1.Antibiotics used indentistryprepared by zirgi

2. DEFINATION Antibiotics are chemical substance elaborated by various species of micro- organism such as fungi, actinomycetes and bacteria. They suppress the growth of other micro-organism and may ultimately destroy them in low concentration. 3. History 4. Early history 3500 BC the Sumerian doctors would give patientsbeer soup mixed with snakeskins and turtle shells. Babylonian doctors would heal the eyes by using anointment made of frog bile and sour milk. The Greeks used many herbs to heal ailments. All of these "natural" treatments contained some sortof antibiotic. 5. Modern history Louis Pasteur was one of the first recognizedphysicians who observed that bacteria could be usedto kill other bacteria. In 1929 Sir Alexander Fleming a Scottishbacteriologist, went on a vaction and left a petri dishof staphylococci bacteria uncovered. When hereturned, he noticed that there was mold growing onit. Upon further examination, he saw that the areaaround the mold had no bacteria growing. He namedthe mold Penicillium, and the chemical produced bythe mold was named penicillin, which is the firstsubstance recognized as an antibiotic. 6. Almost immediately after penicillin was introduced,resistance in certain strains of staphylococci wasnoticed. In 1935, Domagkdiscovers synthetic antimicrobialchemicals (sulfonamides). During World War II, because of need for antibioticagents, penicillin was isolated and further tested byinjection into animals. It was found to be extremelyuseful in curing infections, and to have extremely lowtoxicity to the animals. Because of these findings, useof penicillin greatly increased. This also spurred asearch of other chemical agents of similar use. 7. the late 1940s through the early 1950s, streptomycin,chloramphenicol, and tetracycline were discoveredand introduced as antibiotics. In 1953, during a Shigella outbreak in Japan, a certainstrain of dysentery bacillus was found to be resistantto chloramphenicol, tetracycline, streptomycin, andthe sulfanilamides. By the 1950s it was apparant that tuberculosisbacteria was rapidly developing resistance tostreptomycin, which had commonly been used totreat it. 8. Classification of antibiotids 9. Classification of antibioticsClassification based on chemical structure & proposed mechanism of actions as fallows1. Agents that inhibits synthesis of bacterial cell wallthese includes a) penicillin & cephalosporin which are structurally simillar b) Cycloserine vancomycin bacitracine & the azole antifungal agent ( e.g clotrimazole, fluconazole & itraconazole which are structurally dissimilar agent 10. 2.Agent that act directly on the cell membrane of the micro organism affecting permeablity & leading to leakage of intercelluar compounde.G polymyxin & polyene antifungal agent nystatinAmphotericin B which bind to cell wall sterolls 11. 3 .Agent that affect the function of 30 s or 50 sribosomal subunit to cause or reversible inhibition ofprotein synthesise.G chloramphenicalTetracyclineErythromycinClindamycin 12. 4 .agent that bind to 30s ribosomal subunit &alterprotein synthesis which eventually lead to cell deathE.g. aminoglycosides5.agent that affect bacterial nucleic acid metabolismsuch as rifamycin (e.g. rifampin ) which inhibit RNApolymerase & the quinilones which inhibittopoisomerase 13. 6 . agent that block essential enzymes of folate metabolisumE.g. trimethoprim& sulfonamide7 . Antiviral agent which are of several classes includingeNuclic acid analog such as acyclovir or gancyclovirthat selectively inhibit viral DNA polymerase andzidovidine which inhibit reverse transcriptaseNon nucleoside reverse transcriptase inhibitors suchas nevirapiner Inhibitor of other essential viral enzyme. E.g.inhibitors of HIV protease or influenza neuraminidase 14. classification According to spectra1.Antibiotic effective against gram positive bacteriaa.For systemic infection, erythromycin, lincomycin,novobiocin.b. Those employed topicallye.g. bacitracin2.Antibiotic mainly against gram negative bacteriaa.For sylstemic infectione.g. strepomycin & other aminoglycosidesb.Those used locally in intestinee.g.paromomycin 15. 