Clinical Uses of Antibiotics PDF

Clinical uses of Antibiotics  Objectives  After this lecture you will be able to answer  What are antimicrobials, antibiotics, chemotherapeutic agents (Terminologies used in antimicrobial treatment)  Classification of antibiotics  Mechanisms of action of antibiotic...

Clinical uses of Antibiotics  Objectives  After this lecture you will be able to answer  What are antimicrobials, antibiotics, chemotherapeutic agents (Terminologies used in antimicrobial treatment)  Classification of antibiotics  Mechanisms of action of antibiotics  Resistance development in antibiotics  Multidrug resistant microorganisms  Terminology ▪Chemotherapy – ▪Use of drugs to treat infections 6 and malignancy. (Antimicrobials and Antineoplastic agents) ▪Chemotherapeutic agents- ▪Selectively acting against microbes or malignant cells. (Don’t touch body cells) ▪Antimicrobials – ▪Used in treating infectious diseases. ▪Antibiotics – ▪Produced from microbes to inhibit or kill other microbes. All antibiotics are antimicrobials but all antimicrobials are not antibiotics ▪ Bacteriostatic- ▪ Stop the growth of bacteria , so acts by preventing bacteria from multiplying and then hosts defences deal with the small number of bacteria left ▪ Bactericidal- ▪ Kill the bacteria ▪ Minimum Inhibitory Concentration (MIC)- ▪ Which stops the growth ▪ Minimum Bactericidal Concentration (MBC)- ▪ Which kills by 99.99%  The modern age of antibiotic therapeutics was launched in the 1930s with sulfonamides and the 1940s with penicillin  Since then, many antibiotic drugs have been developed, most aimed at the treatment of bacterial infections  These drugs have played an important role in the dramatic decrease in morbidity and mortality due to infectious diseases  The modern age of antibiotic therapeutics was launched in the 1930s with sulfonamides and the 1940s with penicillin  Since then, many antibiotic drugs have been developed, most aimed at the treatment of bacterial infections  These drugs have played an important role in the dramatic decrease in morbidity and mortality due to infectious diseases  Disadvantages:limited effect against G-ve, hydrolysis by gastric acid, inactivation by B- lactmase, hypersensitivity reactions in 1-10% of patients (anaphylaxis( death) in 0.5%, skin rashes, hemolytic anaemia, nephritis and drug fever).  ANTIBIOTICS ▪One of the most commonly used group of drugs ▪In USA 23 million kg used annually; 50% for medical reasons ▪May account for up to 50% of a hospital’s drug expenditure ▪Studies worldwide has shown a high incidence of inappropriate use  Broad-spectrum:  Justifiable in life-threatening disease, with unidentified organism  In general more expensive more likely to → resistance  More adverse effects than narrow spectrum (inc. superinfection) Narrow spectrum:  Preferable if possible  Dangerous choice in life-threatening disease unless organism (and sensitivities) known  Choice of an antibiotic ▪ Aetiological agent ▪ Patient factors ▪ Antibiotic factors  Aetiological agent ▪Clinical diagnosis ▪the most likely site/source of infection ▪the most likely pathogens ▪empirical therapy ▪universal data ▪local data ▪Resistance patterns vary ▪From country to country ▪From hospital to hospital in the same country ▪From unit to unit in the same hospital  Laboratory diagnosis ▪ ▪ what is isolated is not necessarily the pathogen ▪ was the specimen properly collected ? ▪ is it a contaminant or coloniser ? ▪ sensitivity reports are at best a guide  Patient factors ▪Age ▪Physiological functions ▪Genetic factors ▪Pregnancy ▪Site and severity of infection ▪Allergy  Antibiotic factors ▪Pharmacokinetic/pharmacodynamic (PK/PD) profile ▪absorption ▪excretion ▪tissue levels ▪peak levels, Time above MIC ▪Toxicity and other adverse effects ▪Drug-drug interactions ▪Cost  Principles of Antibiotic Guidelines  Guide to the empiric use of antibiotics.  Empiric treatment is the choice of antibiotic prior to sensitivity results being available  Avoid unnecessary use. If clinically feasible await results of microscopy /culture /susceptibility data for directed therapy  Principles of Antibiotic Guidelines  Specimens for microbiology should be taken prior to commencement of empiric treatemnt. In an emergency , at a minimum a set of blood cultures should be taken e.g meningitis.  