Antibiotics in Dentistry Antibiotics for Infection Control and Prevention in Dentistry MSc. Carlos Daniel Ferreira Fonseca 25.11.2024 1 Learning Objectives • Understand the role of antibiotics in dental infections. • Identify antibiotic classes commonly used in dentistry. • Discuss antibiotic resistance and its impact on dental practice. • Implement proper antibiotic prescribing practices and dosage guidelines. • Agenda: • Importance of Antibiotics in Dentistry • Classes of Antibiotics • Antibiotic Resistance and Stewardship • Activities 2 Before we start… Palmer, N. (Ed). Antimicrobial Prescribing in Dentistry: Good Practice Guidelines. 3rd Edition. London, UK: Faculty of General Dental Practice (UK) and Faculty of Dental Surgery; 2020. 3 Why Antibiotics in Dentistry? • Antibiotics treat bacterial infections in/around the oral cavity. • Common indications: • Local infections • Focal infections • Orofacial infections: Odontogenic and nondontogenic • Common symptoms: Pain and Swelling • Prophylactic use: • Preventing infections in high-risk patients (e.g., prosthetic heart valves). • Untreated conditions lead to much severe disease states! 4 5 Correct clinical assessment (Infection) • Assessment of the presence of fever (> 38°C), malaise, fatigue or dizziness • Q: In what situations fever would not be present? • A: antipyretic effect of patients taking analgesics may temporarily lower the temperature • Few examples: paracetamol, NSAIDs, metamizole, celecoxib, Meloxicam, nimesulide, piroxicam • Measurement of the patient’s pulse and temperature (normal temperature range is 36.2°C-37°C) • Definition of the nature, location and extent of the swelling, and any lymphadenopathy • Identification of the cause of the infection • Assessment of presence of sepsis using a decision support tool, e.g. NICE Sepsis: Risk stratification tools Importance of Medical Records Critical ! Activity 1 6 7 Selective toxicity 7 Target the disease-causing organism while causing no or minimal harm to the patient! Exploit the differences between host cell and bacterial • MIC (Minimum Inhibitory concentration) • Lowest conc. of ATB that inhibits visible growth of a microorganism after overnight incubation • Effective treatment = conc. ATB higher than MIC (2-5x) • Predictive value • Gives an idea of susceptibility and potential resistance 8 Principles of antibacterial therapy 8 9 • MBC (Minimum bactericidal concentration) • Lowest concentration of antibiotic required to kill the bacteria • Concentration-Dependent Killing • Rate and extent of ATB killing is related to the peak concentrations achieved • Aminoglycosides • Time-dependent killing • Effect is dependent on the time during which ATB concentration at site of infection is above MIC • Importance is shifted to adherence to therapy • Beta-Iactams • Concentration-dependent and time-dependent killing • Dependent on the AUC • Related to the amount of time above the MIC and the total exposure of antibiotic to the organism • Importance is shifted towards total daily dose • Fluoroquinolones 9 Principles of antibacterial therapy 9 • Antibiotic prophylaxis • Immunosuppressed patients • With a history of cancer • Individuals with infective endocarditis • With metabolic disorders: diabetes and splenectomies • With prosthetic joints • In-dwelling catheters • Neurosurgical shunts • Valvular heart diseases • Surgical pulmonary shunts • Hypertrophic cardiomyopathy • Mitral valve prolapsed • Prosthetic heart valves When Are Antibiotics Indicated? High infection risk • Antibiotic prophylaxis • Healthy Patients • Surgery for benign tumours • Bone grafting • Implant placement • Periapical surgery • Removal of impacted teeth 10 • Acute conditions • Necrotizing ulcerative gingivitis • Stage III-grade C/incisor-molar pattern periodontitis (formerly referred to as localized aggressive periodontitis) • Acute periapical abscess • Cellulitis • Local or systemic spreading of infection in the periodontal abscess • Pericoronitis • Periimplantitis • Infection of deep fascial layers of the head and neck, and in the case of fever and/or malaise When Are Antibiotics Indicated? 