3.Antibiotic mainly effective against gram ve & +ve bacteriaa.Used for systemic infectione.g. ampicillin, amoxycillin, cephalosporinb.For topical applicatione.g. neomycin4. Effective against rickettsial & chlamydiae.g. tetracycline & chloramphenicol5.Effective against acid fast bacillie.g. steptomycin, rifampicin & viomycin 16. 6.Effective against protozoae.g. paramomycin & tetracyclin7.Effective against fungie.g.nystatine, amphotericin B8.Effective against malignancye.g. actinomycin, mitomycin 17. PRINCIPLES OF ANTIBITICTHERAPY IN DENTAL INFECTIONS 18. Following are the points by which the clinician can make a decision of when to use antibiotic, which are to select, and how to use both therapeutic and prophylactic situations. To do this one should atleast know about the following 1. Bacterial flora causing most odontogenic infections 2. The basic mechanism of host defenses 3. The variety of contemporary antibiotics and principles to choose 19. Bacterial flora causing mostodontogenic infections The indigenous microbial flora of the mouth is bacteria, which are almost always the cause of odontogenic infections. The usual flora is both aerobes and anaerobes 20. The basic mechanism of hostdefenses Host defense mechanism is the most important factor in the final outcome of a bacterial insult.Each patient has many defenses against infections.1. Physiologic depression of host defence,ShockDisturbances of circulation caused by advanced age ObesityFluid imbalance2. Diseases and disease state that may inhibit host defenseMalnutrition syndromePatient with cancer and leukemia 21. 3 Congenital defect which causes defective hostmechanismAgammaglobulinemiaMultiple myelomaTotal body radiation therapyChildren who have had splenectomy 4. Therapeutic drugs that impares host defensemechanism Cytotoxic drugs Immunosuppressive drugs 22. principles to chooseAntibiotics Once the decision has been made to use antibiotics as an adjunct to treating infection the antibiotics should be properly selected. The followingguide lines are useful1. Identification of causative organism2. Determination of antibiotic sensitivity3. Choice of antibiotics 23. 1. Identification of causative organismCausative organism can be isolated from pus blood, or tissue fluids. Based upon the knowledge of pathogenesis and clinical presentation of specific infection,antibiotic therapy will be either initial or definitive depending upon whether or not the organism is diagnosed previously. 24. 2. Determination of antibiotic sensitivityWhen treating an infection that has notresponded to initial antibiotic therapy or whentreating a postoperative wound ,the causative agentmust be previously identified and the antibioticsensitivity must also be determined. 25. 3 Choice of antibioticsUpon receipt of the culture and sensitivity report,there may be a choice of four or five antibiotics.Selection should be based on consideration of severalfactors like 1. Patients previous history of allergy 2. Antibiotics with narrow spectrum 3. Drug that cause fewest adverse reactions. 4. Drug which is least toxic 5. The well established still effective antibiotics 6. Bactericidal rather than bacteriostatic drug 7. The less expensive still effective antibotic 8. Combination antibiotics 26. 1. Patient`s history of allergyAllergic reaction to drugs should be consideredfirst. When it exists, alternative drugs must be used.Example erythromycin or clindamycin is usually use ifthe patient is allergic to penicillin 27. 2. Antibiotics with narrow spectrum The only majour indication for use of broad spectrum antibiotics coverage is in severe life threatening infection where identification of causative agent is obsure. Each time bacteria are exposed to antibiotics, the opportunity for development of resistant strains is present. If narrow spectrum antibiotics is used ,fewer organisms have the opportunity to become resistant. 28. 3. Drug that cause fewest adverse reactionsThe goal of antibiotic therapy is to provide aneffective Drug that causes least problem to the patient 4. Drug which is least toxic Toxicity reactions are those that occur as a resultof excessive dose or duration of therapy, but canoccur in individual patients with normal doses. 29. 