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ANTIBIOTIC USE PRESENTOR: DR HASSAN FACILITATOR: DR MUASYA OUTLINE Introduction Overview of antibiotics mechanism of action Rationale use and choice of antibiotics. Combination therapy. Resistance to antibiotics Summary Introduction Antibiotics are substances produced by various microorganisms ( or synthetic agents ) that suppress growth of other microorganisms. Among the most prescribed drugs. Proper use can be life saving Indiscriminate use: more cost of h/care, side effects, drug interactions and foster emergence of drug resistance. Bacteriostatic vs bacteriocidal Bacteriocidal Aminoglycosides B-lactam antibiotics Vancomycin Quinolones Isoniazid Pyrazinamide Rifampicin Bacteriostatic Chloramphenical Clindamycin Macrolides Sulfonamides Tetracycline Ethambutol Rationale use of antibiotics Is an antimicrobial agent indicated on the basis of clinical finding? Have appropriate clinical specimens been obtained? What are the likely etiologic agents for the patients illness? What measures should be taken to protect individuals exposed to the index case to prevent secondary cases? Is there clinical evidence that antimicrobial therapy will confer clinical benefit for the patient? Choice of an antibiotic To choose the appropriate antibiotic to use, one needs to consider: 1. Infectious agent. 2. Antimicrobial agent to use. 3. Host factors. Factors affecting choice of an antibiotic Host factors Concomitant disease states (e.g immune status) Prior adverse drug effects Impaired elimination of the drugs Age of the patient Pregnancy status Factors affecting choice of an antibiotics Pharmacologic factors Pharmacodynamics of the drug (concentration dependent vs. time dependent killing) Site of infection (BBB, vegetations in IE) Toxicity of the agent Interactions with other drugs Bactericidal or bacteriostatic Resistance patterns Antibiotic therapy Empirical therapy. -Based on best guess guided by knowledge of likely pathogen in that site or clinical setting. -appropriate in life threatening infections, justified for by the hope that early intervention will improve the outcome Rx comm. Acquired infections e.g. CAP, UTI -Once MCS results out change to specific agent -Adv: immediate. Rx, short hosp. stay -Disadv: use of many drugs, unnecessary S/E, good clinical acumen needed. Empirical therapy: Approach Formulate a clinical diagnosis of microbial infection Obtain specimen for laboratory examination Formulate a microbiologic diagnosis Determine the necessity for empirical therapy Institute treatment Examples of empiric antibiotic therapy based on microbiological aetiology Suspected org. 1st choice Alternative drug N. Gonorrhea Ceftriaxone Spectinomycin N.Meningitidis Pen G Ceftriaxone E.coli, klebsiella Septirin, Ceph, Quinolone, AG Pseudomonas Antips+AG Antips+QN,CPH S. Pneu Pen Cphl,macrldes,qnlns V.Strep Pen Cphl, vanco Enterococcus Pen+AG Vanc+AG Clostrdm Metrndzle Vanc, bacitracin Definitive therapy -depend on susceptibility & sensitivity tests. -requires isolation of the pathogen. -requires knowledge of the MIC and MBC. -Advantage: accuracy, cheaper -Disadvantage: delay treatment, specimen may be difficult to get, varying sensitivity patterns in different hospitals. Methods of susceptibility tests Broth microdilution Microdilution Agar dilution method Disk diffusion test (Bauer Kurby procedure) Susceptible Intermediate Resistant Duration of therapy Depends on: the pathogen; site of infection and host factors. Duration of Therapy for Bacterial Infections Duration of therapy Infections Single dose GU, Strep pharyngitis, prim and secondary syphilis 3 days Cystitis in young women, community/travel acquired dirrhea 3-10 days CAP(3-5days);CAM(pnemo or meningo);Antbtc assctd diarrhea(10 days);cellulitis ;epididymitis 2 weeks H.Pylori assctd PUD; neurosyphilis; disseminated gon infctns; acute pyelonephritis; Pen-suscptble VSE 3 weeks Lyme disease; septic arthritis (NG) 4 weeks Acut and chronic prostitis; IE (Pen resistant) >4 weeks A and C ostemyltis; S.aureaus endocarditis; FB infections Combination of antibiotics USED