Ensure any history of allergy is documented on the cover of notes prior to commencing antibiotics  Prescribing Practice -Document reason for starting agent or any change  Principles of Antibiotic Therapy Empiric Therapy (85%) Directed Therapy (15%)  Infection not well  Infection well defined defined (“best guess”)  Narrow spectrum  Broad spectrum  One, seldom two  Multiple drugs drugs  Evidence usually only 2  Evidence usually randomized controlled stronger trials  Less adverse reactions  More adverse reactions  Less expensive  More expensive  Why So Much Empiric Therapy?  Need for prompt therapy with certain infections  Life threatening infection  Mortality increases with delay in these cases  Cultures difficult to do to provide microbiologic definition (i.e. pneumonia, sinusitis, cellulitis)  Negative cultures  Provider Beliefs  Fear of error or missing something  Not believing culture data available  “Patient is really sick, they should have ‘more’ antibiotics”  Myth of “double coverage” for gram- negatives e.g. pseudomonas  “They got better on drug X, Y, and Z so I will just continue those”  To Increase Directed Therapy for Inpatients:  Define the infection 3 ways  Anatomically,microbiologically,pathophysiologically  Obtain cultures before starting antibiotics  Use imaging, rapid diagnostics and special procedures early in the course of infection  Have the courage to make a diagnosis  Do not rely solely on “response to therapy” to guide therapeutic decisions;follow recommended guidelines  If empiric therapy is started, reassess at 48-72 hours  Move to directed therapy  General Principles of Therapy  Antibiotic Tables ( see hospital policies) - Use empirically before results of Culture and Sensitivity available - Change when this information is available TO DIRECTED THERAPY - Specimens ( e.g for culture , PCR etc) should be taken before therapy exception e.g meningitis) - In serious sepsis Parenteral route of Administration to be use  General Principles of Therapy  Pharmacokinetics/ Pharmacodynamic may require dose/choice adjustment  Avoid use of topical antibiotics  Consultations: Microbiologists or ID physicians  Treatment and Prophylaxis clearly defined  Antibiotic classes  Beta-lactam  Lipopeptides  Tetracyclines  Chloramphenicol  Polymyxins  Sulfonamides  Trimethoprim  Rifamycins  Nitrofurantoin  Aminoglycosides  Quinolones  Macrolides  Lincosamides  Metronidazole  Glycopeptides  Oxazolidinones  MECHANISM OF ACTION 1\ inhibition of cell wall synthesis : Eg.(bactracin, cephalosporins , cycloserine , penicillins and vancomycin). Injury to cell wall (e.g. by lysozymes) or - inhibition of it is formation may lead to lysis of the cell.  2\ inhibition of the cell membrane function : Eg. (clostin , immedazole,polymaxin,amphotericin ) function of cell membrane :- - a) selective permeability barrier. b) control the internal composition of the cell. If the funtional of cytoplasmic membrane is - disrupted , macro_molecules and ions escape from the cell , and cell damage or death.  3\ inhibition of protein synthesis : Eg. (chloramaphenicol, erythromycin,lincomycin,tetracyclins and amino glycosides ). -bacteria have 70 S ribosomes where as mammalian cells have 80S ribosomes. The subunit of each type of ribosomes, their chemical composition and functional specificities are sufficiently to explain why antimicrobial drugs can inhibit protein synthesis in bacterial ribosomes without any effects on mammalian ribosomes.  4\ inhibition of nucleic acid synthesis : Eg.(quinolones , rifampin,sulfonamides( block tetrahydrofolic acid),trimethoprim(inhibit dihydrofolate reductase enzyme) - rifampin inhibit bacterial growth by binding strongly to the DNA – dependent RNA polymerase of bacteria,thus inhibits bacterial RNA synthesis(mRNA). - All quinolones and floroquinolones inhibit microbial DNA synthesis by bocking DNA gyrase  B-Lactams: Penicillins  Penicillin(bind to penicillin biding protein on bact. Surface) ,bacteria produce B-lactamase enzyme  Classes of penicillins:  Natural penicillins:  Penicillin G (Benzyl penicillin ,procaine,benzathine)- parenteral route Penicillin G first isolated from a pencillium mold  Penicillin V(same as phenoxymethylpenicillin)- oral route  Mainly active against Gram Positive organisms e.g.Spirochetes, Streptococci and Staphylococci, oral anerobes: peptostreptococcus and prevotella , some gram negative organisms are susceptible in higher concentrations  Aminopenicillins:Ampicillin,amoxicillin.Uses: Covers same stuff as penicillin and expanded activity against gram negatives ( E.coli, Proteus,H. influenzae, H. pylori, N. meningitidis, shigella, klebsiella); covers most spirochetes including lyme disease. Clavulanate enhances the gram negative spectrum to include additional anaerobes such as bacteroides.  