5. The well established still effective antibiotics Since its initial availability, penicillin, has beenused for oral infection and it has been very effective,with low incidence of adverse reaction. Newerantibiotics should be used only when they haveproved advantage over the older ones . 30. 6. Bactericidal rather than bacteriostatic drug Bactericidal drugs are effective during the log phase of bacterial growth the time . If growth is slowed or brought to stop,cidal drugs have a greately diminished effect. As a result, in these situations, when combination drug therapy is to be used,cidal and static combination should not be used in combination. 31. 7. The less expensive still effective antibotic Most effective but less expensive drug should beconsidered first. 8. Combination antibiotics There are situations in which the use ofantibiotic combination is clearly indicated. Example iswhen it is necessary to increase the antibacterialspectrum in patients with life threatening sepsis ofunknown cause. 32. Bacterial resistance toantibiotic When the drug does not reach its target The drug is not active3. Target is altered. 33. Selection of antibiotics When an antibiotic is indicated the goal is tochoose a drug that is selectivley active for themost likely infecting micro-org.& that has leastpotential to cause toxicity or allergic reaction inindividual being treated. Antibiotic are used in three general ways as empirical therapy as definative therapy As prophylactic or preventive therapy 34. Pharamacokinetic factor thataffect the selection of antibiotic Location of the infection access of antibiotic to sites of infectione.g. if the infection in the CSF the drug mustpass the blood brain barrier 35. Host factors Host factor for the selection of antibiotics Host defense mechanisms action in the immunocompetant host can becure mearly by halting multiplication of microorganism { bacteriostatic effect} if host defense are impaired bacteriostaticactivity may be inadequate and a berteriocidalagent may be required for curee.g. pt with bacterial endocarditis pt with AIDS 36. Local factors Antimicrobial activity may be significantlyreduces in pus Large accumulation of Hb in infectedhematomous cab bind penecillin andtetracycline & thus may reduce theeffectiveness of other drug Penetration of antibiotic into infected areassuch abscess is imparied because vascularsupply is reduce 37. Genetic factors A no. of drug (e.g. sulfanamides, chloramphenicol and nalidixic acid ) may produces acute hemolysis in pt with glucose 6- phosphate dehydrogenase deficiency 38. pregnancy Pregnancy may impose an increased risk ofreaction to antibiotic for both mother &fetus Hearing loss in child with administration ofstreptomycin to the mother duringpregnancy Tetracycline can affect bones & teeth offetus , may develop fatal acute fatty necrosisof liver pancreatitis & associated renal 39. Drug allergy A antibiotics especially- B-lactum arenotorious or provoking allergic reaction Sulfonamides trimethoprim nitrofurapterinand erythromycin also has been associatedwith hypersentitivity reaction especiallyrash. Antimicrobial agent like othe drugs cancaused drug fever 40. Therapy with combinedantimicrobial agent Indication Empirical therapy of severe infections in which acause is unknown Treatment of polymicrobial infection Enhancement of antibacterial activity in thetreatment of specific infection. 41. Disadvantage of combination ofantimicrobial agents Risk of toxicity from two or more agent The selection of multiple drug resistance micro organism Increased cost to the patient 42. Some commonly usedantibioticsPenicillinIt is the extract from mould penicilium notatumBelonging to group called beta lactum antibiotics 43. Classification1. natural penicillinE.g.penicillin g benzyl penicillinProcaine 44. 4.penicillin effective against gram +ve &some gram -ve organism Ampicillin Amoxicillin Talampicin 5.extended spectram penicillin a.carboxypenicilin Carbenicillins b.amidinopenicillin Mecillinam 45. Mechanism of action Act by inhibiting cell walll synthesis in bacteria. they prevent sythesis & crosslinkage of peptidoglycans which is the integral part of bacterial cell wall. 46. Antibacterial spectrum ofpenicillin Effective mainly against gram +ve & gram ve cocci &and some gram +ve bacilli. 