Pharmacology of Infectious Processes PDF

PHARMACOLOGY OF INFECTIOUS PROCESSES GENERAL PRINCIPLES OF USE OF ANTIBACTERIAL DRUGS Antibiotic - anti-infective compound produced by microorganisms - today, it has lost its restrictive meaning and is also used to name synthesised chemical drugs...

PHARMACOLOGY OF INFECTIOUS PROCESSES GENERAL PRINCIPLES OF USE OF ANTIBACTERIAL DRUGS Antibiotic - anti-infective compound produced by microorganisms - today, it has lost its restrictive meaning and is also used to name synthesised chemical drugs - common property to all antibiotics selective toxicity = toxicity towards invading organisms is greater than the toxicity towards humans (host tissues) Spectrum - anti-infective activity of a drug is defined by their spectrum - antimicrobials can be antibacterial, antiviral or antifungal, i.e the range of pathogens that are affected by the antibiotic J Microorganism Antibiotic bacteria antibiotic viruses antiviral antimycotic or fungi antifungal parasites antiparasitic Bactericide / bacteriostatic - according to the mechanisms of action - antimicrobial agents behave as bactericidal when they produce the death of organisms responsible for infectious process e.g. β-lactams, quinolones, aminoglycosides - behave as bacteriostatic when they inhibit bacterial growth and replication although the microorganisms remains viable, so after discontinuing antibiotic the microorganism can recover and multiply again eliminating bacteria requires the action of the immune system of the host e.g. tetracyclines, macrolides, sulphonamides - agent can be bactericial or bacteriostatic depends on - its mechanism of action - concentration achieved at site of action - inoculum size - type of microorganism Type of antibiotic treatment - empirical - treatment chosen without knowing the specific germ causing the infection - specific - treatment chosen after identifying the germ and knowing the antibiogram Antibacterial activity - bacterial strains can be susceptible, intermediate or resistant - quantification of antibacterial activity os chirped by testing the susceptibility of microorganism in contains with antibiotic - antibiogram that can be based on diffusion and dilution technique MIC - minimum inhibitory concentration is the lowest concentration of antibiotic that is capable of inhibiting the growth of 10 5 bacteria in 1 ml of growth medium after 18-24h of incubation  MBC - minimum bactericidal concentration is the lowest concentration that can destroy or kill 105 bacteria in 1 ml of growth medium after 18-24 h of incubation Purpose of the anti-infective therapeutics will be to achieve an antibiotic tissue concentration exceeding MIC Quantification of antibacterial activity - · Antibiogram - sensitive strains / resistant strains - depending on the information obtained about the MIC of the germ, we will know whether a bacterial strain is sensitive to one or more antibiotics and thus the infection produced by this strain treated with standard doses of these antibiotics will respond satisfactorily - by contrast, resistant strain to these antibiotics unlikely a good therapeutic result even with administration of higher doses PK / PD - relationship between antibacterial activity and concentration achieved at site of action pharmacokinetics / pharmacodynamics - according to PK / PD, 2 antibacterial drug categories - concentration-dependent action antibiotic - greatest bactericidal activity is obtained when reaching concentrations above the MIC at the site of action higher the concentration, the greater the bactericidal effect - time-dependent action antibiotic - concentration of the drugs in this group at the site of action has to exceed the MIC for at least half of the dosing interval time-dependent post-antibiotic effect, as other frugs, the antibiotic is still being when below the effective even though MIC, it has no they are lower than MIC, effect only for period of time aminoglycosides beta-lactams exam antibacterial activity antibacterial activity when long duration when high CMAX / MIC of action (concentration is greater than MIC for 1/2 dosing interval Mechanism of action - increased permeability of cell membrane - inhibition of cell wall synthesis - altered DNA and RNA synthesis - inhibition of protein synthesis (ribosomes 50S / 30S) - antimetabolites Fundamental rules of antibiotic treatment - treatment indications - choice of antibiotic  - route of administration - duration of treatment FUNDAMENTAL RULES OF ANTIBIOTIC TREATMENT Treatment indication - fever (bacterial origin) bacteriological study (isolate sensitive microorganism) - pathogen most likely involved by location - excluding situations - non-infectious fever - fever caused by no susceptible organisms - ten to receiver spontaneously (viral infections) In dentistry - important local extension - systemic involvement - high risk (e.g. immunocompromised patients) Choice of antibiotics - microorganism - clinical features and location - in dentistry - empirical treatment - gram stain - serology - culture - antibiogram - prescribing antibiotics without knowing germ - in seriously ill patients - impossible to collect culture - negative cultures in severe infections  - patient - hypersensitivity or allergy - immune system deficiency (bactericidal) - age - diseases (liver and kidney) - pregnancy, breastfeeding - antibiotic - bactericide / bacteriostatic - MIC - toxicity Route of administration - oral - recital - intravenous - continuous - intramuscular - intrathecal - inhaled Treatment duration - according to - disease severity - permanence of microorganism in place of infection serial cultures - antibiotic guidelines - generally, between 3 and 7 days (that can be longer or shorter) - re-evaluate patient 2-3 days after starting treatment - discontinue antibiotics 24 hours after signs and symptoms disappear ASSOCIATION OF ANTIBIOTICS Reasons - preventing resistance - synergistic effect - enlarge spectrum of action Situations - infections by various germs - unknown gem infection in critically ill patient - seriously infections in inaccessible tissues / inaccessible bacteria (e.g. tuberculosis, effective tuberculosis (TB) treatment is difficult due to the structure and chemical composition of the mycobacterial cell wall) BACTERIAL RESISTANCE Growing problem Every day drug resistant strain appear Why is this? - misuse of antibiotics - inadequate doses - duration of therapy (short or long) - use broad spectrum of antibiotics More serious in hospitals Causes - natural selection of resistance strains - spontaneous mutations - transfer of important information between bacteria Mechanisms - inactivation of antibiotic - decreasing antibiotic permeability - modification of target structures How antibiotic resistance happens - lots of germs, a few are drug resistant - antibiotics kill bacteria causing the illness, as well as good bacteria protecting the body from infection - drug-resistant bacteria are now allowed to grow and take over - some bacteria give their drug-resistance to other bacteria, causing more problems How antibiotic resistance spreads ANTIBIOTIC THERAPY CONSIDERATION Bacteria provoke infection in the host Host activates immune response Antibiotic player bacteriostatic or bactericidal effect Pathogen reacts to antibiotic by developing resistance mechanisms Antibiotic can alter normal physiology of patients as a result of toxicity or secondary effects Host interacts with antibiotic, thereby determining associated pharmacokinetics RATIONAL USE OF ANTIBIOTICS Common for clinicians to inappropriately prescribe antibiotic treatment Some of the reasons that dentist may misuse antibiotics include - inadequate knowledge about management of infections - pressure from patients requesting antibiotics - failure to consider treatments other than systemic antibiotics (e.g. surgery) - belief that broad-spectrum antibiotics are the most effective treatment - demands of running a busy practice Management of endodontic infections is best achieved through proper root canal debridement, disinfection, and drainage of the abscess and discourages the use of systemic antibiotics due to their  inability to reach necrotic tissue and their contribution to antibiotic resistance and Clostridium difficile infection Consideration when deciding whether or not to prescribe antibiotic treatment - overall health and immunity of the patient - pre-existing conditions of the patient - type and location of the infection - whether the infections show signs of spreading - if the condition can be treated with surgical treatment - if