Penicillinase-resistant penicillins(antistaphylococcal penicillins: Methicillin  Cloxacillin  Dicloxacillin:Nafcillin,oxacillin  Uses: Only good for staphylococcal spp producing penicillinase (except MRSA), pneumococcus and other streptococci  Extended spectrum penicillins(antipseudomonal penicillins): Azlocillin  Carbenicillin  Carboxy penicillins: Ticarcillin  Ureidopenicillins:Mezlocillin  Piperacillin   Uses: cover pneumococcus, streptococcal spp including enterococcus, gram negative including pseudomonas. Piperacillin with great activity against pseudomonas and klebsiella  Does not cover MRSA.  Beta-lactamase inhibitors: Clavulanic acid  B-Lactams: Cephalosporins Well tolerated and fewer hypersensitivity reactions (10% chance that pt. allergic to penicillin being hypersensitive to cephalosporin) 1st generation  Cefazolin,cephalothin,cephapirin,cephradine , cefadroxil,cephalexin:  Uses: G positive cocci e.g staph, strep; prophylactic in clean surgeries, cellultis, folliculitis  Minimal coverage of gram negative bacteria 2nd Generation  Cefuroxime(maxil):  Use:respiratory infections--Strep pneumoniae, H.influenzae and M.cattarhalis; , meningitis due to pneumococcus,H.influenzae and N.meningitidis.  Limitations: enteric organisms/abdominal anaerobes  Cefoxitin/Cefotetan, cefmetazole:  Use: intra-abdominal infections especially anerobes  Limitations: staph and other gram positives 3rd Generation  Cefotaxime & Ceftriaxone(samixon):  Uses: Good for staph and non-enterococcal strep; broad coverage of gram negative and oral anaerobes, CNS, pulmonary, endovascular, GI infections (excluding gut anaerobes), sinusitis, otitis, head & neck.  Limitations: does NOT cover Pseudomonas; ceftriaxone can cause biliary sludging and limits its utility in treating biliary tree infections  Ceftazidime:  Use: Good gram negative coverage including Pseudomonas; CNS infections- good for Pseudomonas meningitis  Limitations: reduced activity against the gram positives and oral anaerobes. 4th Generation  Cefepime & Cefpirome:  Uses: Enterobacter, Citrobacter and Serratia;Pseudomonas; gram positives; used in CNS infections.  5th Generation  Ceftaroline  Uses: Staphylococci including MRSA and streptococci resistant to penicillin  Beta-Lactams: Carbapenems  Imepenem:  activity against gram positive bacteria and gram negative  Ertapenem:  Good for aerobic gram negatives  poor coverage of pseudomonas ,E. faecalis, nocardia  Meropenem:  Good for aerobic gram negatives  Doripenem:  Good for CNS coverage and pseudomonas  Beta-Lactams: Monobactams  Aztereonam  Uses: G-ve only ,enterobacteriaceae and Pseudomonas aeruginosa  Cautions:  Beta-lactam allergy can occur in up to 10%  5%-10% cross-sensitivity in penicillin, cephalosporins, and carbapenems  Side effects:  diarrhea, nausea, rash  B-lactam in combination with B-lactamase inhibitors:  Amoxicillin+ clavulanic acid  -Co-amoxiclave or Amoclan  Pipracillin+ tazobactam  Ticarcillin+clavulanic acid  Glycopeptides:  Vancomycin  Teicoplanin  Uses: MRSA, Clostridium difficile and streptococci  Ciprofloxacin: Use: Covers most aerobic gram negatives including Pseudomonas. penetrates CNS, prostate, lungs Limited against staph  Non-ciprofloxacin quinolones: Ofloxacin, norfloxacin ,Levofloxacin, Moxifloxacin: Gemifloxacin:  Uses: Great for respiratory pathogens, most enteric gram negatives Only levofloxacin covers pseudomonas Covers some atypicals: Mycoplasma, Chlamydia, Legionella Nalidixic acid is less active ,use only in urinary tract infections  Cautions: Can cause Qt prolongation, tendon rupture, CNS toxicity , not used in pregnant women or children because they damage growing cartilage Do not use in patients with epilepsy or existing CNS lesions or inflammation  Side effects: Commonly causes Clostridium difficile infections  Uses:  Broad spectrum against gram positives , including strep, staph aureus (MSSA)  alternative in penicillin allergic patients. Good for atypical organism such as Mycoplasma, Chlamydia, Legionella  Covers N.gonorrhea, H influ.  