Provide broad-spectrum empiric therapy in seriously ill patients. Treat polymicrobial infection such as intraabdominal abscess. To decrease emergence of resistance strains. To enhance antibacterial activity (synergy) To use lower doses of a toxic drug Antibiotic prophylaxis Risk of infection must be greater than S/E of drugs Shortest time possible Primary or secondary prophylaxis Surgical or nonsurgical prophylaxis Antibiotic prophylaxis Surgical Contaminated and clean contaminated procedures Operations in which postop infections may be catastrophic eg open heart surgery Placement of prosthetic materials Procedures in imunocompromised pts. Nonsurgical Individuals at high risk for temporary exposure to selected virulant org. Patients at increased risk for developing infection because of underlying disease e.g immunocompromised pts MISUSE OF ANTIBIOTICS Treating FUO Improper dosing Inappropriate reliance on chemotherapy alone Lack of adequate bacteriological information Resistance to antibiotics RESISTANCE TO ANTIBIOTICS Genetic determinants of resistance Biochemical mechanisms of resistance Current status of antibiotic resistance Limiting resistance to antibiotics Genetic determinant of Resistance Chromosomal determinant Spontaneous mutation rate in bacteria popn. For any particular gene very low (1: 1000000) In most org., resistance from chromosomal mutation not of great significance coz mutants have decreased pathogenecity Impo. in MRSA and mycobacterium infections - TB Genetic determinant of Resistance Extrachromosomal determinants Plasmids: extra chromosomal genetic elements called plasmids that exist free in the cytoplasm. These genetic elements can replicate on their own. They are closed loops of DNA that consist of single gene or many genes. Plasmids that carry genes for resistance for antibiotics (r genes) are called R plasmids. Much drug resistance in clinical medicine is plasmid mediated. Transfer of r genes between bacteria take place in one of these form: 1. 2. 3. Transposons: stretches of DNA that can be transferred (transposed) from one plasmid to another or plasmid to chromosome. Conjugation: conjugate plasmids which cause bacteria to make a connecting tube btn bacteria through which the plasmid or other plasmids can pass. Transduction: transmission of r gene-carrying plasmid by bacteriophage (bacteria virus) BIOCHEMICAL MECHANISM OF RESISTANCE TO ANTIBOITICS 1. 2. 3. 4. Production of enzymes that inactivate the drug:B lactamase –penicillins, cephalosporins, acetyltransferase –CAF Alteration of drug sensitive site or binding site -plasmid mediated alt 50s binding site-erythromycin - alt of 30s subunit- amino glycoside (xsomal mutation) Decreased drug accumulation in the bacteria -active efflux of the drug: resistance to B lactams, amino glycosides, quinolones. -plasmid mediated resistance to TCs through efflux of the TCs Alteration of enzyme pathways -plasmid mediated synthesis of DHFR with low affinity for trimethoprim. Examples of antibiotic resistance Enteroccocci: B-lactam: b-lactamse enzyme AG: enzymes that modify the drugs Clindamycin:gene that effluxes the drug Vancomycin: modified targets of vanco (low level and high level resistance) Examples..ctd MRSA Many strains of staph now resistant to all currently available antibiotics. Produce B-latamase –resist to B-lactams -B-lactam binding protein –resist to methicillin -staph also show resistance to other antibiotics: streptomycic(alt of target site) -CAF & macrolides, (change enzymes -trim/sulfo,(DHFR, incr PABA) -amino glycosides (alt target site) -quinolones( decr uptake. Summary 1. 2. 3. 4. 5. 6. 7. Make a diagnosis as precisely as possible state org. responsible and site of infection Decide if chemotherapy is necessary: if no symptomatic rx. If yes: Select best drug Administer drug: best route, optimum dose , freq & duration. Continue therapy until cured/improvement. Test for cure/improvement. (clinical & lab.) ? Prophylaxis & how long EXAMPLE: IE Referances: Katzung pharmacology Harrisons internal med 17th ed Uptodate.com Hopkins-abxguide.com Idsociety.org YA MUNGU NI MENGI!!!!