Introduction to Antimicrobial Treatment PDF

Introduction to Antimicrobial Treatment  Topic Objectives At the end of this topic, you should be able to: 1)Describe what an infection is and list the common micro-organisms that infect human. 2)Explain the infection process. 3)List the mode of transmission of different infec...

Introduction to Antimicrobial Treatment  Topic Objectives At the end of this topic, you should be able to: 1)Describe what an infection is and list the common micro-organisms that infect human. 2)Explain the infection process. 3)List the mode of transmission of different infections. 4)Define common terminologies used in the context of infections.  What is an infection? An infection happens when microorganisms (e.g. bacteria, fungi, viruses or parasites) enter the human body and start to multiply  What happens in an infection? People with an infection may or may not have any signs and symptoms If the infection causes harmful effects on the body, it is called a disease Infections can be described as local infection if they are restricted to a small area of the body If it spreads throughout the body system, it is called systemic infection  Patterns of Infection Mixed infection – several microbes grow simultaneously at the infection site Primary infection – an infection that develops in an otherwise healthy individual Secondary infection – an infection that develops in an individual who is already infected with a different pathogen Acute infection – comes on rapidly, with severe but short-lived effects Chronic infections –progress and persist over a long period of time 5 Infectious Disease Process  CHAIN OF INFECTION  Infectious agent or pathogen  Reservoir  Portal of exit  Mode of transmission  Portal of entry  Susceptible host  Infectious Agent/Pathogen Microorganisms that can cause diseases E.g. Bacteria Viruses Fungi Protozoa Parasites  Reservior Animate sources (humans, animals, insects) Inanimate sources (soil, water, food, medical equipment) Pathogens need a proper environment to survive (food, oxygen, water, temperature, pH, light)  Living Reservoirs Carrier – an individual who inconspicuously shelters a pathogen and spreads it to others; may or may not have experienced disease due to the microbe Asymptomatic carrier – – incubation carriers – spread the infectious agent during the incubation period – convalescent carriers – recuperating without symptoms – chronic carrier – individual who shelters the infectious agent for a long period Passive carrier – contaminated healthcare (their provider picks up pathogens and transfers them to other patients body themself didn't infected 10  3 m r * 11  Portal of Exit/Entry Skin and Mucous Membranes Respiratory Tract Urinary Tract Gastrointestinal tract Reproductive Tract Blood  Modes of Transmission Contact (Direct & Indirect) Droplet Airborne Vehicles Vectors ·. ⑳ · ⑳ G mmmm mus ·  I spread > - · isin ⑪ manaka tahun things Whea Cohh simple , 14  Susceptible Host Susceptibility (refers to degree of resistance to infection) Factors which influence susceptibility: - Age - Nutritional status - Chronic disease history - Immunity - genetics - personal hygiene  The Infection Process 4 distinct stages of clinical infections: – incubation period - time from initial contact with the infectious agent to the appearance of first symptoms; agent is multiplying but damage is insufficient to cause symptoms; several hours to several years – prodromal stage – vague feelings of discomfort; nonspecific complaints – period of invasion – multiplies at high levels, becomes well established; more specific signs and symptoms – convalescent period – as person begins to respond to the infection, symptoms decline 16  Major Factors in the Development of an Infection True pathogens – capable of causing disease in healthy persons with normal immune defenses – influenza virus, plague bacillus, malarial protozoan Opportunistic pathogens – cause disease when the host’s defenses are compromised – Pseudomonas sp & Candida albicans Severity of the disease depends on the virulence of the pathogen 18 How to break the infection chain? 1. Pathogenic microorganism - Identification of infectious agent and appropriate treatment 2. Reservoirs - Potential hosts and carriers must practice asepsis and maintain personal hygiene - sanitation, disinfection/sterilization of equipments 3. Portal of exit - covering mouth and nose while coughing/sneezing - handwashing, - use of personal protective equipment  How to break the infection chain? 