Caution:  can interact with statin to cause myopathy  Can cause Qt prolongation Side effects: GIT upset  Clarithromycin, Azithromycin effective against wide range of organisms, long half life can be taken once or twice daily  Gentamicin, amikacin (tobramycin, streptomycin)  Mainly active against gram negative bacteria (enterobacteria,pseudomonas), Mycobacteria, staph including MRSA  Mainly used to treat nosocomial infections: pneumonia , septicaemia  Limiting factors are nephrotoxicity (and ototoxicity) and resistance  Also used in combination , poorly absorbed from GIT so cannot given orally  Streptomycin: Use in combination with other antituberculous drugs in treatment of TB patients, endocarditis, brucellosis  Tetracyclines(doxycycline , minocycline, oxytetracycline): Bacteriostatic , Rickettsial and chlamydial infections, mycoplasma pneumoniae. Not given during pregnancy or to young children (brown staining of the teeth of fetuses and young children - avid calcium chelators) , also it suppresses normal flora of GIT causing diarrhea  Chloramphenicol: Haemophilus influenzae,Neisseria meningitidis, Streptococcus pneumoniae meningitis, typhoid fever, anaerobic infections (Bacteroides fragilis). Bone marrow toxicity and aplastic anemia limit use to severe infections. Uses: Reasonable gram positive aerobic coverage against strep and many staph including MRSA Special role in treating strep in necrotizing fascitits Anaerobic coverage better than penicillin but not as good as metronidazole  Caution: can interact with neuromuscular blocking agents and cyclosporine  Side effects : Pseudomembranous colitis - Diarrhea, commonly causes C difficile—avoid clindamycin if other good options exist. Effect on Microbes: -Wide range of AM activity against both G+ve & G- ve bacteria. - But now resist. strains have become common & usefulness of these agents has diminished. - The Sulf. exert only bacteriostatic action. - Cellular & humoral defense mech. of the host are essential for final eradication of the Infection. Anti bact. Spectrum : - Resistance is increasingly a problem Still sensitive strains are most of the Strept. pyogenes , Haemophilus ducrei & influenzae , Vibrio cholerae. In 1970s however the combination of Trimethoprim & Sulfmethoxazole has increased the use of sulf.s for the treatment & prophylaxis of specific microbial diseases. 1. Urinary Tract Inf.s : Sulf.s are no longer a therapeutic choice in UTI. Preferred agents are –Trimethop. + Sulfamethoxazole , Sulfisoxazole may be used effectively 2. Nocardiosis – good response with Sulf.s e.g.- Sulfisoxazole & Sulfadiazine 3. Toxoplasmosis : Sulfadiazine+ Pyrimethamine. 4. Treatment & Prophy. of resist. Malaria: Sulfadoxine + Pyrimethamine( Fansidar) 5.Ophthalmic inf.s : topical –e.g.- Sulfacetamide. 6. Infection of Burns : e.g.- topical Silver sulfadiazine.  Uses : No aerobic activity Does not stand alone for mixed infections Good coverage of anaerobes.Can be used for C diff, parasites, bacterial vaginosis,abdominal surgery,dental abscesses Caution: May require reduced dose in liver disease.Can increase effect of warfarin  Side effects: Nausea, GI toxicity, headache, seizure, peripheral neuropathy with prolonged therapy.  PURPOSE OF DISCRIPTION: 1\ FOR TREATMENT. 2\ FOR PREVENTION.  GENERAL RULE OF USING ANTIMICROBIAL : 1\ Do not describe medicines of antimicrobial drugs that proved in Lab have not effect in bacteria. 2\ Giving medicine of antimicrobial drugs in sufficient amount and time. 3\ when give combination sure that not antagonistic effect of each to other.  FACTOR CONCERN ANTIMICROBIAL DRUGS Drug shape : a) in form of tablets. b) in form of capsule. c) in form of injection. d) in form of suspension.  * mechanisms of drug resistance: a) micro organisms produce enzymes that destroy the activity of the drug eg: ~Staphylococcus → B-lactamase ~Gram –ve → chloramphenicol acetyl transferase against chloramphenicol. b)Microorganism alters its permeability to the drug eg tetracyclin and polymyxin. Streptococci have natural barrier to aminoglycosides. c)Microorganism develops an altered structural target eg: Penicillin resistance →change in penicillin binding protein “PBP”.  