47. Adverse effect of penicillin Intolerance Thrombophlebitis Allergy with manifestation like 1.skin rash 2.serum sickness like syndrome 3.renal disturabane 4.haemopoitic disturabance 5.anaphylaxis 48. Jarish herxiheimer reaction on syphilitic pttreated with penicillin Superinfection e.g. candida hypermia 49. Classification Usual adult Activity against Natural penicillin resgimen oral pathogens 250-500mgvk QID Gm+vegm+ve PenicillinasegmveresistanceDicloxacillin250mg 6 hrly Arobes anarobesanarobes Nafcillin 500mg QID+ve +ve +-ve Amoxicilline Amox/ potassium 250-500mg clavulanate 8hrly (augmantin) 250-500mg Ampicillin8hrly 250-500mg QID stap.only-ve 50. AMINOGLYCOSIDES These are group of natural & semisynthetic drugs having polybasic amino groups & linked glycosidically to two or more amino sugars. 51. Mechanism of action The drugs combine with the bacterial ribosomes & interfares with m-RNA ribisomes combination which ultimately prevents protien synthesis. 52. Absorbtion fate and excreation It is excreted mainly by glomerular filtration &asmall portion in bile 53. spectrum Vibrio comma Proteus E-colli Enterobacteria Klebsiella H- influenza 54. This group includes drug like Streptomycine Gentamycine Kanamycine 55. Tetracycline They are naphthalene derivatives its nucleus is made up by the fusion of foci partialy unsaturated cyclohexiane radius and hence named tetracycline 56. Mechanism of action Interfer with protein synthesis by blocking the attachment of amino acyl transfer rna to acceptor site on m-RNA ribosome complex. 57. Absorption fate & excretion Tetracycline form insoluble complexesby chelation with calcium ,magnesium& aluminium Iron interferes with absorptionexcreted mainly in urine 58. Spectrum Includes both gram +ve & -ve orgamism Dose orally-250-500mg TDS Parantally- 1-2gms in two equal doses 12hrlyinterval. Newer drug are- Doxycycline Demeclocycline Methacycline Minocycline lymecycline 59. Disadvantages GI system Diahrroea Nausea Vomiting Suprinfection Candida infectionis comman Fetal hepatic disfuction Azotemia may be agrevated to renalimpairment Chelating effect in teeth & bone 60. Cephalosporins 1st generation They are highly effective against gram +vebut weaker against gram _ve bacteria These are cephalexim Cephalethin Cephaloridine Cephradine cefadroxil 61. Cephalexin Only orally active first generation cephalosporin withspectrum Strptococcus Staphylococci Gonococci Closridia C. diptheria Actinomyces Klebshiella Protease Salmonella shingella 62. Dose Adult 25mg to 1gm 6 to 8 hrly. children 25mg to 100mg/kg/day 63. Cefadroxil A it is close congener of cephalexim& hasgood tissue penetration B can be given 12 hrly C spectrum is same as cephalexim Dose 0.5gm -1gm BD. 64. SECOND GENARATION They are newer to first genaration. They have more activity against gram ve organisms. E.g. cefuroxime it is higher activityagainst penicilliase producing organismsand all ampicillin resistant H-influenzae. 65. Other spectrum More active against klebsiella, E-coli,enterobacter, indole positive protiens. Dose a. 0.75 1.5 gms/ IM or IV/9 hrly b.30- 100mg/kg/day. Available as- supacef. 66. Third generation These were developed in end of 1980s. They have augmentation activity against veEndobactericeae. They are resistant to lactamase. These are- Cefotaxamine Ceffizoxime Ceftriaxone Moxalactum ceftazidium 67. Cefotoxamine Potent action on gram-ve as well as gram+ve It is not so active against anaerobic like bact.Fragillis, Staphylococcous aureus, Pseudomonasaerugemosa. It is very important drug in teratment ofmeningitis, hospital acquired diseases septicaemiaand infection in immuno compromised pt. Dose A.1-2gms/Imor IV/6- 12hrly 50-100mg/kg/day 68. Available as - Omnatax claforan 69. Ceftizaxone Long acing cephalosporin One daily dose is good enough and it has good CSF penetration Dose Adult - 1-2gms/IM or IV /day Child- 75-100mg/kg/day 70. Ceftazidime Most prominent feature is high activity againtpseudomonas. It is used in febrile pt including pt with burns. It is less effective to staphylococcus aureus. Dose Adult-0.5-2gms/IM or IV/ every 8 hours Child- 30mg/ kg/day 71. Forth generationcephalosporine E.g. cefepime(maxipime) and cefpirome It is new cephalosporine with properties like those of3rd generation cephalosporine but more resistance tosome beta-lactumase. It is active against streptococci and methycilinesensetive staphylococci but not against methycilineresistance staphylococci. 