11 1st to be discovered – Alexander Fleming (1928) – Inhibition of growth in culture plate with Staphylococci – Genus Penicillium • Non-toxic to host – least toxic drug was the first to be discovered – very safe • Reason to be used as 1st choice agent • Part of the cell wall inhibitors • Selective toxicity – Damage to cell wall of bacteria while lacking effect against mammalian cells • Interference with last step of cell wall synthesis – inhibition transpeptidation or cross linking – lysis • Binding to PBPs (Penicillin Binding Proteins) enzymes responsible for transpeptidation • Resistance mechanisms: • Alteration of PBPs - E.g: MRSA (Methicillin Resistant Staphylococcus Aureus) → ↓ Efficacy • ß-Lactamase producing organisms (Break of ß-Lactam ring) → ↓ Efficacy • Efficacy depends on the existence of a growing cell wall 12 Penicillins Bactericidal (+)-6- aminopenicillanic acid 13 Resistance mechanisms • Natural resistance • Innate • Microorganisms without a cell wall (e.g.: Mycoplasma pneumoniae) • Intrinsically ß-Lactamase producing • Microorganisms with a cell wall • Impermeable to drugs • Acquired resistance • Plasmid mediated ß-Lactamase - Antibiotic gene resistance • Gram-Positive - secretion extracellularly • Gram-Negative - Inactivation in periplasmic space • Efflux Pump (e.g.: Klebsiella pneumoniae) • ↓ Intracellular concentration • Alteration of PBPs (e.g.: MRSA) • ↓ Lower binding affinity • Decrease of permeability through the cell wall • ↓ Amount of drug that reaches PBPs (+)-6-aminopenicillanic acid ß-Lactamase 14 Beta-Lactam Antibiotics • Pharmacokinetics (ADME) • Absorption Incomplete oral absorption Absorption Time of Gastric Emptying GIT disturbances Destruction by stomach Acid Interference with intestinal flora Must be taken on an empty stomach! 15 • Pharmacokinetics (ADME) • Distribution • Generally, well distributed • Can cross placental barrier • Limited penetration to bone and CSF (unless in inflammatory states) • Elimination • Kidneys are the primary route of excretion (Tubular excretion + Glomerular Filtration) • Renal Impairment requires dose adjustment • Penicillins in general have a relative short T1/2 • Excreted on the breast milk Beta-Lactam Antibiotics 16 Beta-Lactam Antibiotics Bactericidal • Groups of Penicillin's • Natural Penicillin's – Produced from fermentation of fungus Penicillium chrysogenum • penicillin G (benzyl penicillin) – administered IV, IM – poor oral absorption • Effective against: Gram-Positive Bacilli, Gram-Negative Cocci, Spirochetes • Treatment of: Gas Gangrene (Clostridium perfringens) or Syphilis (Treponema pallidum) • penicillin V (phenoxymethylpenicillin) - administered PO • Same spectrum (Effective against: Gram-Positive Bacilli, Gram-Negative Cocci, Spirochetes) • Anti-staphylococcal penicillin’s – For ß-Lactamase Resistant • methicillin (Not used - AIN) • nafcillin (administered IV, IM) • oxacillin (administered IV, IM) • dicloxacillin (administered PO) Reserved for ßLactamase producing organisms Not to be used for Gram-Negative organisms Penicillin G 17 • Groups of Penicillin’s • Broad-spectrum PNC • Aminopenicillin’s • ampicillin – administered PO, IV, IM • Effective against: Gram-Positive Bacilli, Gram-Negative Cocci, Spirochetes • Treatment of: Listeriosis (Listeria Monocytogenes), Enterococcal Species • Commonly combined with: sulbactam → ↑ Extended Antimicrobial Spectrum (e.g.: Against MRSA) • amoxicillin – administered PO, IV • Effective against: Gram-Positive Bacilli, Gram-Negative Cocci, Spirochetes • Commonly used by dentists: Prevention of Bacterial Endocarditis in high-risk patients • Commonly combined with: clavulanic Acid → ↑ Extended Antimicrobial Spectrum (e.g.: Against MRSA) • Anti-pseudomonal PNC • Carboxypenicillin’s • ticarcillin - administered IV, IM • Effective against: Gram-Negative Bacilli (Not Klebsiella – produces a constitutive penicillinase) • Treatment of: Pseudomonas aeruginosa • Commonly combined with: clavulanic Acid → ↑ Extended Antimicrobial Spectrum (e.g.: Against penicillinase producing organisms) • Ureidopenicillin’s • piperacillin - administered IV, IM • Effective against: Gram-Negative Bacilli (Not Klebsiella – produces a constitutive penicillinase) • Treatment of: Pseudomonas aeruginosa • Commonly combined with: tazobactam→ ↑ Extended Antimicrobial Spectrum (e.g.: Against penicillinase producing organisms) BactericidalBeta-Lactam Antibiotics amoxicillin Adverse Effects Hypersensitivity Nephritis DiarrhoeaNeurotoxicity Haematologic complications 18 Only with high doses or intrathecal administration Epileptic patients at risk – GABAergic inhibition Cytopenia – monitor necessary – Prolonged therapy Piperacillin, Ticarcillin and Nafcillin ↓ Coagulation More common from extended spectrum agents and are incompletely absorbed Disbalance of the microflora ↑Risk of Pseudomembranous Colitis (caused by Clostridium Difficile) Rashes Angioedema Anaphylactic shock Methicillin – discontinued – Causes acute interstitial nephritis Most characteristic side effect 19 Beta-Lactam Antibiotics (Cephalosporins) Bactericidal • Cephalosporins • Same mechanism of action as Penicillins. Produced semi-synthetically • Affected by the same mechanisms of resistance • Tend to be more resistant to ß-Lactamase Cephalosporin Cephalosporins 1st Generation 2nd Generation 3rd Generation 4th Generation 5th Generation Commercially available Cephalosporins infective against: MRSA, Listeria monocytogenes, Clostridium Diffcile and Enterococci 20 HENS-PEcK organisms Hemophilus influenzae Enterobacter Neisseria gonorrhoeae & meningitidis Serratia Proteus Escherichia coli Klebsiella Cephalosporins 1st Generation MSSA coverage Group A & B Streptococcus PEcK organisms 2nd Generation HENS-PEcK organisms 3rd Generation Streptococcus Pneumoniae HENS-PEcK organisms Pseudomonas aeruginosa 4th Generation HENS-PEcK organisms Pseudomonas aeruginosa 5th Generation MRSA coverage Beta-Lactam Antibiotics (Cephalosporins) Gram (+) Gram (-) Extended-Spectrum Beta Lactamase Producing Bacteria (EBSL) 21 Cephalosporins 1st Generation cefazolin cephalexin 2nd Generation cefuroxime cefotetan cefoxitin 3rd Generation ceftriaxone cefotaxime ceftazidime 4th Generation cefepime 5th Generation ceftaroline Beta-Lactam Antibiotics (Cephalosporins) 22 • Pharmacokinetics (ADME) • Absorption • Poor Oral Absorption most of Cephalosporins are administered IV, IM • Distribution • Well distributed to body fluids • All cross the placental barrier • cefazolin is used pre-surgery due to its short half-life and activity against S.aureus (prophylaxis) • Adequate therapeutic levels in CSF only achieved with a few Cephalosporins (3rd Generation: ceftriaxone or cefotaxime) • Treatment of Meningitis (caused by Haemophilus Influenza) • Elimination • Kidneys are the primary route of excretion (Tubular excretion + Glomerular Filtration) • Renal Impairment requires dose adjustment • ceftriaxone is an exception because is excreted through bile (use in renal dysfunction) Beta-Lactam Antibiotics (Cephalosporins) 23 Adverse Effects Hypersensitivity GIT disturbances Gastritis Headache Nausea and Vomiting Vitamin K Deficiency Risk of biliary sludge 23 If patient showed the following with penicillin: Anaphylactic shock Stevens-Jonhson syndrome Toxic Epidermal Necrosis (do not use Cephalosporins) Diarrhoea Dyspepsia Abdominal Pain Most characteristic side effect Inhibition of synthesis of coagulation factors → ↓ Coagulation Factors → Risk of Bleeding ↑ Risk of Cholecystitis with ceftriaxone ceftriaxone – produces a disulfiram-like reaction: Development of symptoms like nausea, vomiting, flushing, hypotension, and tachycardia when medications are taken