4. Mode of transmission - proper hand washing - isolation of infected patients - disinfection and sterilization techniques 5. Portal of Entry - Aseptic technique - proper catheter and wound care 6. Host susceptibility - Treatment of disease, identify people at risk - immunization, proper nutrition  Antimicrobial Therapy Therapeutic goal – To clear the tissue of the infecting organisms There are a lot of chemicals that will destroy microbes – The problem is that they may also destroy the host  Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany) Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans. He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals  The first antibiotic, Penicillin G, was discovered in 1929 by Alexander Fleming. 1940s: Penicillin was tested clinically and mass produced. A. Fleming  He observed that Penicillium fungus made an antibiotic, Penicillin, that killed S. aureus  In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol, tetracyclines, and S. Waksman erythromycin in soil samples. In 1939 Florey and colleagues at Oxford University again isolated penicillin G. Florey E. Chainy  Antibiotics are chemical substances produced by microorganisms (such as bacteria, fungi, actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them. Some antibiotics have been produced by chemical synthesis or semi- synthetically from natural substances. How To Achieve Therapeutic Goal? Organism must be susceptible/sensitive to the drug Organism must be susceptible to concentrations of drug at infected site Dose and route of administration result in adequate levels of drug at infected site for a sufficient time in order to rid the organisms Host defenses facilitate microbial clearance Adjunctive therapies such as drainage or relief of obstruction be used when necessary 28  Types of Antimicrobial Agents Antibacterial Agents/Antibiotics Antifungals Antivirals Antiprotozoa Antihelmintics Clinical uses of antimicrobial agents Antimicrobials have three general uses 1- Empirical therapy or initial therapy: the antimicrobial should cover all the likely pathogens because the infecting organism(s) has not yet been defined; maybe necessary for pt with serious infection before lab results 2- Definitive therapy or pathogen-directed therapy: once the infecting microorganism is identified, definitive antimicrobial therapy should be instituted with a narrow-spectrum, low-toxicity agent to complete the course of treatment 3- Prophylactic or preventive therapy: e.g. in surgery, pt who had recurrent infection  Antimicrobial regimen selection A generally accepted systematic approach to the selection and evaluation of an antimicrobial regimen involves the following steps: Confirming the presence of infection Identification of the pathogen Selection of rational antimicrobial therapy Monitor therapeutic response 40 MCC MIDSEM Antibacterial Therapy  Topic Objectives At the end of the topic, you should be able to: 1)Explain the different classifications of bacteria. - 2)Define various terminologies related to antibiotic - - - - use. 3)List different - - classes of antibiotics according to their mechanisms - of action and chemistry. 4)List examples of each class of antibiotics, explain = their pharmacological actions, S/E, C/I etc. - - 5)Discuss the development of antibiotic resistance and ways to minimize it. u u  What Are Bacteria? Bacteria are single-celled organisms that come in different shapes They can reproduce quickly by cell division They can be classified by their cell wall into Gram- positive and Gram-negative species They can also be classified by their shape, their motility and their need for oxygen – aerobes or - anaerobes = Many bacteria are commensals but can cause diseases when the opportunity arises - these are called opportunistic pathogens Bacteria Classification by Cell Wall The bacterial cell wall contains a substance unique to bacteria called peptidoglycan which give strength and integrity to the cell wall Gram positive bacteria have thicker layer of peptidoglycan compared to Gram negative bacteria The enzyme that is responsible for production of peptidoglycan is called Transpeptidase Gram negative bacteria are more resistant to antibacterial drugs because of their cell wall is more complex and makes drug penetration more difficult  Gram +ve Vs Gram -ve Examples of Gram +ve species Examples of Gram –ve species Enterococci species Escherichia coli Staphylococcus aureus