the patient has symptoms other than localised pain Antibiotic use for the urgent management of pulpal- and periapical-related dental pain and intra-oral swelling - new guideline recommends against using antibiotics for most pulpal and periapical conditions and instead recommends only the use of dental treatment and,if needed, over- the-counter pain relievers such as acetaminophen and ibuprofen - instead of prescribing antibiotics, dentists should prioritise dental treatments such as pulpotomy, pulpectomy, nonsurgical root canal treatment, or incision and drainage for symptomatic irreversible pulpitis, symptomatic apical periodontitis and localised acute apical abscess in adult patients with a normal immune response - if a patient's condition progresses to systemic involvement, showing signs of fever or malaise, then dentists should prescribe antibiotics ANTIBIOTIC PROPHYLAXIS IN DENTISTRY Antibiotic prophylaxis prior to dental procedures should be reserved for patients at high risk of post- treatment complications If antibiotic prophylaxis is used, it should be given in a single dose prior to the procedure Post-intervention prophylaxis or multi-day guidelines are not recommended in any case Prophylaxis of infective endocarditis - most frequent cause of infective endocarditis after dental procedures is Streptococcus viridans - rare and serious disease - reduce the risk of infectious endocarditis it is more important to maintain a good oral hygiene - antibiotic prophylaxis prior to dental procedures should only be administered in patients at high risk of bacterial endocarditis before dental procedures considered to be at high risk of bacteremia Patients at high risk of infective endocarditis - acquired valve disease with stenosis or insufficiency - hypertrophic cardiomyopathy - structural congenital heart disease - carrier of valve prosthesis - previous infectious endocarditis Patients with prosthetic joint implants - in general, antibiotics are not recommended prior to dental procedures for patients with prosthetic joint implants in cases where antibiotics are deemed necessary, it is most - appropriate that the orthopedic surgeon recommend the appropriate antibiotic regimen Antibiotic prophylaxis to prevent implant failure - no evidence for the routine use of antibiotic prophylaxis to prevent post-implant infections in healthy patients  - antibiotic prophylaxis to prevent implant failure would only be recommended in complex cases and in immunocompromised patients What procedures? - bleeding procedures - procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. - in dentistry - tooth extraction, periodontal surgery, dental implant, endodontics - antibiotic prophylaxis is not suggested in anesthetic injections through noninfected tissue, taking dental radiographs, placement or adjustment of orthodontic appliances, shedding of primary teeth, and bleeding from trauma to the lips or oral mucosa Antibiotics - amoxicillin 2g oral, 1 hour before intervention - ampicillin 2g IM or IV 30 minutes before Antibiotics when being allergic to penicilin - cephalexin 2g oral (not if history of anaphylaxis or angioedema with penicillin) - macrolides clarithromycin 500mg or azithromycin 500mg) - clindamycin 600mg oral ANTIBIOTICS CLASSIFICATION Antibiotics that inhibit bacterial wall synthesis - betalactam antibiotics - glycopeptides Antibiotics that alter the cytoplasmic membrane Antibiotics that inhibit protein synthesis - aminoglycosides - tetracylcines - macrolides - lincoasmides - mupirocin Antibiotics that affect the synthesis of nucleic acids - quinolones - metronidazole - trimethoprim - sulphonamides BETALACTAM ANTIBIOTICS β-lactam ring - bactericial antibiotics - inhibit bacterial cell wall synthesis - commonly used antibiotics - wide therapeutic index very safe - low toxicity digestive system are the most common side effects (taken orally) nausea, vomits, abdominal pain, dyspepsia - not teratogenic Classification - penicillins - cephalosporins - carbapenems N - monobactams O - beta-lactamase inhibitors β-lactam all contain moiety and compromise over a dozen classes of antibacterial compounds Mechanism of action - bactericide - inhibits the synthesis of bacterial wall inhibit the transpeptidase activity of the penicillin binding proteins (PBP) (enzymes participating in the synthesis of the bacterial wall) 3 direct defence mechanisms - inactivation of antibiotic - by enzymes beta-lactamases = proteins that bind to beta-lactates and produce inactivation of antibiotic - reduce uptake into the cell - loss of prints and pumps of influx or active effluent from the cells - alteration of target enzyme - produce enzymes with less affinity for beta-lactams Resistance mechanisms - for example a amoxicillin will work on a bacteria that has not created a to betalactams resistance - but when it synthesised enzyme beta lactamases it creates resistance towards the antibiotic bacteria has become resistant to amoxicillin by betalactamases - beta lactamase inhibitors clavulanic acids - beta lactamase inhibitors prevents the action of beta lactamases and bacteria again becomes sensitive to amoxicillin - porines alteration - antibiotic entreat through porines and destroy bacteria - porines are modified avoiding entry of antibiotic while letting the nutrients pass through - antibiotic is actively transported out of cell by effluent pumps - modification of PBPs - PBP is found in membrane of bacteria and synthesise the wall - amoxicillin inactivates the PBP by binding to it - PBP has mutated continues synthesising bacterial wall because amoxicillin cannot bind to these altered PBPS Pharmacokinetics properties - oral or parental administration - cross the BBB - good tissue concentration wide distribution all over the body with appropriate serum and tissue concentrations at most of the compartments (peritoneal, pleural, bile) - cross placenta barrier nevertheless they are safe during pregnancy (safe antibiotics) - little metabolism remain active until they are eliminated - renal elimination Adverse reactions - hypersensitivity reactions urticaria, angioedema (pharmacological group most frequently related to this reactions) - anaphylactic shock, bronchospasm (severe dyspnoea) - less frequent adverse reactions (with long term use) - haematological - fever, eosinophilia, haemolytic anaemia - renal toxicity - renal failure Classification - penicillins - cephalosporins - carbapenems - monobactams - beta-lactamase inhibitors  PENICILLINS 1928 Alexander Fleming Most commonly used beta lactam antibiotics Bacteria defend themselves with penicilinase production (beta-lactamase) Penicilin types - natural penicillins - penicillin G (IM, IV) - penicillin G procaine (IM) - long effect 4-5 days - penicillin G benzathine (IM) - long effect 26 days - penicillin V (ORAL) - resistant to acid degradation - penicillinase resistant - cloxacillin (oral, parenteral) - methicillin - amino penicillins - expand spectrum to gram negative (no antipseudomonas) - amoxicillin (oral - penicillin with better oral bioavailability) - ampicillin (IM) - broad spectrum penicillins (parenteral) - antipseudomonas - piperacillin - ticarcillin - betalactamase inhibitors - clavulanic acid (amoxicillin-clavulanate, oral or IV) - sulbactam (ampicillin-sulbactam, parenteral) - tazobactam (piperacillin-tazobactam, parenteral) Antimicrobial spectrum - natural penicillins - penicillin G - gram positive cocci (except S. aureus) - gram negative cocci - gram positive bacillus - resistant to penicillinases - cloxacillin - Staphylococcus (MSSA) - aminopenicillins - amoxicillin, ampicillin - gram positive cocci (except S. aureus) - gram negative bacillus (except Pseudomonas) - anti-pseudomonal - piperacillin - gram negative bacillus Main use - respiratory infections - pharyngitis - Streptococcus pyogenes penicillin G or amoxicillin - otitis - Streptococcus pneumoniae and H. influenza, that produces betalactamases amoxicillin-clavulanic acid - bronchitis in COPD - Streptococcus pneumoniae and H. influenza, that produces betalactamases amoxicillin-clavulanic acid - skin and soft tissue infections - cellulitis - Streptococcus pyogenes amoxicillin - erysipelas - S. aureus amoxicillin-clavulanic, cloxacillin - bone and joint infections - S. aureus cloxacillin + gentamicin - sexually transmitted diseases (STDs) - gonorrhea and syphilis penicillin G - endocarditis - Streptococcus viridans amoxicillin - Staphylococcus aureus cloxacillin - Enterococcus ampicillin + gentamicin Penicillin V - oral Penicillin G endocarditis - aqueous - IM, meningitis - procaine - IM, pneumonia, gonorrhea - benzathine - IM, syphilis, tonsillitis prophylaxis - odontogenic infections necrotising gingivostomatitis Aminopenicillins - major spectrum than natural penicillins - ear infections, respiratory, odontogenic - can be used in pregnancy Resistant to penicillinases - cloxacillin - first choice in Staphylococcus infections (skin and soft tissue) Antipseudomonal - piperacillin - hospital use, parenteral Adverse reactions - hypersensitivity reaction (5-10%) - cross reactivity with other betalactams - gastrointestinal problems - rare side effects - haematologic - haemolytic anaemia - liver - elevated transaminases - renal toxicity - renal failure Hypersensitivity reactions - immediate - 2-3 mins - appear within second or minutes after administration of drug urticaria, pruritus, dyspnea (laryngeal oedema, bronchospasm) and anaphylactic shock - rapid - 1-72 hours - delayed - appear after several days of treatment skin eruption Interaction - oral contraceptives - ampicillin decrease its effect - bacteriostatic antibiotics - reduced efficacy of penicillins by antagonism between bactericidal and bacteriostatic antibiotics - aminoglycosides - synergistic effect with beta-lactams CEPHALOSPORINS E.g. cloxacillin or antipseudomonal penicillins are often used in sever infections or when other antibiotics have failed Bactericidal More expensive than penicillins MOst of this group of antibiotics are administrated parenterally and there are oral cephalosporins being used as an alternative in moderate infections Share 7-ACA group (7-aminocephalosporanic acid) formed by the fusion of two rings - beta-lactam - duhydrothiazine - intrinsically resistant to some beta-lactamase Generations of cephalosporins - acocorindg to their spectrum of activity - first generation - cefadroxil, cefazolin, cefalexin - second generation - cefaclor, cefoxitin, cefuroxime - third generation - cefotaxime, ceftriaxone, cefixime - third generation - IV, in hospital use - antipseudomonal - ceftazidime - fourth generation - IV, hospital use - cefepime - fifth generation - IV, in hospital use - ceftaroline 1st generation - cefadroxil (oral, every 12 hours) - cefazolin - cefalexin (oral) - gram positive cocci (included Staphylococcus that produced lactamases) (MSSA) - less active against gram negative 2nd generation - cefaclor (oral) - cefoxitin - cefuroxime (oral, buccal cellulitis in children) - gram positive cocci - more gram negative (not Pseudomonas) and anaerobic (Bacteroides fragilis) 3rd generation - antipsedomonal - ceftazidime (IV, in hospital use) - very active against gram negative including Pseudomonas (only ceftazidime) - lose activity against gram positive 4th generation - cefepime (IV, hospital use) - broad spectrum - very active agains gram negative 4th and 5th gen. - activity against gram positive have the broadest - cross BBB spectrum of all 5th generation - ceftaroline - IV, in hospital use - activity against S. aureus methicillin-resistant Oral route - cephalexin (1st generation) - cefadroxil (1st generation) - cefaclor (2nd generation) - cefuroxime (2nd generation) - children's infection of oral cavity - ceftibuten (3rd generation) - cefixime (3rd generation) Parenteral route - rest of them Clinical use - prophylaxis before surgical procedures, including major oral surgery - pneumonia in patents with risk factors (elderly, hospitalised) - neutropenia patients with fever - pseudomonas infections - oral infections - no advantages over penicillins Pharmacokinetics - short half-life - every 4-8 hours - cefadroxil - every 12 hours (1st generation) - ceftriaxone - every 24 hours (3rd generation) - most of them have renal elimination - need adjust dose if renal failure - some biliary elimination (ceftriaxone) Adverse reactions - hypersensitive reactions (cross reactions with penicillins, 10-15%) - nephrotoxicity can enhance nephrotoxicity of o the drugs - haemorrhaging ractions - abnormal platelet function - phlebitis when administrated by peripheral vein - diarrhoea when administrated orally Drug interactions - potentiation of nephrotoxicity - aminoglycosides - diuretics CARBAPENEMS Imipenem - rapid metabolism by renal dipeptidase - administrated with cilastatin (dipeptidase inhibitor) IV administration - broad spectrum antibiotic - gram positive - gram negative aerobic and anaerobic including Bacteroides fragilis (resistant to other beta-lactamas) - must be restrictive serious nosocomial infections, caused by various germs - adverse reactions - not frequent - hypersensitivity reactions (cross with other penicillins) - phlebitis - seizures - IV, in hospital use only Other carbapenems - IV, in hospital use only - metropenem - ertapenem  MONOBACTAMS IV, in hospital use Aztreonam - narrow spectrum bacterial infection caused by gram negative aerobic bacteria (mainly Enterobacteriaceae and Pseudomonas) - not a first-line antibiotic - used as an alternative to aminoglycosides - hospital infection - parenteral route - no cross-reactivity with penicillins or cephalosporins useful if patient i allergic to these antibiotics - very resistant to beta-lactamases BETA-LACTAMSE INHIBITORS Lack of antibacterial activity act by inhibiting penicillinase or beta-lactamases from different bacterial species enhance the activity and spectrum of penicillin and cephalosporins Clavulanic acid = clavulanate - inhibits beta-lactamases of gram negative and gram positive bacteria - commercialised associated with amoxicillin - oral and IV - indications - respiratory infections - otitis - urinary tract infection (UTI) - orla infections - adverse reactions - diarrhoea and gastrointestinal disorders Tazobactam - commercialised associated to piperacillin - route of administration - IV Sulbactam GLYCOPEPTIDES Interfere will cell wall synthesis other glycopeptides - teicoplanin Bactericide Spectrum - gram positive cocci - drug of choice to methicillin resistant Staphylococcus (MRSA) IV, hospital use only Vancomycin - belongs to family of glycopeptides - interferes with cell wall synthesis - bactericide - spectrum - gram positive cocci - drug of choice to Methicillin resistant Staphylococcus (MRSA) - pharmacokinetics - IV more frequently used - orally administrated (not absorbed) - treatment of pseudomembranous colitis - side effects - most common one is Red man syndrome (due to histamine release) pruritus, erythema and flushing of head and thorax (upper part of thorax), secondary to rapid infusion - nephrotoxicity - ototoxicity - narrow therapeutic range - required plasma levels (peak and valley)  - IV vancomycin - indicated from serious infections caused by gram positive bacteria sensitive to vancomycin that can not be treated or that are resistant to other antibiotics such as penicillins and cephalosporins - endocarditis, bone infestations (osteomyelitis), pneumonia, soft tissue infections - orally vancomycin - antibiotic with broad spectrum (clindamycin) may produce a modification of normal intestinal flora - one of the germs that can grow exorbitantly is Clostridium difficult - beside growing, it produces a toxin that causes inflammation and diarrhoea in the colon (colitis) - when colitis is very severe = pseudomembranous colitis (orally administered vancomycin for its treatment) AMINOGLYCOSIDES Important antibiotics for their activity against Enterobacteia and other gram negative (especially Pseudomonas) that are often resistant to other antibiotics Mechanisms of action - bactericides - inhibit protein synthesis (inhibit translation of mRNA by binding irreversibly to 30S subunit of ribosomes) Antibacterial activity - gram negative aerobic, including P. aeruginosa (no activity against anaerobic) - synergistic effect with beta lactam antibiotics IV, in hospital use Pharmacokinetics - basic substances, low oral absorption - IV and IM administration - low intracellular tissue concentration except in kidney tubule cells and in perilymph - not metabolised - excreted in urine in their active from Indications - severe urinary infection - abdominal infections, endocarditis, osteomyelitis Adverse reactions - high toxicity (especially in treatment > 7 days) - vestibular ototoxicity (irreversible) - nephrotoxicity - at high doses neuromuscular blocking Classification - parenteral administration - gentamicin - tobramycin - amikacin - streptomycin (tuberculosis treatment) - orla administration (nor absorbed) - neomycin - paromomycin Streptomycin - IM - used in treatment of tuberculosis Neomycin - oral route (not absorbed) - treatment of hepatic encephalopathy - neomycin (not absorbed) reduces ammonia produced by