with alcohol 2424 Beta-Lactam Antibiotics (Carbapenems) Bactericidal • Carbapenems • Really broad agents • Same mechanism of actions as Penicillins and Cephalosporins • Generally unaffected by ß-lactamases • Affected by Metallo-ß-lactamases Carbapenem Carbapenems doripenem imipenem meropenem ertapenem 25 HENS-PEcK organisms Hemophilus influenzae Enterobacter Neisseria gonorrhoeae & meningitidis Serratia Proteus Escherichia coli Klebsiella Beta-Lactam Antibiotics (Carbapenems) • Carbapenems • Bacterial Coverage • Hens-PecK organisms • Anaerobic bacteria (Clostridium, Bacteroides, Pepto streptococcus, Fusobacterium, Actinomyces) Extended-Spectrum Beta Lactamase Producing Bacteria (EBSL) Carbapenems doripenem imipenem meropenem ertapenem 2626 • Pharmacokinetics (ADME) • Absorption • Poor oral Absorption • Carbapenems are administered IV, IM • Distribution • Well distributed to body tissues and body fluids • imipenem + cilastatin – Penetration to CNS • Metabolism • cilastatin (renal dehydropeptidase inhibitor) blocks imipenem metabolism and prolongs its half-life • Elimination • Kidneys are the primary route of excretion (Tubular excretion + Glomerular Filtration) • Renal Impairment requires dose adjustment Beta-Lactam Antibiotics (Carbapenems) 2727 Adverse Effects Seizures Diarrhoea Eosinophilia and Neutropenia Nausea and Vomiting 27 High doses of imipenem Less common with other carbapenems 282828 Beta-Lactam Antibiotics (Monobactams) Bactericidal • Monobactams • aztreonam – only representative • Same mechanism of actions as Penicillins, Cephalosporins and Carbapenems • Generally unaffected by ß-lactamases • Affected by Extended Spectrum-ß-lactamases • Coverage against Hens-PEcK organisms (Gram -) • No coverage against Gram + • IV administration • Used in penicillin-allergic cases Monobactam 29 vancomycin and fosfomycin Bactericidal vancomycin • Glycopeptide - vancomycin - administered IV (more common), PO • Phosphonic Acid - fosfomycin – mainly used in UTIs – administered IV,PO • Mechanism of action – Inhibition of peptidoglycan synthesis • Agents in reserve! • Use in severe infections: MRSA,MRSE and Enterococcal • Usually, 1st option in the following situations caused by MRSA: • Hospital-Acquired Pneumonia • Skin and soft skin issues • Complicated UTI • Septic arthritis, osteomyelitis • Community-Acquired Meningitis (by S. pneumoniae) • Hospital-Acquired Meningitis • Sepsis • PO administration (not absorbed) allows for treatment of Cl. Difficile 30 31 Adverse Effects Direct Nephrotoxicity Ototoxicity DRESS Red Man syndrome Phlebitis Drug-related eosinophilia and systemic symptoms Classic tetrad of: Fever Rash ↑ eosinophils Lymphadenopathy Whenever vancomycin is pushed too quickly Manifest as: Red, itchy rashes Muscle spasms Precipitate hypotension and a little bit of tachycardia Whenever vancomycin is pushed too quickly Most characteristic side effect 32 Polypeptides Bactericidal • polypeptides • bacitracin – combined with Vit. A – prevention of skin infection after cuts • Effective against streptococci, pneumococci, and staphylococci. • In addition, most anaerobic cocci, neisseriae, tetanus bacilli, and diphtheria bacilli are sensitive • Mainly topical use • Polymyxins: polymyxin B and Polymyxin E (colistin) • Mechanism of action – Disruption of cell membranes • Mainly topical use • Gram-positive organisms, Proteus sp, and Neisseria sp are resistant. • Significant Nephrotoxicity polymyxin B 33 34 Adverse Effects Neurotoxicity Nephrotoxicity Dermatitis Respiratory Failure Seizures, myoclonus, encephalopathy, serotonin syndrome With polymyxins With bacitracin 35 Inhibitors of Protein synthesis • Characterized by their selective toxicity • Bacterial protein synthesis – bacterial ribosomes contain a 50S and 30S subunit • Mammalian ribosomes have a 60S and a 30S subunit • Inhibition of translation process • 1st step - Inhibition of Aminoacyl-tRNA binding – tetracyclines and