Salmonella species Streptococci species Helicobacter pylori Clostridium difficile Klebsiella Pseudomonas aeruginosa Campylobacter species Clamydia traachomatis Haemophilus influenzae Bacteria Classification by Shape Classification by Oxygen Requirement Aerobic – grow and live in presence of oxygen – Staph & Strep Anaerobic – cannot grow in presence of oxygen – Deep wounds – Characterized by abscess formation, foul-smelling pus and tissue destruction  How Bacteria Cause Disease? Many bacteria are opportunistic pathogens that multiply when the conditions are favorable and cause diseases Bacteria such as Staphylococci, Streptococci and Clostridium release toxins that damage the host cells and their membranes Gram –ve bacteria such as Escherichia, Pseudomonas and Salmonella have components in the cell walls that are toxic  Principles of Antibacterial Action Antibacterial drugs target bacteria cells that are living and reproducing within the human body They must be able to kill harmful bacteria without damaging the host cells Since bacteria are prokaryotic so antibacterial drugs must target bacterial cell structures that are different from those in eukaryotic human cells (principle of selective toxicity) A bacteriostatic antibacterial is **not suitable** for treating a bacterial infection in an HIV positive person. Here's why: 1. **Bacteriostatic vs. Bactericidal**: - Bacteriostatic drugs only inhibit bacterial growth - Bactericidal drugs kill bacteria 2. **HIV and Immune System**: - HIV positive individuals have compromised immune systems - They need more aggressive treatment to fight infections 3. **Treatment Effectiveness**: - Bacteriostatic drugs rely on the body's immune system to clear the infection - In HIV positive patients, the weakened immune system may not effectively eliminate the bacteria Therefore, a bactericidal antibiotic would be more appropriate for treating bacterial infections in HIV positive individuals.,,  Bacteriocidal vs. Bacteriostatic O Bacteriocidal: drug actually kills bacteria ▪Irreversible inhibition of growth ▪When the antibiotic is removed, almost none of the bacteria can replicate - E.g. beta-lactams, vancomycin & Bacteriostatic: drug inhibits bacteria reproduction so host defenses can kill ▪Reversible inhibition of growth ▪When the antibiotic is removed, almost all of the bacteria can replicate - E.g. neomycin that is put on a cut  Bacteriostatic and bactericidal antibacterial agents Bacteriostatic Bactericidal Chloramphenicol, Aminoglycosides, Clindamycin, Ethambutol Cephalosporins, Macrolides, Penicillin, Nitrofurantoin, Isoniazid, Sulfonamides, Metronidazole, Polymyxins, Tetracyclines, Fluoroquinolones, Trimethoprim Rifampin, Vancomycin  Concentration Dependent Vs Time Dependent Killing Bactericidal drugs can be divided into 2 subgroups: Concentration-Dependent Killing - The rate & extent of killing increases as the peak drug concentration increases - E.g. Aminoglycosides , fluoroquinolones, metronidazole Time-Dependent Killing - Bactericidal activity continues as long as the plasma concentration is above the minimum bactericidal concentration (MIC) - plasma concentration must be maintained above the MIC for the entire time interval between doses - E.g. beta-lactams , vancomycin, macrolides, tetracycline  Selective Toxicity and Spectrum of Activity Selective toxicity: Drug is toxic to the microorganism but not to the human host Narrow spectrum: Drugs that are effective against a limited range of microorganisms Broad spectrum: Drugs that are effective against a wide variety of microorganisms  Principles of Antimicrobial Selection 1.Match the drug to the bug Identify pathogen: culture, gram stain Determine microbial susceptibility to drug: culture and sensitivity test 2. Consider Drug Spectrum Narrow vs. Broad Spectrum drug 3. Consider Combination therapy antibiotics that work by different mechanisms may be synergistic In the case of mixed infections with more than one bacterial species, a combination may be required. In some instances, antibiotic resistance is discouraged by combinations. 