bacteria in intestine preventing the onset of encephalopathy ass complication of liver disease Paromomycin - oral route (not absorbed) - parody in is active against Entamoeba history ti a Post-antibiotic effect (PAE) - means persisting bacterial growth inhibition through antibiotic contraction is below minimum inhibitory concentration (MIC)  - higher the peak concentration achieved by antibiotic greater the duration of post antibiotic effect - aminoglycosides and quinolones are this characteristics - concentration-dependent action antibiotics Narrow therapeutic range / - to avoid toxicity is recommended to monitor plasma concentration plasm concentration - necessary to adjust the dose at the beginning of treatment, in combination therapies to assess the possible interactions, when treatment is not effective to assess compliance, or suspected toxicity Monitoring of plasma levels - to avoid toxic effects, plasma levels must be measured - peak - antibiotic maximum concentration - measured a few minutes after finishing IV perfusion - valley - minimum concentration of antibiotic - concentration just before the next dose - when the "peak" and "valley" are not in therapeutic range, dose or dose interval are modified TETRACYCLINES Chlortetracycline Oxytetracycline Minocycline Doxycycline Mechanism of action - bacteriostatic - block protein synthesis, bonding to 30S ribosomal subunit - sometimes bactericides (very high doses) Antibacterial spectrum - aerobic gram positive and aerobic gram negative not 1st choice - actinomyces, rickettsia, mycoplasma, chlamydia, spirochaetes - at high doses active against protozoa Reduces use today due to resistance Resistance - prevent transport inside cell (gram negative) - transport of antibiotic form inside to outside cell (gram positive) - can be cross-resistance between antibiotics of the same group Classification - short action - chlortetracycline (topical use only) - oxytetracycline (topical use only) - long action - doxycycline - minocycline Pharmacokinetics - oral administration - variable half-life and bioavailability - decreased absorption with food (specially with milk) and with the presence of cations (calcium, magnesium, aluminium) - high lipid solubility: easy to diffuse across membranes - cross the placenta, they have affinity for bone and teeth of foetus - contraindicated in pregnancy and in children - renal clearance (and doxycycline through bile secretion) Indications - Rickettsiosis - Brucellosis - sexually transmitted diseases - chlamydia infections  - gonococcal infections - often the presence of Neisseria gonorrhoeae and Chlamydia trachomatis together possible to use a single dose of beta-lactam followed by tetracycline - in the case of gonorrhea in patients allergic to beta-lactams, tetracyclines can be used -borrelia - lyme's disease -mycoplasma -Helicobacter pylori (+ metronidazole) -grnaumola inguinale caused by Klebsiella granulomatis -acne Adverse reactions - digestive - nausea, vomiting, esophagitis (including oesophageal ulcers). alterations in the oral and pharyngeal mucosa. black tongue due to fungal infection - kidney - increased bun (blood ureic nitrogen) - bones - decreased bone growth - teeth - enamel colour alteration (grey pigmentation) - benign intracranial hypertension (children) - thrombophlebitis - photosensitivity - teratogenic Contraindications - children - pregnancy - breastfeeding Interactions - may antagonise the effect of bactericidal antibiotics (betalactams) - reduce the effect of oral contraceptives - enhance the effect of oral anticoagulants - their absorption is decreased when administered with antacids and other drugs containing Ca, Mg or Fe MACROLIDES Macrocyclic lactose ring Bacteriostatic - inhibit protein synthesis by binding to ribosomal 50S subunits (as clindamycicn and chloramphenicol) - prevent translocation of amino acids from A to P site Traditionally used as alternatives of beta-lactams in pregnancy but embryo-toxic effects have been described recently Low toxicity but usually ineffective due to low plasma concentrations Antibacterial spectrum - all macrolides have a similar broad spectrum - gram positive (not Staphylococcus) both aerobic and anaerobic - few gram negative (clarithromycin and azithromycin) - intracelularni bacteria (mycoplasma, chlamydia) Pharmacokinetics - erythromycin - inactivated by low gastric pH (enteric coated tablets) - oral bioavailability of erythromycin varies considerably between preparation - bioavailability of clarithromycin is more than twice that of erythromycin - bioavailability of a zithromax in is 1.5 times that or erythromycin - widely distributed due to its lipid solubility but do not cross BBB - cross placenta, some embryotoxic effects have been described - erythromycin and azithromycicn hepatic metabolism (P450) and biliary clearance - clarithromycicn hepatic metabolism and renal elimination Classification - lactose ring of 14 carbon atoms - erythromycin (every 6-8 hours) - clarity romy in (every 12 hours) - lactose ring of 15 carbon atoms - azithromycin (every 24 hours) - lactose ring of 16 carbon atoms - spiramycin (every 6-8 hours) Indications - rarely first choice, except Legionella pneumonia and Mycoplasma pneumonia - alternative to beta-lactams (e.g. if allergy) - erythromycin - pneumococcal infections, pharyngitis in penicillin-allergic - azithromycin - respiratory infections Haemophylus influenza - clarithromycicn - Helicobacter pylori infections - any of these can be alternative to beta-lactams in oral infections an din prophylaxis of endocarditis Resistance mechanisms - gram negative natural resistance (difficulty passing through cell membrane of weak bases) - chromosomal mutation in subunit 50S (methylation) - efflux of antibiotic - drug inactivation - cross resistance between various components of this group Adverse reactions - low toxicity, they are very safe - gastrointestinal problems (most common) abdominal pain, nausea, vomiting (more frequent with erythromycin) - thrombophlebitis when administered IV (slow infusion) - IM administration is not used due to pain that it produces - QT prolongation on ECG (avoid in patients with risk of arrhythmias) - candida infections - hepatotoxicity (liver cholestasis) - deafness (reversible, with high doses or erythromycin in elderly patients or patients with renal failure) Interactions - reduce hepatic metabolism of other drugs, especially erythromycin - e.g. oral anti-coagulants, carbamazepine, methylprdenisolone avoid erythromycin in these patient (clarithromycicn and a zithromax in - less interactions) Fidaxomicin administered orally (minimal oral absorption, local effect) - - different mechanism of action than other macrolides - bactericidal - inhibits bacterial RNA polymerase (specificity for C. difficile) - inhibits sporulation of C. difficile in vitro - indications - for Clostridium difficult infection if the risk of recurrence is high (alternative to oral vancomycin) LINCOSAMIDES Lincomycin - first antibiotic of this group - produced by fungus Streptomyces lincolnensis - mechanism of action - bacteriostatic - inhibiting protein synthesis by binding to 50S subunit of bacterial ribosome - resistance - similar to erythromycin - cross-reaction between both lincosamides - could be cross-resistance to erythromycin Clindamycin - antibacterial spectrum - gram positive and some protozoa - no activity against aerobic gram negative - pharmacokinetic properties - oral / IM / IV topical - good oral absorption - good distribution  - high concentration in bone - does not cross BBB - crosses placenta - hepatic metabolism and biliary elimination - indications - anaerobic infections - intra-abdominal infections - pneumonia, empyema, lung abscess - can be an alternative to erythromycin in oral infection in patients allergic to penicillin - alternative to penicillins in suspected Staphylococcus infections, e.g. osteomyelitis and arthritis - adverse reactions - most frequent - gastrointestinal pain, diarrhoea (30-35%), nausea, vomiting - most important (2% of diarrhoea) pseudo membranous colitis - other - muscular pain and thrombophlebitis - allergic reactions Diarrhoea secondary to antibiotic treatment broad spectrum antibiotic high doses modification of intestinal flora long term treatment diarrhoea (C. difficult colitis) C. difficile growth and toxin production Pseudomembranous colitis - broad spectrum antibiotic treatment can produce a modification of normal intestinal flora - one of germs that can grow is C. difficile - besides growing, it produces a toxin that causes inflammation and