aminoglycosides – bind to 30S subunit • 2nd step – Inhibition of peptidyl transferase activity (transpeptidation) – chloramphenicol – bind to 50S subunit • 3rd step – Inhibition of translocation – macrolides and streptogramins – bind to 50S subunit Bacteriostatic 36 Tetracyclines Bacteriostatic • Tetracyclines • tetracycline - administered PO,IV • doxycycline – administered PO,IV • Mechanism of action – inhibition of protein synthesis – binding to 30S ribosomal subunit • Broad therapeutic index (both Gram + and Gram -, mycoplasma, chlamydia, rickettsiae, Borrelia burgdorferi) • Lack of activity and resistance is common (efflux pumps – decrease intracellular concentration – reduction of therapeutic value) • Low toxicity • Cross placental barrier (contraindicated in pregnancy) Tetracycline↓ Absorption 37 Tetracyclines accumulate slowly in bones and teeth, because they have a high affinity for calcium, and should not be used in children for this reason Tetracyclines Weaken the tooth enamel Contraindicated in children up to 8 years old 38 Adverse Effects Diarrhoea Vestibular problems Yellow TeethPhotosensitivity Suprainfection Contraindicated in pregnancy and children before 8 years old! Candida (vagina) or resist. staphylococcus (gut) vertigo, nausea, vomiting Most characteristic side effect 3939 Macrolides Bacteriostatic • Macrolides – administration PO, IV • Basic (erythromycin, spiramycin) • Modified (clarithromycin, azithromycin, roxithromycin) • Spectrum: mainly on G+, neisseria, leptospirosis, mycoplasma, chlamydia, helicobacter, legionella, toxoplasma • clarithromycin, azithromycin much more active against H.Influenzae • Mechanism of action – Inhibition of translocation – bind to 50S subunit • They enhance the killing of bacteria by phagocytes because they to be concentrated in the lysosomes • Good tolerance (Ery-motilin!), low tox., good penetration into the tissues and cells • CYP3A4 inhibitors (strongest erythromycin, clarithromycin) and P-gp inhibitors • Prodrugs such as clopidogrel have dimished therapeutic efficacy • Increase in blood levels of drugs such as warfarin Macrolide 404040 Lincosamides Bacteriostatic • clindamycin – administration PO, IM, IV or topical • Spectrum: Gram + • MRSA, Streptococcus • Clostridium • Bacteroides • Pepto streptococcus • Fusobacterium • Actinomyces • Mechanism of action – Inhibition of translocation – bind to 50S subunit • Treatment of Staphylococcal infections of bones an joints – what's great about clindamycin – big penetration to bones and joints • Treatment of bacterial conjunctivitis as eye drops • Low toxicity but risk of pseudomembranous colitis and worsen Myasthenia Gravis Anaerobic coverage – above diaphragm Important AB in dentistry! clindamycin 41 Chloramphenicol Bacteriostatic • chloramphenicol – administration PO, IV, IM, topical • Bacteriostatic • - Broad therapeutic index (both Gram + and Gram - and rickettsiae) • - Good penetration into CNS and abscesses • Mechanism of action – Inhibition of peptidyl transferase activity (transpeptidation) – bind to 50S subunit • Liver is the primary organ of inactivation • Indication: meningitis, MRSA • Reserved for serious infections: Typhoid Fever (Ciprofloxacin and amoxicillin are better options), Haemophilus Influenzae or meningitis (when penicillin cannot be used) • History: typhus and paratyphus, severe pneumonia, anaerobic or abdominal infections chloramphenic ol Safe use as topical agent for bacterial conjunctivitis 4242 Adverse Effects Grey baby syndrome Hypersensitivity GIT disturbances Bone marrow suppression Pancytopenia – decrease in all blood cell elements. Aplastic anemia and myelosuppression Vomiting, diarrhoea, flaccidity, low temperature and grey colour Most characteristic side effect Plasma monitoring to avoid grey baby syndrome in newborns! Systemic use is reserved for very serious infections due to haematological toxicity! 