4. Consider Site of Infection &  Principles of Antimicrobial Selection and Administration Maintain Adequate Blood Levels Many antibiotics should be administered around-the- clock, i.e. every six hours for 4 times per day, every eight hours for 3 times per day, etc. – This depends on the half-life of the medication – Also depends on how fast the medication is excreted through the liver or the feces Oral antibiotics should be administered on an empty stomach and should not be co-administered with other oral medications. – Ex. antacids and other forms of calcium can many times inactivate the antibiotics  Principles of Antimicrobial Selection and Administration Antibiotic Combinations Combinations of antibiotics that work by different mechanisms may be synergistic or they may work against each other. In the case of mixed infections with more than one bacterial species, a combination may be required. In some instances, antibiotic resistance is discouraged by combinations. Combinations should be used only when indicated.  Empiric Therapy Administration of antibiotics based on the practitioner’s ranm judgment of the pathogens um most likely to be -m causing the infection; it involves the presumptive umm treatment of an infection to avoid - treatment delay before specific culture information has been obtained.-  Definitive Therapy O Antibiotic is given based on the culture and Amm sensitivity test results Use a narrow spectrum antibiotic with the least toxicity  Prevention Prophylactic Antibiotic Therapy Antibiotics taken before anticipated exposure - to an infectious - organism in an effort to prevent un the development re c e of infection. – IV antibiotics given prior to surgery  Superinfection An infection occurring during antimicrobial - treatment for another infection, resulting - from overgrowth of an organism not - susceptible to - the antibiotic used. A secondary infection that occurs due - weakening of the patients immune system by - u the first infection. ~  Examples of Superinfections Fungal or yeast infection Diarrhea due to diminished normal flora of the gastrointestinal tract. Destruction of normal flora allows pathogenic pathogens to dominate disease & bluyour  Organism Sensitivity Organism Sensitivity: drug is toxic to the - microorganism causing the infection. - - – A laboratory test will determine this.  Culture - and Sensitivity Testing of Bacteria Bacteria isolated from the site of infection are cultured on a plate - Paper discs soaked with various antibiotics are applied to the plate – If the bacteria is affected by the antibiotic (is sensitive to it), a clear area will develop around the antibiotic-soaked disc The extent of the clear area is a measure of how well the antibiotic works against that particular bacterium  Classification of Antibacterials Antibiotics are usually classified according to: Chemical Structure Mechanism of Action  Chemical Classification 1. Aminoglycosides – e.g. Gentamicin, Neomycin, - => streptomycin > - etc & 2. Penicillins – e.g. Penicillin G, Penicillin V, Ampicillin, - - m Amoxycillin, Cloxacillin um um 3. Cephalosporins – e.g. Cephalexin, Cefuroxime, - - ceftriaxone - 4. Macrolides – Erythromycin, Clarithromycin, = - - - Azithromycin = - 5. Tetracyclines – Tetracycline, Doxycycline, Minocycline um um -u 6. Fluoroquinolones – Ciprofloxacin, Norfloxacin -- 7. Sulphonomides – Sulfamethoxazole, Sulfanilamide 8. Polypeptides – e.g. Polymyxin, Bacitracin 9. Miscellaneous antibiotics – e.g. Rifampicin, Vancomycin, Chloramphenicol, Fusidate sodium  Mechanism of Action of Antibiotics 1. Inhibition of cell wall synthesis 2. Inhibition of protein synthesis 3. Inhibition of nucleic acid synthesis 4. Injury to plasma membrane 5. Inhibition of synthesis of essential metabolites Modes of Antimicrobial Action Inhibition of Cell Wall Synthesis Most bacteria possess a cell wall to protect from osmotic pressures Bacterial cell walls are composed of strands of peptidoglycan linked together by the enzyme transpeptidase to form a rigid structure Microbe divides – needs to create a new cell wall – Interrupt this leads to new microbes being susceptible to external influences – Cell ruptures → Microbe death Eg. Penicillins, cephalosporins, cabapenem, vancomycin-  Inhibition of Protein Synthesis These drugs target bacterial ribosomes and prevent bacteria from producing proteins Proteins vital for growth and repair Cells need protein to undergo cell division, therefore drugs which inhibit protein synthesis are bacteriostatic Eg. Tetracyclines, Aminoglycosides and Macrolides (erythromycin) -  Inhibition of Nucleic Acid Synthesis These drugs interfere with the enzymes involved in DNA replication and transcription such as Topoisomerase and DNA Gyrase Inhibition of these enzymes prevent bacteria from dividing E.g. Rifampicin and Fluroquinolones  Inhibition of synthesis of essential metabolites Bacteria