diarrhoea in the colon (colitis) - when this turn into sever ulcerative pseudomembranous colitis - treatment - discontinue the antibiotic treatment - astringent diet - first choice - vancomycin (oral) - fidaxomicin (oral) (if high risk of recurrence) - alternative - metronidazole (IV or oral) MUPIROCIN Natural product produced by Pseudomonas fluorescens Bacteriostatic BUT at high concentration is bactericidal Topical use Binds to transfer RNA competing with isoleucine and inhibits protein synthesis Spectrum - broad - including methicillin-resistant Staphylococcus aureus (MRSA) Indications - skin infections - impetigo, folliculitis, furunculosis - skin decolonisation of MRSA Adverse reactions - local (itching, eczema) QUINOLONES Chemical structure - dihydroquinolein ring Mechanism of action - bactericide  - inhibit DNA gyrase - interfere in replication and DNA synthesis Classification - 1st generation (no longer marketed in the EU) - nalidixic acid - pipemidic acid - 2nd generation - norfloxacin - ciprofloxacin - 3rd generation - levofloxacin - 4th generation - moxifloxacin Antibacterial spectrum - all active against gram negative - 3rd and 4th generation also against gram positive - 4th generation are the only ones active against anaerobic bacteria - ciprofloxacin has good antipseudomonal activity Bacterial resistance - cross-resistance between them - no cross-resistance with otero antibiotics - mechanism of resistance - enzymatic modifications of DNA gyrase - impermeability - major problem with gram negative (strict selection patients) Pharmacokinetics - quick oral absorption and good bioavailability - food delay their absorption - low plasma protein binding - good tissue distribution - cross placenta and are eliminated in breast milk - 2nd generation hepatic metabolism and renal elimination - 3rd and 4th generation renal elimination in active form - high concentration in urine, useful in urine infections Used in a wide spectrum of bacterial infections, such as urinary and respiratory tract infections (if Pseudomonas aeruginosa is suspected, ciprofloxacin is recommended), genital and gastrointestinal infections, skin, bone and joint infections In March 2019, they were reviewed at a European level due to the appearance of incapacitating, long- lasting and potentially irreversible ADRs, which affect the nervous and musculoskeletal systems Due to the severity of the reactions observed and given that they can occur in previously healthy people, quinolones will be prescribed based on a careful benefit/risk assessment In patients with severe infections caused by sensitive bacteria, quinolones are an important therapeutic option, but resistances are a big problem Should not be used in mild and/or self-limiting infections Its use should be restricted to - multi-resistant bacteria - infection in tissues with poor accessibility to other drugs - contraindication to other antibiotics Adverse reactions - mild and rare - incapacitating, long-lasting and potentially irreversible ADRs have been described - gastrointestinal nausea and diarrhoea (the most common) - leukopenia / thrombocytopenia / hemolytic anemia In G6PD deficiency - CNS - peripheral neuropathy - psychosis, anxiety, insomnia, depression, hallucinations, suicidal thoughts, confusion - hearing or vision disturbances, taste or smell disturbances - dizziness, headache, sedation, tremor, abnormal movements, seizures - joint toxicity (accumulation in articular cartilage) joint oedema, arthralgia, Achilles tendonitis, tendon rupture, myalgia, muscle weakness - hepatotoxicity (moxifloxacin) - C. difficile and MRSA infection - QT prolongation on ECG, aortic aneurysm, valvular insufficiency and cardiac regurgitation Contraindications - pregnancy - best feeding - not prescribed in children affect the growth of plates Interactions - enzymatic inhibitors - antacids with Al and Mg decrease absorption of quinolones RIFAMYCINS Bactericide Inhibit nucleic acid synthesis by inhibiting RNA polymerase Rifamycin natural antibiotic produced by Streptomyces mediterranei Derivatives rifampicin rifabutin Treatment of choice fro combination therapy of tuberculosis Spectrum - mycobacteria (tuberculosis and atypical) - gram positive cocci (Staphylococcus aureus) - gram negative cocci (Neisseria) Indications - combination therapy - S. aureus methicillin resistant infections - osteomyelitis (along with ciprofloxacin) - prophylactic treatment for meningitis Toxicity - hepatic elated liver enzymes, hepatitis with coolest asks (elevated bilirubin) usually reversible with drug withdrawal - staining of body fluids (contact lenses) - hypersensitivity reactios Interactions - with multiple drugs (usually decreases the effect of drug by inducting cytochrome P450 metabolism) Rifampycin - oral and IV route (dose 600mg/per day maximum dose in adults) - hepatic metabolism and elimination - hepatotoxic - potent inducer of hepatic microsomal enzyme (CYP450) and can interfere with metabolism of other drugs decreasing its effect - orange staining of physiological secretion (urine, faeces, tears) (stain contact lenses) - enzyme inducer of cytochrome P450 system that reduces plasma levels of other drugs anti-coagulants contraceptives corticosteroids oral hypoglycaemic agents benzodiazepines digoxin Tuberculosis treatment (6 months)  METRONIDAZOLE Mechanism of action - inhibits DNA synthesis once taken up by anaerobes, it is non-enzymatically reduced which causes production of metabolites that are toxic to anaerobic cells - bactericidal Anti-microbial spectrum - anaerobic bacteria Bacteroides, Clostridium, Peptococcus, Peptostreptococcus - protozoa Amoebas, Trichomonas, Giardia - filaria Pharmacokinetics - oral, IV, topical vaginal - good distribution - crosses BBB and placenta - excreted in breast milk - elimination by hepatic metabolism (80%) - renal elimination of active metabolites Indications - Trichomoniasis, Amebiasis, Giardiasis - anaerobic bacterial infections - intraabdominal - prophylactic colon surgery - vaginitis - pelvic inflammatory disease - Helicobacter pylori (breath test positive) - Pseudomembranous colitis Alternative to penicillins in odontoceti infections in allergic patients or when suspected anaerobic lactamases producers Acute necrotising ulcerative gingivitis (Vincent's angina) tinidazole can also be used Periodontal disease, pericoronaritis Adverse reactions - rare - gastrointestinal problems (minimised when administrated with food) - peripheral neuropathy - superinfection - dry mouth - metallic taste Interactions - inhibits metabolism of anticoagulants - with ethanol disulfiram-like reaction (headache, tachycardia, dizziness, nausea, vomiting, sweating, hypotension) - enzyme inducers increase its metabolism - enzyme inhibitors inhibit its metabolism - contraindicated in 1st trimestre of pregnancy SULPHONAMIDES Classification sulfisoxazole (not marked in Spain) sulfamethoxazole sulfasalazine sulfadiazine Chemical structure - sulphanilamide group Mechanism of action - bacteriostatic - competitively inhibit PABA (p-aminobenzoic acid) interfere in folic acid synthesis (required for nucleic acid synthesis) Antibacterial spectrum - gram positive, gram negative, chlamydia, toxoplasma - no activity against anaerobic bacteria Resistance - chromosomal mutations - transfer of plasmids Pharmacokinetics - good absorption / high bioavailability - variable protein binding (careful with children) - hepatic metabolism acetylation - renal elimination - cross placenta and are eliminated in breast milk Classification - good absorption and short half-life sulfisoxazole urinary tract infections - good absorption and long half-life sulfamethoxazole systemic infections - poorly absorbed sulfasalazine sterilise digestive tract ulcerative colitis - topical sulfadiazine Association with trimethoprim inhibits duhydrofolate reductase blocks folic acid synthesis sulfamethoxazole + trimethoprim = cotrimoxazole Indications - uncomplicated urinary infections - prostatitis (cotrimoxazole) - toxoplasmosis (cotrimoxazole) - respiratory infections (cotrimoxazole) - otitis media - pneumocystis pneumonia (cotrimoxazole) - brucellosis, salmonellosis - sterilise gastrointestinal tract (sulfasalazine) - ulcerative colitis (sulfasalazine) - cotrimoxazole also in bone infections (osteomyelitis) Interactions - cotrimoxazole displace anticoagulants from their binding to proteins TRIMETHOPRIM Bacteriostatic - inhibitor of dihydrofolate reductase, essential for DNA synthesis Enzyme effectiveness 50,000 times higher in microorganisms than in mammals wide therapeutic margin Indications - widespread dissemination of resistance among numerous bacterial species - almost exclusive use in the treatment of genitourinary and respiratory infections - eye drops with the combination trimetoprim + polimixin B are used in the treatment of non-chlamydial non-gonococcal bacterial conjunctivitis and eye surgery prophylaxis Adverse reactions - GI type, mild and transient - do not use in pregnancy and lactation ANTIVIRAL DRUGS Virus - intracellular organisms that replicate, using the same mechanisms of synthesis of the host organism - due to that circumstances, it is difficult to obtain effective antiviral agents and with no toxicity to human body  - antivirals prevent replication of the virus, but that viral clearance requires the normal function of patient's immune mechanisms Viral infection - adsorption of vision of membrane receptors - entry into cell fusion of their membranes or by endocytosis - release of nucleic acid and protein synthesis - duplication polymerase (DNA-DNA) - transcription transcriptases (DNA-RNA) - reverse transcription retrotranscriptases (RNA-DNA) - breakage post-translational proteins proteases Viral infections are more common than bacterial Mild and self-limiting Normally only require symptomatic treatment Exceptions - HIV - immunocompromised patients Antivirals prevent replication of virus Viral infection can be acute - rapid onset of disease, brief period of symptoms (usually less 7-15 days) and are solved spontaneously chronic - can last the entire life of the patient and can produce irreversible damage in some organ Classification - depending on spectrum - effective against HSV (Herpes simplex virus) and VZV (Varicella Zoster virus) - effective against CMV (Cytomegalovirus) - effective against Influenza virus - effective against HIV (human immunodeficiency virus) - antiretrovirals - reverse transcriptase inhibitors - protease inhibitors - integrate inhibitors HSV AND VZV Acyclovir - orally, IV, topical, ophthalmic - inhibits viral DNA polymerase, guanosine nucleoside analog - adverse reactions - diarrhoea, gastrointestinal intolerance, joint pain, dizziness - clinical use - immunocompromised - HSV (reactivation in organ transplantation, prophylaxis and treatment), VZV - immunocompetent - HSV genital, orolabial (topical administration is of little value in labial and genital herpes), herpetic keratoconjunctivitis, neonatal herpes, herpes encephalitis, VZV Valacyclovir - prodrug of acyclovir - orally administrated at longer interval as (every 12-24h) CMV Ganciclovir - inhibits DNA polymerase  - administered IV - treatment of CMV in immunocompromised patients (HIV and transplant patients) - teratogenic - limited use due to its toxicity use in disseminated infection in interstitial pneumonia and retinitis - adverse reactions - neutropenia and thrombocytopenia (reversible) - neurological disorders (delirium, amnesia, psychosis) Valganciclovir - prodrug of ganciclovir - administered orally INFLUENZA VIRUS Oseltamivir - neuraminidase inhibitor (neuroaminidase enzyme is important both for viral entry into uninfected cells and for the release of recently formed virus particles) - prevents viral spread to other cells - active against influenza A and B virus, and against porcine influenza A virus (treatment and prophylaxis) - administered orally - adverse reactions- nausea, vomiting, headache and abdominal pain Zanamivir - oral inhalation - well tolerated, but can produce bronchospasm in asthmatic patients HIV RNA viruses from the family of retroviruses In 1984, it was shown to be agent responsible for AIDS Step to change from RNA to DNA requires an enzyme, reverse transcriptase (then the DNA integrates in genetic material of infected cell) HIV treatment antiretrovirals - reverse transcriptase inhibitors - enzyme that uses RNA as a template to synthesis DNA - protease inhibitors - enzymes that breaks down large proteins that have been synthesised from genetic material - integrase inhibitors - integrase - catalyses the insertion of viral DNA into host cell genome Combination of several drugs (3 or 4 drugs) from different groups (HHART = highly active antiretroviral treatment) Antiretrovirals - reverse transcriptase inhibitors - nucleoside analogs - lamivudine, emtricitabine, abacavir - nucleotide analogs - tenofovir - no analogues - rilpivirine, doravirine - protease inhibitors - indinavir, darunavir - integrase inhibitors - dolutegravir, bictegravir - entry inhibitors - enfuvirtide (fusion inhibitor), maraviroc (CCR5 receptor antagonist) Antiretroviral agents work to inhibit different stages of the HIV lifecycle - maraviroc blocks the binding of HIV to the host cell by targeting the CCR5 receptor, preventing viral entry - enfuvirtide inhibits the fusion of the viral envelope with the host cell membrane - reverse transcriptase inhibitors (e.g. zidovudine, efavirenz, tenofovir) block reverse transcriptase, the enzyme that converts viral RNA into DNA - raltegravir inhibits integrase, preventing the integration of viral DNA into the host cell's genome - protease inhibitors (e.g. saquinavir) block the maturation of new viral particles by inhibiting protease, an enzyme critical for processing viral proteins. Antiretroviral treatment - combination of several drugs (3 or 4 drugs) from the different groups (HAART = highly active antiretroviral treatment) - preferably, different groups to avoid resistance - treatment stops viral replication but does not cure the infection treatment for life - lifelong monitoring and if the patient get worse genetically analyse the virus to seek for drug resistances to guide drug regimen change What to do in case of accidental exposure to HIV (e.g. needle stick) - in case of needle stick 0.3% estimated risk of transmission - go to occupational health center - obtain blood samples patient and worker - assess risk / benefit of treatment - treat with antiviral drugs for one month and - follow up 6-12 months ANTI-FUNGAL DRUGS Later development than antibiotics Anti-fungal drugs are directed against fungi This tape of infections has increased in recent years Increased number of patients belonging to high risk groups such as with transplanted organs or HIV Most infections in healthy patients are cutaneous or affect mucous membranes and are mild Classification of mycosis - superficial - affects skin and mucous membranes of healthy and immunocompromised patients - mycosis affecting epidermis and skin appendages (i.e. nails and hair) due to dermatophyne fungi - examples - ringworms, sporotrichosis (subcutaneous mycoses), candidiasis - treatment is based on topical anti-fungal - deep or systemic - affect immunocompromised patients (AIDS, transplant patients) or treated with antibiotics or prolonged corticosteroid treatments - organs are affected fungaemia (presence of fungi in the blood) - examples - aspergillosis, candidiasis, histoplasmosis, cryptococcosis Factors to consider in the treatment - fungus - virulence - drug resistance - anti-fungal - pharmacology - effectiveness  - toxicity - host - competent - immunocompromised (tumours, haematological disease, HIV, organ transplant) Classification - affecting membrane permeability - amphotericin B - nystatin mechanism of action - azoles - terbinafin - affecting cell wall - echinocandins (caspofungin) Amphotericin B - binds to sterols present in the membrane of fungi variation in membrane permeability - most effective anti-fungal - of choice for most serious fungal infections - IV (hospital use) - adverse reactions - reversible nephrotoxicity in 1st weeks of treatment lower doses - lipidic formulations have less nephrotoxicity - nausea, fever, vomiting (patient is usually premedicated due to its high prevalence) - thrombophlebitis in the infusion line Nystatin - binds to sterols in the cell membrane, forming channels in the cell membrane, causing changes in membrane permeability. - administered topically, oral suspension, mouth washes - not absorbed orally - cutaneous or mucosal candidiasis (oral thrush) - prophylaxis in immunocompromised patients - little side effects - long-term diarrhoea - topical local irritation Azoles - broad-spectrum anti-fungal - inhibition of fungal ergosterol biosynthesis by inhibiting the enzyme 14-alpha-lanosterol demethylase - administred topically, orally, IV - adverse reactions - hepatotoxicity - topical administration - miconazole - fungal skin mycosis (ringworm), candidiasis - ketoconazole - fungal skin mycosis, candidiasis - clotrimazole - fungal skin mycosis, candidiasis - oral and IV administration - fluconazole - superficial and systemic