43434343 Oxazolidinones Bacteriostatic • Linezolid • Spectrum: • Gram + (specially MRSA, Vancomycin resistant enterococci) • Some anaerobes (like Clostridium difficile) • Mechanism of action – Inhibition of tRNA binding – bind to 50S subunit • Last line when everything else did not work! • Treatment of Pneumonia, skin and soft tissue infections linezolid 44 Adverse Effects Serotoninergic syndrome Diarrhea Nausea Thrombocytopenia Linezolid act as non-selective inhibitor of monoamine oxidase Most characteristic side effect 45 Aminoglycosides • Aminoglycosides • Classic - streptomycin, kanamycin, neomycin - administered IV (lack of GIT absorption) • New - gentamicin, netilmicin, tobramycin, amikacin, isepamicin - administered IV (lack of GIT absorption) • Mechanism of action – inhibition of protein synthesis – binding to 30S ribosomal subunit (and mRNA misreading) • Narrow therapeutic index (mainly against Gram -, not much activity against Gram +) • gentamycin used in Pseudomonas aeruginosa (Gram - Baccili) + combination with penicillin or vancomycin – increase in activity • Lack of activity and resistance is common (inactivation by microbial enzymes) • Low toxicity • Cross placental barrier • Kidneys are the primary route of excretion (Tubular excretion + Glomerular Filtration) • Renal Impairment requires dose adjustment Bactericidal Aminoglycosid e 4646 Adverse Effects Neuromuscular Blockade NephrotoxicityOtotoxicity Plasma monitoring to avoid nephrotoxicity! Destruction of sensory cells in the cochlea and vestibular organ of the ear Direct damage of tubules. Specially if combined with nephrotoxic agents such as vancomycin Most characteristic side effect Rare. If given with neuromuscularblocking agents 47474747 Quinolones Bactericidal Ciprofloxacin • Antimicrobial agents affecting topoisomerase • Broad-spectrum Quinolones – administration IV or PO • ciprofloxacin, levofloxacin, ofloxacin, norfloxacin • Effective against: less for Gram (+) and more for Gram (-) (HeNS-PEcK coverage except Neisseria) • ciprofloxacin and levofloxacin are appropriate against Pseudomonas Aeruginosa • Mechanism of Action: Inhibition of topoisomerase II (inhibition of the introduction of a negative coil) • Treatment of: Community Acquired Pneumonia, Git infections (with metronidazole), UTIs • ciprofloxacin not be used in MRSA (weak activity and high resistance) • ciprofloxacin and norfloxacin are CYP450 inhibitors (relevant interaction with theophylline - convulsions) • Narrow-spectrum Quinolones • nalidixic acid • Treatment of: UTIs Note: Sufix -floxacin indicates a fluroquinolone 4848 Adverse Effects Worsen Myasthenia Gravis Teratogenic GIT disturbances Aortic dissection and aneurysm Tendonitis Prolongation of QT interval In children and patients over 60 years old Most characteristic side effect fluroquinolones contraindicated on <18 years old because it can produce cartilaginous damage and arthropathies Production of antibodies against nicotinic receptors moxifloxacin 4949494949 Metronidazole Bactericidal • Miscellaneous Agent • metronidazole • Effective against anaerobic bacteria (Bacteroides, Clostridia spp.) • Mechanism of Action: the formation of reactive oxygen species (ROS) causing damage to the DNA, RNA, and/or proteins • Treatment of: Infections by anaerobic bacteria below diaphragm • Typical Disulfiram-like reaction similar to ceftriaxone • Low incidence of side-effects only diarrhoea metronidazole 505050505050 Sulfonamides Bactericidal • sulphamethoxazole in combination with trimethoprim (as cotrimoxazole) – administered orally decreased importance (increased resistance) • sulfasalazine - complex of a sulfonamide (sulfapyridine) and salicylate • Mechanism of Action: Competition with PABA for the enzyme dihydropteroate synthase and inhibition of production of purines that bacteria need • Cross placental barrier and BBB. • Treatment of Ulcerative Colitis and Crohn's Disease (sulfasalazine) Sulfamethoxazo le 515151 Adverse