cells are impermeable to folic acid so they must synthesize their own from PABA folic acid which is essential for nucleic acid synthesis, without it microbes can not produce the proteins for growth Antibiotics can inhibit folic acid synthesis E.g. Sulphonamides, Trimethoprim  Injury to cell membrane All cells are bound by a cell membrane Certain antibiotics act as detergents to dissolve bacterial cell membranes by binding to phospholipids present in the membranes This increases the permeability of the cell membrane → leakage of cell contents E.g. Polymyxin Note: These agents are more toxic systemically than those agents that inhibit cell wall synthesis INHIBITORS OF CELL WALL SYNTHESIS Beta-lactams Vancomycin  Inhibitors of Cell Wall Synthesis: Beta-Lactam Antibiotics The Penicillins, Cephalosporins and Carbapenems belong to a group called - lactams They all possess a functional group called - lactam ring which is essential to their antibacterial action  Types of Beta-Lactam Antibiotics 1. Penicillins 2. Cephalosporins 3. Carbapenems 4. Monobactams Lehne, 2007, Pharmacology for Nursing Care, 6th ed., Elsevier, p. 39963  Penicillins Penicillins act by inhibiting the enzymes (Penicillin Binding Proteins) involved in the cross-linking of the peptidoglycan layer of cell walls They are bactericidal – cause lysis or rupture of bacterial cells Effective only against multiplying organisms They exhibit time-dependent killing They have high therapeutic index – human cells do not have cell wall  Examples of Penicillins Benzylpenicillin (Penicillin G) Phenoxymethylpenicillin (Penicillin V) Cloxacillin Ampicillin (Penbritin ) Amoxicillin (Amoxil ) Bacampicillin (Penglobe) All oral Penicillins are best given on an empty stomach to avoid absorption delay caused by food  Pharmacokinetics of Penicillins Some Penicillins are destroyed by gastric acid and not suitable for oral use e.g. Benzylpenicillin Others e.g. Phenoxymethypenicillin, Ampicillin, Amoxicillin, Bacampicillin , Cloxacillin are given orally Most have a short half-life – need several doses per day Distribution – Bound to plasma proteins and do not cross blood-brain barrier well except when the meninges are inflamed Excretion - kidneys – Excretion can be delayed by giving together with Probenecid – used to prolong effect – Dose should be reduced for pt with impaired renal function  Penicillin Allergy As with any drug allergy, Penicillin allergy involves the immune system and antibodies that bind to the drug or its metabolites Can be as mild as rash or severe as anaphylaxis Can occur with first or repeated exposure Cross-allergy between various forms of Penicillins & other beta-lactam antibiotics such as Cephalosporins  Adverse Effects of Penicillins Main A/E is allergic reactions – when giving IV or IM observe for ½ to 1 hour after giving Diarrhea due to alteration of normal intestinal flora Neutropenia if Penicillins (or other -lactams) are used at high dose for more than 10 days Overdose can cause neurologic problems, including seizures  Drug Interactions of Penicillins Synergistic with Aminoglycoside antibiotics, but can not be administered in the same IV line – when mixed both drugs are inactivated May decrease the effectiveness of oral contraceptives  Bacterial Resistance to Penicillins The main defense of bacteria against penicillins is to produce -lactamases enzymes -lactamases open the -lactam ring of penicillins and rendering them ineffective Bacteria also modify their PBPs so that they have no affinity for -lactam Other mechanism include reduction in permeability of cell membrane and possession of pumps which remove -lactam molecules that managed to enter  Beta-Lactamases (Penicillinases) Enzymes that cut the beta-lactam ring, inactivating beta lactam antibiotics Bacteria that manufacture beta- lactamases may be resistant to all or most beta lactam antibiotics. Lehne, 2007, Pharmacology for Nursing Care, 6th ed., Elsevier, p. 47 964  Beta-Lactamase Inhibitors Drugs that bind to the active site of beta- lactamases, preventing these enzymes from cutting the beta-lactam ring of the antibiotic – This prevents resistance of the bacteria to these antibiotics Many beta-lactamase inhibitors are irreversible Beta-lactam antibiotics can be administered along with beta-lactamase inhibitors E.g. of -lactamase inhibitors: Clavulanic acid, Sulbactam, Tazobactam Penicillin/Cephalosporin-Beta-Lactamase * Inhibitor Combinations Preparations that combine a beta-lactam drug and