mycosis (1st choice for systemic candidiasis) - itraconazole - when there is resistance to fluconazole, in superficial and systemic mycosis - voriconazole - when there is resistance to fluconazole, in systemic mycosis - posaconazole - one with the broadest antifungal spectrum - adverse reactions - head have, rash, nausea and vomiting, abdominal pain, diarrhoea, increased ALT, AST and alkaline phosphates - drug interactions - they are enzyme inhibitors (CYP450) - greta potential to cause clinically relevant drug interaction with oral anticoagulants, macrolides, statins Liver function controls on the use of systemic anti-fungals - prolonged anti-fungal treatment increases the likelihood of adverse reactions  - protocol to control liver function - at the start of treatment (baseline data) - after one month - if the patient develops symptoms such as nausea, anorexia, fatigue, jaundice, dark urine - monthly until end of treatment even when the patient does not have symptoms Allylamines - terbinafin - mechanism of action - interference with sterol biosynthesis by inhibiting the enzyme squalene monooxygenase - spectrum - dermatophytes, yeasts and mycelial fungi - of choice in dermatophytosis - pharmacokinetics - oral or topical administration - absorbed quickly and reaches high concentrations in skin, hair, nails (stay 3 months after discontinuation of the drug) and fat tissue - adverse reactions - gastrointestinal, taste (dysgeusia) and cutaneous hypersensitivity - 1 : 45,000 patients, idiosyncratic hepatic dysfunction (4-6 weeks after starting treatment) Echinocandins - Caspofungin - lipopeptide synthesized by the fungus Glarea lozoyensis - inhibits the synthesis of glucan, an essential component of the wall, disturbing the integrity of the fungal cell wall - spectrum - azole-resistant Candida. Aspergillus - only IV Mechanisms of antifungal drugs, which target various processes in fungal cells - terbinafine and tolnaftate inhibit squalene epoxidase, blocking the conversion of squalene to lanosterol, leading to a reduction in ergosterol synthesis - azoles (voriconazole, miconazole) inhibit 14-alpha-demethylase, disrupting the production of ergosterol, a key component of the fungal cell membrane - amphotericin B and nystatin bind to ergosterol in the fungal cell membrane, creating pores that disrupt membrane integrity - caspofungin and micafungin inhibit 1,3-beta-glucan synthase, preventing the synthesis of 1,3-beta- glucan, a vital component of the fungal cell wall - griseofulvin disrupts mitotic spindles, inhibiting fungal mitosis - flucytosine (5-FU) inhibits thymidine synthesis, interfering with fungal DNA and RNA production ORAL ANTI-FUNGALS Thrush can appear associated with use of antibiotics (for alteration of oral bacterial flora) or systemic disease or immunosuppression In the first case usually subsides after discontinuation of general antibiotic, in other cases oral antifungals are used Oral and / or mild oesophageal candidiasis are treated with nystatin, clotrimazole or miconazole Recurrent oral candidiasis, possibly associated with immunosuppression, is usually treated with fluconazole or itraconazole If patients have dentures remove the dentures at bedtime to allow tissues to heal when denture is inserted, apply antifungal to the denture as well as their mouth ANTISEPTICS AND DISINFECTANTS Antiseptics - local antiseptics = anti-microbial products that are applied topically to kill  microorganisms or inhibit their growth - disinfectants = substances applied to non-living objects to kill microorganisms and prevent infections - sterilisation = total and complete destruction of all microorganisms Good germicidal Broad spectrum Diffuse easily through necrotic tissues and pus Rapid and maintained activity Do not damage tissues Do not alter objects Not all antiseptics and disinfectants eliminate all germs - gram positive - gram negative - mycobacteria order of resistance - fungi (low to high) - virus - spores Classification - alcohols - ethanol - isopropyl - aldehydes - formalaldehyde - glutaraladehyde - oxidants - hydrogen peroxide - chlorinated compounds - chlorine - chloramine - iodinated compounds - povidone-iodine - biguanide - chlorhexidine - other - cetylpyridinium chloride - triclosan ALCOHOLS Ethanol and isopropyl - 70% is the optimal concentration to reduce surface tensions of bacteria - bactericidal (also kills virus and fungi, but no spores) - on skin - kills in 2 minutes 90% of bacteria - germicidal activity is higher if zoo have previously cleaned skin gently with water and detergent - do not apply to wounds (irritation) - used prophylactically before injection - can not be used as surgical instrument disinfectants ALDEHYDES Formaldehyde and glutaraldehyde - surgical instrument disinfectants (irritant on body tissues) - broad spectrum anti-infective (including spores) OXIDISING Hydrogen peroxide - antiseptics with low potency - useful only for anaerobic bacteria - often used at 3%  CHLORINATED COMPOUNDS Chlorine is a powerful germicide (bacteria, fungi, viruses and protozoa) Used to purify drinking water Chloramine - used to disinfect surgical equipment IODINATED COMPOUNDS Povidone-iodine - powerful germicide (bacteria, fungi, viruses, cysts and protozoa) - used in hand washing, pre operative preparations, wounds, abrasions - can cause contact dermatitis with repeated use BIGUANIDES Chlorhexidine - mechanism of action - reacts with an ionic groups on bacterial surface, altering its permeability - bacteriostatic at low concentrations, bactericidal at high concentrations (the one used in dentistry) - broad spectrum - more active against gram positive than gram negative - active against some fungi and viruses - little absorbers through skin - low toxicity - used fro minor skin wounds and burns, pre operative skin cleaning - oral antiseptic in mouthwashes, oral cavity antiseptic (0.12 - 0.2%) - precautions - in patients with periodontitis, chlorhexidine causes an increase in supragingival calculus (tartar) - adverse reactions - frequently (10-15%) and during prolonged treatment (more than a week) - standing of teeth, fillings, dentures and oral appliances - reversible coloration of tongue - increased tartar (calculus) on teeth - altered taste perception - uncommon - mouth irritation - allergic reactions (more common in certain countries) OTHER Cetylpyridinium chloride - quaternary ammonium cationic surfactant - mechanisms of action - binds to negatively charged surface of bacteria cell membrane, altering permeability of membrane - induces protein denaturation and enzyme inactivation - broad spectrum of action against gram positive and gram bacteria, viruses and fungi - spectrum similar to chlorhexidine (in association increases activity to chlorhexidine) - safe and effective anti-microbial for control of plaque-induced gingivitis, in concentrations of 0.045% to 0.1% (rinse 3 times per day, for 30 second with 15 ml after brushing) Triclosan - phenolic type disinfectant agent - mechanism of action - diffuses through bacterial membrane and interferes with lipid metabolism  - induces significant changes in intracellular free Ca2+ homeostasis - produces reactive oxygen species (superoxide anion and hydrogen peroxide) which produces oxidative stress that leads to - loss of cytoplasmatic membrane integrity - depolarisation of cytoplasmic and mitochondrial membrane - reduced metabolic activity - intracellular pH acidification - finally, apoptosis or cell death - broad spectrum - gram positive and negative - fungi - bacteriostatic at low concentration, bactericidal at high concentration - present in max toothpastes and mouthwashes for periodontal disease to control accumulation of plaque and improve gingivitis CARIES (CAVITIES / TOOTH DECAY) Damage of the surface of teeth due to acid produced by bacteria as they break down sugars Streptococcus mutants play an important role in early stages of caries process Lactobacillus contributes to progression of disease Main cause for oral pain and loss of teeth WHO estimates that nearly all adults have dental caries at some point in time More common in developed world drug to greater simple sugar consumption Fluoride - primary intervention for prevention of dental caries (very efficient, safe, cost-effective) - mechanism of action - inhibits enamel demineralisation and stimulates remineralisation by binding with calcium and phosphate from demineralised enamel - reduces conversion of dietary sugar to acid by plaque bacteria - forms fluoropatite and fluorohydroxyapatite, which are more resistant to acid attack than