72. Spectrum Its main use is in serious gram ve infection (H-influenza, Neisseria- gonorrhoae and Neisserameningities) including infection of CNS inti which ithas exelent penetration. Half life is of 2hrs. Dose -2gm I.V. every 12hrs 73. Fifth generationcephalosporine Ceftobiprole has been described as "fifthgeneration",though acceptance for this terminology isnot universal. Ceftobiprole (and the soluble prodrug medocaril) areon the FDA fast-track. Ceftobiprole has powerfulantipseudomonal characteristics and appears to beless susceptible to development of resistance. 74. These cephems have progressed far enough to benamed, but have not been assigned to a particulargeneration. Cefaclomezine Cefaloram Cefaparol Cefcanel Cefedrolor Cefempidone Cefetrizole Cefivitril 75. Cefmatilen Cefmepidium Cefovecin Cefoxazole Cefrotil Cefsumide Ceftaroline Ceftioxide Cefuracetim 76. Adverse effect Pain after injection. Diarrhoea due disturbance in Gut ecology Hypersensitivity reaction- anaphylaxis,angiodema, asthma, urticaria. Nephrotoxicity Neutropenia or thrombocytopenia Hyperprothombinemia A flase +ve cmbs test may occur in as manyas 60%of pt or cephalathin therapy. 77. Macrolides They are antibiotics having a macrocycliclactone ring with attached sugars They are bacteriostatic drug 78. Erythromycin Used as aternative in penicillin sensitiveindividuals CONTRAINDICATIONS Hypersensiivity Liver dieases- ester salt is avoided Available as tablet & syrup Dose ADULT- 250-500mgQID CHILDREN-30-50mg kg/dayin form of divided doses. 79. Adverse reaction Nausea Vomiting Diahrroea Hypertention Cardiac arrythmias Revesible hearing loss ONSET OF ACTION- 2to4hrs 80. Azithromycin This new azalide longer of erytromicin has an expanded spectrum, hyper, Pharmacokinetics, better tolerability and drugs interation profile however it is not effective against erythromycin resistant bacteria. 81. IndicationsRespiratory track infectionUrenary track infection.Otitis media 82. Contraindications Hypersensitivity Hepatic impairmentDOSE- ADULT-500mg OD for 3days OR 500mg OD on days one followed by 250mg OD for 4 days.CHILDREN- 10mg/kg/ day for 3 days OR 10mg/kg/day followed by 5mg/kg/day OD for 5day.ONSET OF ACTION- one to two hrs 83. Adverse effect Mild gastric upset Abdominal pain Headache Dizziness 84. Imidazoles Metronidazole Prototype netroimidazole Active against anarobes 85. Mode of action In anarobic micro-organisms metronidazoleis converted into an active form byreduction of its nitro group. This binds to DNA and prevents formationof nuclic acid. 86. Absoption fate and excretion The drug is well absorbed after oral orrectal administration. It is elimanated urine, partly unchanged &party metabolized 87. Contraindications Neurogenic diseases Blood dyscrasias first trimester of pregnancy 88. Uses Acute ulcerative gingivitis Dental infections Amoebiasis Giardiasis Trichomoniasis 89. Dose Orally 400mg 8hrly IV infusion 0.5gms/8hrs. Treatment should be continue for 7 days. 90. Adverse effects Anorexia Nausea Metalic taste Headache Glossitis Dryness of mouth Thromphlebitis of injected veins 91. Indication for antibiotic usedn Systemic indicationsiCongnital or acquired heart a. Rheumatic heart disease b. Valvular diseases c. Pt with ventricular defects2. Severe kidney diseaesa. chronic glumerulonephritisb. pt undergoing dialysis 92. 