d)Microorganisms develop an altered metabolic pathways that →bypass the reaction inhibited by the drug eg: Sulfonamides →can use the preformed folic acid without need to extracellular PABA.  e)Microorganisms alter an enzyme eg: Trimethprim resistant bacteria → dihydrofolic acid reductease is inhibited. Enzyme-based resistance– Break down of antimicrobials. Ribosomal modifications– Methylation of ribosome interferes with antibiotic binding. Protein modifications– Mutations leave target protein unrecognizable to antibiotic Metabolic resistance– Overcome competitive inhibition by alternate pathway. Efflux–  ORIGINS Non Genetic genetic Extrachromosomal chromosomal  Non genetic origin: *Active replication of bacteria is required for most antibacterial drug action eg : Mycobacterim tuberclosis stay many years in the body with slow multiplying. * Microorganism may lose target structure and so becomes resistant ,eg: penicillin susceptible organisms may have difficiency in L-aminoacids →cell wall diff- and so become resistant to cell wall  *microorganisms may infect cells which drug cann’t reach them,eg: Aminoglycosides → salmonella enteric fever Because salmonellae are intracellular microorganisms and aminoglycosides cannot enter the cell.  Bacteria naturally resistant e.g., Gram-negative bacteria resistant to penicillins Genes transferred to the bacterial progeny.  Bacteriamay be resistant because No mechanism to transport the drug into the cell. Do not contain antibiotic’s target process or protein.  Genetic origin : Either :a)chromosomal “mutation” :this develops as a result of spontaneous mutation in a locus that controls susceptibility to a given drug( F fertility plasmid governs the transfer of bacterial chromosome). b)extrachromosomal “plasmid mediated resistance”: bacteria often contain extrachromosomal gentic elements called plasmids. *R-factor(resistance factor) are a class of plasmids , circular ,double stranded DNA that carry genes for resistance to one –and often several – antimicrobial drug. 1) It occurs in many different species , specially gram –ve rods. 2) Plasmids frequentely mediate resistance to multiple drugs. 3)plasmids have a high rate of transfer from one cell to another by conjugation(under control of R-plasmid) The plasmid genes control the formation of enzs capable to destory the drugs eg:plasmids determine resistance to penicillins and cephalosporins by carring genes for the fomation B-lactamase ~Genetic material and plasmid can be transferred by transformation ,transduction ,conjugation and transposition. Is the uptake of the extra cellular DNA by bacteria thus ,altering its genotype. This can occur through labrotary manipulation (e.g: in recombinant DNA technology ). The genetic transfer occur when a fragment of DNA is carried to the recipient cell by virus “bacteriophage “ e.g :the plasmid carring of the gene for B-lactamase production ,can be transferred from apenicillin –resistant to a susceptible staph aureus. It is a unilateral transfer of genetic material between bacteria of the same or different genera occurs during (conjugation ) process. This is mediated by a fertility factor that result in extension or extrusion of sex pili from the doner (F+) cell to the recipient (F-). A transfer of short DNA sequences (transposons,transposable element ) occurs between one plasmid and another or between a plasmid and a portion of the bacterial chromosome.     ATTACK OF THE SUPERBUGS: ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative Quarterly. Jan 07 Microorganisms resistant to a certain drugs may also be resistant to other drugs that share a mechanism of action eg: ~different aminoglycosides are closely related chemically ~macrolides and lincomycins :have a similar mode of action or binding. Prescription related factors: Overuse Early discontinuation Over continuation Less dose, duration Livestock doping: Animals exposure 1\ by maintainig sufficiently high level of the drug in the tissues to inhibit both the original population and the first step mutants 2\by simultaneously administering two drugs that don’t give cross resistance (each of which delays the emergence of mutants resistant to the other drug eg :Rifampin and isoniazide in treatment of T.B) 3\ by avoiding exposture of microorganism to a particularely valuable drug by limittig its use specially in hospital. 4\health awareness about missuse of Antibiotics 5\ Antibiotic sensitivity testing ,minimal inhibitory concentration(MIC),minimal bactericidal concentration(MBC)  Beta-lactams:- Hydrolysis , mutant PBP  Tetracycline: - Active efflux from the cell  Aminoglycosides- Inactivation by enzymes  Sulfonamides- Alternate pathway,  Fluoroquinolones- Mutant DNA gyrase  Chloramphenicol- Reduced uptake into cell  Macrolides - RNA methylation, drug efflux *Refrences: 1\GOODMAN & GILLMANS pharmacological basis of theraputics 2\ jawetz MEDICAL MICROBIOLOGY 3\ESSENTIALS OF MICROBIOLOGY WELSY.A.VOLK