those formed without fluoride - forms of administration - systemic - fluoridated water - only means of caries prevention that does not require personal compliance - water for public consumption (0.7 - 1.2 mg) should be targeted at areas with higher caries levels - bottled water (depends on the water) - foods such as chicken, lettuce or salmon (between 0.01 to 0.17mg/100 gr.) and tea (1 to 6 mg/liter). - topical - domestic use - toothpaste - should be encouraged in all individuals at risk of developing caries - 6 years 1450 ppm and one centimeter of quantity - important to spit out the paste residue to limit swallowing and minimize the risk of fluorosis development (best not to rinse with water)  - mouthwashes - combined with toothpastes, they enhance the cariostatic effect of fluoride - these agents are of greatest value for children at risk to caries (not advised for children under 6 years old) and adults suffering from a dry mouth, medically compromised individuals and those undergoing orthodontic treatment - daily use in concentration of 0.05% - weekly use in concentration of 0.12-0.2% - professional use - application linked to risk of prevention dental caries - beneficial in patents with fixed appliances - recommended frequency (2-4 annual applications, depending on risk) - fluoride gels - acidulated fluorophosphate (APF) (the most widely used), contains a fluoride concentration of 1.2% (12,300 ppm) - could alter composite restorations and the surfaces of porcelain crowns - for patients older than 6 years old - fluoride varnishes - method of spot application of a high- concentration fluoride to areas of risk, highly effective for prevention of caries - 5% sodium fluoride (NaF) (22,600 ppm) in a synthetic resin that provides prolonged contact (about 12 hours) - safe for children < 6 years old - allergic reactions (rare, typically when history of asthma or allergies) - safety - fluoride in caries prevention has been studied for over 70 years, and a huge body of evidence indicates its use is safe and beneficial - no sound evidence to link fluoride to osteoporosis, bone cancer, decreased intelligence - fluorosis - opaque, white or brown areas, lines or flecks in enamel surface, most noticeable on front teeth - can be due to ingestion of excessive fluoride during the period of enamel formation use of fluoride dietary supplements in optimally fluoridated areas or eating of fluoride toothpaste in early childhood - use of fluoride toothpaste in areas with optimally fluoridated water supplies has been shown to result in only a small increase in the mildest forms, which mostly pass unnoticed - parents should supervise toothbrushing of children under 7 years of age and use small amount of toothpaste Water fluoridation is the best public health measure if there is a high prevalence of dental caries However, in populations with a low prevalence of caries, as is currently the case in Spain, fluoridation of public drinking water is not the only option The identification of a high risk of individual caries in minors recommends the use of oral fluoride supplements, but their correct indication requires knowing the fluoride concentration in the water they consume on a daily basis Casein Phosphopeptide - Amorphous Calcium Phosphate (CPP-ACP) - delivery system for bioavailable calcium and phosphate ions, helping to maintain a saturated state of these ions in dental plaque, inhibiting demineralisation and enhancing enamel remineralisation - binds to surface of teeth and bacteria in plaque reduces adherence of Streptococcus mutans and Streptococcus sobrinus to dental biofilm formation of less pathogenic dental plaque - potentiates the remineralizing effect of fluoride - in toothpastes, mouthwashes, varnishes, chewing gum Fissure sealants - thin resin coating professionally applied to the pits and fissures of molar and premolar - only effective on the biting surface of teeth - prevent access of plaque and plaque acids to enamel surface - important in children at high risk of caries Recurrent aphthous stomatitis - recurrent formation of benign, non-contagious mouth ulcers (RAS) - aetiology not know - treatment - most mild cases do not require treatment - aims at mitigating symptoms, shortening the healing time and as prophylaxis against recurrence. - most have demonstrated little or no therapeutic efficacy - topical regimens are standard treatment in mild cases of RAS - good oral hygiene is important to prevent secondary infection of the ulcers - vitamin B12 supplementation may prevent recurrence in some individuals - topical treatment - corticosteroids - hydrocortisone, dexamethasone, triamcinolone, clobetasol - first-line treatment - reduces the local inflammation that induces ulceration - contraindicated in ulcers of infectious origin - local anaesthetics - lidocaine, benzocaine, mepivacaine - viscous solution, gel or spray - reduces the pain associated to RAS - if throat is numbed, avoid eating/drinking in 2 hours - antiseptics - povidone-iodine, chlorhexidine, benzalkonium chloride, tetracycline, diluted hydrogen peroxide - reduce the duration and pain of oral aphthae - bioadhesives - form a protective coating in the oral cavity that shields the exposed nerve endings of the lesion, thus avoiding further irritation and reducing pain - help mucus to fulfill its function lubrication, cell protection, bacterial degradation  - prophylaxis - avoid spicy and acidic foods and drinks - avoid gum chewing - avoid oral products containing sodium laurel sulphate Sodium lauryl sulphate (SLS), a surfactant present in many brands of toothpaste and other oral healthcare products, can be irritant and produce oral ulceration in some individuals HALITOSIS Unpleasant odor that comes from a person's breath and that comes from the mouth, nasal cavity, sinuses or pharynx 3rd cause of consultation to the dentist Highly variable prevalence Related to the decomposition of food particles, cells, blood and some components of saliva, which gives rise to the emission of volatile sulfur derivatives and other gases that come from the increase in the number of anaerobic bacteria In 80-90% of cases, germs from the oral cavity are involved Treatment - mechanical reduction of microorganisms - maintain good hygiene and dental health - floss dials (interdental cleaning) - brushing with fluoride paste at least twice a day, including the back of the tongue and palate - remove and clean dentures and prosthetic materials once a day - tongue scrapes (more effective than a toothbrush) - chemical reaction of microorganisms - mouthwashes with antiseptic action (cetylpyridinium chloride, triclosan) are best used at night, since the remains of the product remain in the mouth, which is - when bacterial activity is greatest and saliva flow is least - must be kept in the mouth for 30 seconds - periodic reviews at the dentist - eat diet rich in fresh fruits and vegetables, avoiding fat and meat as much as possible (avoid foods that promote bad breath such as onions garlic and alcoholic beverages) - tobacco abstention - probiotic tablets (Lactobacillus salivarius) - photodynamic therapy - encouraging results - agents that mask halitosis sprays, toothpastes and chewing gum with products similar to mouthwashes and menthol oil, may have a short-term effect Zinc chloride - mechanism of actions - zinc ions have a strong affinity for thiol groups present in volatile compounds and cause interference in the production and volatilisation of odorous products - effect of zinc - ability to form non-volatile compounds from volatile sulphur compounds (VSC) - decreases the permeability of membranes to the passage of VSC - anti-microbial activity, due to non-selective precipitation of proteins - reduces the degradation of cellular elements in saliva by inhibiting thiolproteinase activity (proteolytic enzyme with an -SH group in the active site) Treatment in other types of halitosis - specific oral or extraoral causes - management of specific cause - refractory halitosis - diagnostic tests may be indicated for the detection of Helicobacter pylori, since a clear correlation between the two has been observed and if presence of the germ is confirmed, proceed to eradication therapy - pseudohalitosis (the patient perceives a bad odor in his breath that others do not detect and cannot be confirmed with diagnostic tests) - must be informed that the intensity of their breath is not above socially accepted levels, although it is convenient for them to continue using the general measures described before - halitophobia (after treating halitosis or pseudoha