3. Active leukemia, agranulocytosis, aplasia ,anemia4. Metabolic disturbances diabetes5. Pt on chemotherapeutic drugs6. Pt with vascular graft 93. B. Maxillo- facial trauma1.Hard tissue trauma-the consensus is thatantibiotic convert should be used for anymandibular or maxillar fracture compentedinto mouth or paranasal sinus through mouth.2.Soft tissue trauma3.Orthognathic & recontructive maxillo- facialsurgery.4.Odontogenig infection5.Pericoronities6.Osteomylitis 94. contraindication Minor chronic localised abscess. Well localised vesibular abscess . Localised ostitis For sterilizing root canal Pt with mild pericoronitis, minor gingival oedema & mild pain which do not required antibiotcs 95. Prophylactic antibiotic therapy Standard recommendation A cephalosporin cefadroxil preferred 1preoperatively 500 mg orally 1hr before surgery 2 post operatively 250 mg orally 6hr after initialdose or Clindamycin in penicillin allergic pt 1 pre operatively 300 mg orally 1 hr before surgery 2 post operatively 150 mg orally 6hr after initialdose 96. Principles of antibioticprophylaxis 1 antimicrobial agent t is chosen on basis ofmost likely micro organisum to causeinfection 2 an antibiotic loading dose should beemployed 3 antibiotic should present in sufficientconcentration in blood and targate tissueprior to dissemination of offending microorganisum 97. 4 antibiotics should be continued only aslong as microbial contamination fromoperative site persist 5 patient benefits from prophylaxis shouldout high risk of antibiotic included allergy ,toxicity , superinfection. 98. Dental procedure that requireendocardititis prophylaxis Tooth extraction Periodontal suergery Subgingival dental prophylaxis Endodontic surgery Incision & Drainage of infection 99. do not require endocardiatisprophylaxis Supragingival prophylaxis Restorative tooth preparation Placement of orthodontic appliances Conserative endodontic theraphy 100. REASONS FOR ANTIBIOTICFAILURE INAPPROPIATE choice of antibiotics Too low blood concentration Poor penetration to infected site Limited or decreased vascularity Impaired host defence Unfavourable local factors 101. Increased plasma protein binding Antibiotic antagonism Slow microbial growth Antibiotic resistant organisms Patient failure to take antibiotics Failure to eradicate sorce of infection 102. Myths &misconception inantibiotic th erapy Myth- antibiotics cure pt1 except in immunocompramised pt antibiotics are not curative but rather function to provide time for normal host defence initially overwhelmed by micro organisum to gain and control &eventually eliminate the in fectious process 103. 2 .Antibiotics are substitute for surgical drainage - never are antibiotics a substituted for eradication of the source of infection ( extraction, incision, drainage ) unless the infection is too diffuse (pericoronitis) 104. 3 culture and sensitivity test are required - orofacial infection are characteristically acute in nature, polymicrobial in cause, short in duration with proper treatment. These infection require immediate attention and a dealy of 18 to 36 hrs for result of culture & sensitivity tests prior to initiation of antibiotics therapy is usually not appropriate because the microbial cause Is commly such that common antibiotics are effective, incision &drainage are relatively easy. 105. Myth antibiotics incresedhost defence to infection The followoing condition appear valid at present 1 antibiotic that can peenetrate into themammelion cell (tetracycline , eryt hromycin) aremore likely to affect host defence than those thatcan not (beta lactum) 2 tetracycline may supress white cell chemotaxiswhere as betta lactum do not 3 most antibiotics (except tetracycline) do notdepress phagocytosis Tnb lymphocyte transformation may be depressedby trtracyclines 106. Multiple antibiotics aresuperior to as single antibiotics. It is often assume that antbiotic combination aresuperior to single antibiotic such as notcommonly the case. The primary clilical indication for antibioticconbination therapy is severe infection in whichofending organism is unknown and majorconciquences may ensue if antibiotic therapy isnot instituted immediatey before culture andsensetivity test are available. 107. Antibiotic prophylaxis usuallyeffective It is commonly assume that antibioticsadministered prior to invasive surgicalprocedure remain post operative infection. The reality based on laboratoru studies isthat antibiotic prophalaxis is only sometime effective. 108. Bacteriocidal agents are alwayssuperior to bacteriostatic agent Bacteriocidal antimicrobials are required in pt with impaier host defenses (nutropenia, meningitis) but bacteriostatic agent are uaually satisfactory, if host defence against infection are adequqte. 