histoplasmosis, Paracoccidioidomycosis)  Clotrimazole Adverse effects – liver enzymes – Nausea and vomiting – Burning, painful mouth sensations – Dry mouth  Ketoconazole Oral absorption requires acidic environment T1/2 – 8 hours Metabolized in liver Excreted in bile Minimal excretion in urine Contraindicated in hepatic disease, porphyria Use with caution in hepatic disease  Drug interactions Alcohol – Hepatotoxicity may increase, Disulfiram – like reaction Antacids - gastric acidity absorption Ciclosporin, tacrolimus, sirolimus – Metabolism inhibited Corticosteroids – Metabolism inhibited Warfarin – Anticoagulant effect potentiated  Adverse effects Hepatotoxicity Dyspesia Nausea, vomiting and diarrhoea  Fluconazole Well absorbed orally T1/2 – 20 – 50 hours 80% excreted in urine Use with caution in renal/hepatic impairment  Drug interactions Numerous but of relevance is anticoagulant effect of warfarin is potentiated  Adverse effects Nausea, vomiting, diarrhoea Headache Skin rash  Itraconazole Absorption of capsule increase by food T1/2 – 21 hours Metabolised in liver Contraindicated in liver disease Use with caution in CCF, porphyria  Drug interactions Numerous but of relevance is anticoagulant effect of warfarin is potentiated  Adverse effects Nausea, vomiting, diarrhoea Headache Skin rash  Voriconazole Metabolised in liver Excreted in urine Contraindicated in hepatic impairment Use with caution in porphyria  Adverse effects Anaphylaxis Transient and reversible changes in vision Stevens – Johnson syndrome Mechanisms of antifungal resistance  Principles of Prescription Writing Overview Prescription example Abbreviations commonly used on prescriptions  Dr I. M. Pain BDS(Wits) Practice No: 1234567 38 Molar Street Tel: (011) 121-3141 Wisdom City Email: [email protected] 5161 Emergency: 082-911-1112 Date: Mr. P. L. Z Help 11 Incisor Street Eg of prescribing suspension Palate City 3848 Rx 1. Amoxicillin 500mg capsules Amoxicillin 125mg/5ml susp 15 (Fifteen) capsules 200ml 1 tds pc finish course 5ml tds pc for 5 days 2. Ibuprofen 400mg tablets 30 (Thirty) tablets 1 q8h prn for pain cc 3. Andolex C Mouthwash 200ml 10ml bd. Rinse. Do not swallow Dr I. M. Pain BDS(Wits)  Abbreviations used on prescriptions Rx The drug prescribed Mitte Supply i.e. quantity Sig Label i.e. dosage i or 1 One ii or 2 Two iii or 3 Three die Daily nocte At night bd Twice a day Three tds times a day Four qid times a day Every q4h 4 hours q6h Every 6 hours q8h Every 8 hours prn When necessary ac Before meals cc With meals pc After meals tab/s Tablet/s cap/s Capsule/s susp Suspension syr Syrup ung Ointment qs As much as is sufficient md As directed stat Immediately gtt Drops