Effects Hypersensivity Renal Crystalluria Steven- Johnson Syndrome GIT disturbances Cyanosis Caused by methemoglobinemia Most characteristic side effect Precipitation of acetylated metabolites in urine Rashes, fever, erythema multiforme 525252525252 Antimycobacterial agents • Treatment of Tuberculosis and Leprosy • Caused by M. Tuberculosis and M. Leprae • Mycobacteria survive inside macrophages after phagocytosis • 1st line drugs: isoniazid, rifampicin, rifabutin, ethambutol and pyrazinamide • 2nd line drugs: capreomycin, cycloserine, streptomycin, clarithromycin and ciprofloxacin • Combination therapy needed → ↓Resistance • Initial Treatment phase – 2 months – isoniazid + rifampicin + pyrazinamide and ethambutol (if resistance) • Continuation phase – 4 months – isoniazid + rifampicin Mycolic Acid makes Mycobacterium hard to kill 53 Antimycobacterial agents • isoniazid • Limited to treatment of infections by Mycobacterium • Administered orally and parenterally • Inhibits growth and replication of Bacteria • Passes freely to mammalian cells and is effective against intracellular organisms • Pro-drug • Mechanism of action: Inhibition of production of Mycolic Acid • Well absorbed from GIT • Metabolism by acetylation and excretion in urine • Short Half-life (T1/2 ≈ 3 hours) Bacteriostatic and Bactericidal isoniazid 54545454 Adverse Effects CNS disturbances Fever Systemic lupus erythematosus Hepatoxicity Most characteristic side effect As consequence of Vitamin B6 deficiency. Supplementation is necessary undergoing treatment Symptoms of hepatitis and jaundice 55 Antimycobacterial agents • rifampicin • Active against procaryotic agents but not eukaryotic. Effective against Leprosy and Tuberculosis • Administered orally • Inhibits growth and replication of Bacteria • Passes freely to mammalian cells and is effective against intracellular organisms • Pro-drug • Mechanism of action: Inhibition of DNA dependent-RNA polymerase • Resistance develops quickly (hence combination with other agents is necessary) • Widely distributed to various tissues, body fluids and CSF • Excreted in urine and bile • Short Half-life (T1/2 ≈ 1-5 hours) • Low toxicity rifampicin Orange urine characteristic of Rifampicin administration Inducer of CYP450 - DDI with warfarin, HIV antiretroviral drugs, glucocorticoids, narcotic analgesics 56 • Ethambutol • Active against Mycobacteria • Administered orally • Mechanism of action: Inhibition of bacterial cell wall synthesis (blocking arabinosyltransferase, which synthesizes the arabinogalactan) • Passes freely to mammalian cells and is effective against intracellular organisms • Resistance develops quickly (hence combination with other agents is necessary) • Widely distributed to various tissues, body fluids and CSF • Causes gout and optic neuritis as side effects Antimycobacterial agents Gout ethambutol Optic Neuritis 57 Antimycobacterial agents • pyrazinamide • Active at tuberculostatic acid pH • Administered orally • Mechanism of action: Inhibition of production of Mycolic Acid • Passes freely to mammalian cells and is effective against intracellular organisms • Widely distributed to various tissues, body fluids and CSF • Pyrazinamide can cause gout • Other side effects are arthralgias, anorexia, nausea, and vomiting. But the most important is liver damage. pyrazinamide 58 Key insights Increased use of Aminopenicillins with Beta-Lactamase Inhibitors and Lincosamides (clindamycin) Decline in Narrow-Spectrum Penicillins, Tetracyclines, and Macrolides Empirical Use Based on Clinique and Bacteriological Factors Commonly Used Antibiotics in Pediatric Dentistry: β-lactam antibiotics, macrolides, tetracyclines, clindamycin, and metronidazole Commonly used antibiotics in 59 When Are Antibiotics Indicated? • Acute conditions – Specific situation – Acute periapical abscess • Local or systemic spreading of infection in the periodontal abscess Q: How do we deal with this