109. Antimicrobials are effective inchronic infectious disease Antimicrobials are never been successful in the eradication of a chronic infection because the prolong exposure of micro-organism to chemical leads to eventual dominance of drug resistance organism 110. Antibiotics are safe and nontoxic Most antimicrobials are among safest drugyet all are associated with allergy, ecologicaldamage to human and microbialenvironment. 111. Infection require a completecourse of therapy There is no such things as predetermine completecourse of antibiotic therapy. The only guide for determining the effectiveness ofantibiotic therapy and hence duration of treatment isrelated to clinical improvement of pt. 112. Misconceptions Prolong therapy destroy resistant micro-organism. Prolong therapy is necessary for rebound infectionthat recur as organism is suppresed but noteliminated (orofacial infections do not rebound ifthe sourse of infection is properly eliminated) Antibiotic doseges and duration of therapy can beextra polated from one infection to another 113. REFERENCE GOODMAN & GILLMAN TEXTBOOK OF PHARMACOLOGY BY TRIPATHI BY SATOSKAR 114. Antibiotic LoadedHAP/TCP Bone Substitute forProphylactic Action: ATANTIK Genta In VivoStudy 115. INTRODUCTION: Infections and their consequences are a considerableproblem inorthopedic surgery. Despite systemic prophylaxis, infection rates afterorthopedic surgery are above1%. Antibiotic loaded PMMA bone cements have beenshown to enhance the efficiency of intravenousprophylactic treatments for total hipreplacement1. However, less than 10% of the load is released duringthe first 5-10 days ofimplantation2: the remainingantibiotic is released at low levels over many months3and could select antibiotic-resistant strains2. 116. Methods A commercial bone substitute composed of 70%Hydroxyapatite and 30% - Tricalcium Phosphate4containing 125 mg of Gentamicin (ATLANTIK Genta,Medical Biomat, France) was used in this study. The release rate of Gentamicin from the bonesubstitute was investigated after implantation in thefemoral condyle of 5 sheep. In order to investigate thelocal and systemic Gentamicin concentrations,synovial fluids and blood samples were assessed byimmunoassay over a 5 day period. 117. There were differences in local Gentamicin concentrations between individuals but for all animals, the local Gentamicin concentrations measured during the first 8 hours were higher than the minimal bactericidal concentration of the majority of the germs responsible for infections in orthopedic surgery, i.e. 6-12 g/ml. After 48 hours, the concentration in blood and synovial fluids was less than 0.5 g/ml. 118. The mean Gentamicin concentration peak obtained inblood was 4.2 g/ml and then mean local Gentamicinconcentration obtained in synovial fluids during thefirst 8 hours was305 g/ml The Gentamicin amount remaining in the implantexplanted at day 8 was less than 0.003% of the initialamount 119. New era of antimicrobialtherapeutics 120. It is a fact that selection of multi-drug-resistantbacteria has occurred throughout history.Unfortunately, however, drug-resistant bacteria havebeen met with antibiotics that are nothing more thanrecapitulations of earlier drugs. There has been anurgent need for new avenues of therapeutictreatment, and a new era of prophalytic (preventative)treatment has begun. Here the most plausibleapproaches are described: bacterial interference 121. bacteriophage therapy bacterial vaccines cationic peptides cyclic D,L-a-peptides 122. Bacterial interference 123. One way is to inoculate hostswith nonpathogenic bacteria. Bacterial interference, also known as bacteriotherapy, is the practice of deliberately inoculating hosts with nonpathogenic (commensal) bacteria to prevent infection by pathogenic strains. To establish an infection and propagate disease, pathogenic bacteria must find nutrients and attachment sites (adhesion receptors).. 