specific situation? Does it make sense to make use of antibiotics? A: Depends on the signs! • If there is elevated temperature, evidence of systemic spread and local lymph node involvement. • Strong recommendation + moderate quality evidence • Uncomplicated dental acute infections - removal of the cause by drainage of the associated abscess, removal of infected pulp contents or by extraction of the tooth • Strong recommendation + low quality evidence Use of ABs Avoiding the use of ABs Complementary Clinical Advice: Analgesics – Control of pain and fever + Maintenance of fluid balance + Assessment after 3 days Activity 2 6060 When Are Antibiotics Indicated? • Acute conditions – Specific situation – Acute periapical abscess • Local or systemic spreading of infection in the periodontal abscess Q: What antibiotic would I use for this specific situation? What would be the dose and duration of treatment? A: 1st choice: • A penicillin (phenoxymethylpenicillin or amoxicillin) • Coverage against most Gram + organisms • Penicillin V is narrow spectrum while amoxicillin is broader spectrum • 500mg orally four times a day for up to 5 days (Penicillin V) • 500mg orally three times a day for up to 5 days (Amoxicillin) 2nd choice: • Metronidazole • Coverage against anaerobic bacteria (Clostridium, Bacteroides, Pepto streptococcus, Fusobacterium, Actinomyces) • When patients are allergic to penicillin • If a predominantly anaerobic infection is suspected or microbiologically proven • 400mg orally three times a day for up to 5 days Activity 2 Most infections are resolved in 2-3 days! ASSESS clarithromycin is a valid 2nd option too 61 Extra considerations • Acute conditions – Specific situation – Acute periapical abscess • clindamycin could also be considered for this patient • Good option for infections with anaerobes that occur above the diaphragm - Very common seen the prescription of this drug • Why should the use be reconsidered? • ↑ Risk of Infection by Clostridium difficile - significant morbidity/mortality associated with Clostridium difficile • GIT problems – Diarrhoea ,Vomiting Same efficacy as penicillins but ↑↑ adverse effects Pseudomembranous Colitis 626262 When Are Antibiotics Indicated? • Specific situation – Pericoronitis • Without evidence of systemic spread Q: What antibiotic would I use for this specific situation? What would be the dose and duration of treatment? A: It is not necessary! Managed with local measures, such as removal of the cause (extraction or operculectomy), incision and drainage where necessary. Activity 3 6363 When Are Antibiotics Indicated? • Acute conditions – Periodontitis - Stage I, II, III; Grade A, B periodontitis • The recent reclassification of periodontitis is based on staging (initial [I], moderate [II], severe [III], very severe [IV]) in terms of interproximal bone loss and grading (slow [A], moderate [B], rapid [C]) progression in terms of percentage bone loss compared to patient age Q: What antibiotic would I use for this specific situation? What would be the dose and duration of treatment? A: There is no recommendation. Root surface debridement (RSD) combined with good patient oral hygiene. doxycycline might be considered for a host modulating agent inhibiting collagenase activity present in periodontitis, however… Activity 4 The adverse effects outweigh the benefits! 646464 When Are Antibiotics Indicated? • Prophylaxis – Healthy Patients – Dental implant Q: What antibiotic would I use for this specific situation? What would be the dose and duration of treatment? A: Depends if there is bone augmentation or not. Without: No antimicrobial regimen is recommended. With: ↑↑↑ risk of having an infectious complication • 1st choice: Amoxicillin 3000 mg orally 1 hour before surgery • 2nd choice: Clindamycin – consider the side effects 600mg orally (4x150mg) one hour before surgery Activity 5 Nausea, Vomiting 65 The End Thank you for your attention!