124. Infection by pathogenic bacteria is prevented by commensal bacteria, which compete with pathogenic bacteria for nutrients and adhesion receptors or spur attack through secretion of antimicrobial compounds 125. This treatment has had promising results in infections of the gut, urogenital tract, and wound sites. The major advantage of using bacteria in a positive way to benefit health, known as probiotic usage, is that infection is avoided without stimulating the hosts immune system and decreases selection for antibiotic resistance. Understanding how bacterial species compete, an essential criterion for research, has been known for at least 20 years but its practical application has yet to be realized. 126. Bacteriophage therapy 127. Bacteriophages (commonly called phages) are viruses that infect bacteria and were recognized as early as 1896 as natural killers of bacteria. Bacteriophages take over the hosts protein-making machinery, directing the host bacteria to make viral proteins of their own. Therapeutically, bacteriophages were used as a prophylaxis against cholera, typhoid fever, and dysentery from the 1920s to the early 1940s. 128. The practice was abruptly stopped when synthetic antibiotics were introduced after World War II. Now that there is a plethora of multi-drug-resistant bacteria, bacteriophage therapy once again has become of keen interest. 129. Pathogens may be targetedthrough manipulation ofphage DNA. Bacteriophage therapy is quite attractive for thefollowing reasons: phage particles are narrow spectrum agents, whichmeans they posses an inherent mechanism to notonly infect bacteria but specific strains 130. Other pathogens may be targeted throughmanipulation of phage DNA exponential growth and natural mutational abilitymake bacteriophages great candidates for thwartingbacterial resistance. Development of bacterial vaccines has become anincreasingly popular idea with the advent of completegenomic sequencing and the understanding ofvirulence regulatory mechanisms. 131. Bacterial vaccines 132. Bacterial genomics allows scientists to scan an entirebacterial genome for specific sequences that may beused to stimulate a protective immune responseagainst specific bacterial strains. This approachexpedites the drug discovery process and, moreimportantly, provides a more rational, target-basedapproach. The best targets are essential bacterial genes that arecommon to many species of bacteria, which code forproteins with the ability to gain accesses through lipidmembranes, and possess no homology to humangenes. 133. Regulatory genes that control virulence proteinproduction are excellent vaccine candidates forpriming the human immune system or inhibitingvirulence production. Bacterial genomics can also detect conservedsequences from bacterial species and strainsworldwide. This technology will inevitably yieldsuperior clinical vaccine candidates. 134. Cationic peptides 135. These diverse peptides are natural compounds that posses both hydrophobic and hydrophilic characteristics, which means portions of the molecule are water avoiding or water loving. Cationic peptides are found throughout nature in the immune systems of bacteria, plants, invertebrates, and vertebrates 136. Other Peptides are synthetic,and are engineered to killbacterial cells. These peptides are not the usual synthetic drugs encountered in pharmaceutical drug design; however, they do exhibit antibacterial effects. Cationic peptides have several mechanisms of action, all of which involve interaction with the bacterial cell membrane leading to cell death. From a therapeutic standpoint, these proteins have great promise, as they have coevolved with commensal bacteria yet have maintained the ability to target pathogenic bacteria. 137. Other peptides are synthetic,or engineered, to kill bacterialcells. Unlike cationic peptides, cyclic D,L-a-peptides are synthetic and amphipathic (molecules having both water loving and water hating characteristics) cell membrane disruptors. As the name implies these peptides are cyclic in nature and are composed of alternating D and L amino acids. Cyclic D,L-a- peptides are engineered to target gram-positive and negative membranes (not mammalian cell membranes). 138. In contrast to any other known class of peptides, these peptides can self-assemble into flat ring shaped conformations forming structures known as nanotubes, which specifically target and puncture bacterial cell membranes resulting in rapid cell death