beta-lactamase inhibitor: Amoxicillin + clavulanic acid = Augmentin® Ampicillin + sulbactam = Unasyn® Cefoperazone + Sulbactam = Sulperazon® Piperacillin + tazobactam = Tazocin®  Cephalosporins Widely used drug derived from fungus Molecular structures closely related to penicillin – presence of beta-lactam ring Mechanism of action similar to penicillins- they are bactericidal and exhibit time- dependent killing First generation Cephalosporin drugs do not reach therapeutic levels in CSF (cerebral spinal fluid) but 2nd, and 3rd generation drugs do – especially important in treating meningitis Mechanism of Action of Cephalosporins Cephalosporins inhibit cell wall synthesis by binding to enzymes called penicillin binding proteins (PBP) They are bactericidal They exhibit time-dependent killing – optimal dosing regimens should continuously maintain drug levels above MIC  Pharmacokinetics of Cephalosporins Widely absorbed and distributed in most bodily fluids – placenta and breast milk Most are excreted unchanged in the urine – dose reduction in pt with renal impairment First generation Cephalosporin drugs do not reach therapeutic levels in CSF (cerebral spinal fluid) but 2nd, and 3rd generation drugs do – especially important in treating meningitis Wide distribution allows treatment of infection at most sites including bone, soft tissue, muscle and CSF  Classification of Cephalosporins Based on their spectrum of activity, Cephalosporins can be categorized into 4 generations Each newer generation has better Gram –ve activity than the preceding generation but less Gram +ve activity 1St generation Cephalosporins have better activity against Gram +ve bacteria & less Gram –ve activity 3rd generation Cephalosporins have better Gram –ve activity and less Gram +ve activity 4th generation agents have both Gram –ve & Gram +ve activity  Cephalosporin Route Dose 1st Generation Cefazolin IV/IM 1-2g Q8H Cephalexin Oral 250-500mg Q6H Cefadroxil Oral 500mg Q12H 2nd Generation Cefuroxime IV/IM, Oral IV/IM: 1-2g Q8H, PO:250-500mg Q12H Cefaclor Oral 250-500mg Q8H Cefprozil Oral 250-500mg Q12-24H 3rd Generation Cefataxime IV/IM 1-2g Q6-8H Ceftriaxone IV/IM 1-2g Q12-24H Cefoperazone IV/IM 1-2g Q12H 4th Generation Cefipime IV/IM 1-2g Q12H  Major Differences between Cephalosporin Generations Activity against Resistance to Distribution to Gram Negative Beta- CSF Lactamase Generation enzymes 1st(e.g. Low Low Poor Cephalexin) 2nd (e.g., Higher Higher Poor Cefuroxime) 3rd (e.g. Higher Higher Good Ceftriaxone) 4th (e.g. Highest Highest Good Cefepime)  Clinical Uses of Cephalosporins Their broad spectrum of activity and safety profile make the Cephalosporins one of the most widely prescribed class of antimicrobials The earlier generation Cephalosporins are commonly used for community-acquired infections while the later generation agents, with their better spectrum of activity against gram- negative bacteria make them useful for hospital-acquired infections or complicated community-acquired infections Adverse Effects of Cephalosporins Cephalosporins are well tolerated Most common side effects are allergic reactions Cross allergy between Penicillins in about 7% of pt - contraindicated in pt who have severe or immediate allergy to penicillin Pain at injection site Prolong blood clotting time with large doses Broad spectrum of 3rd gen agents kills off normal flora in GIT – causes diarrhea & superinfection Dah Nephrotoxicity in pt with renal disorder Disulfiram-like reaction when taken with alcohol (flushing, HR, N/V, headache, visual disturbance)  Mechanisms of Bacterial Resistance 1. Destruction of -lactam ring by -lactamases – an intact -lactam ring is essential for antibacterial activity 2. Altered affinity of cephalosporins for their target site, the PBPs 3. Decreased penetration of cephalosporins to the target site especially Gram –ve bacteria  Carbapenems This is another group of -lactam antibacterials They have very wide spectrum of activity – bactericidal against most Gram +ve & Gram –ve aerobic and anaerobic pathogens Their structure is resistant to hydrolysis by - lactamases Antibiotics of last resort for many bacterial infections – e.g. septicemia, intra-abdominal infection, nosocomial pneumonia E.g. Imipenem, Meropenem(for bacterial meningitis , crosses CSF) ROA: IV  Vancomycin (Vancocin ) Vancomycin is a glycopeptide antibiotic Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram +ve bacteria treatment with other antibiotics failed It is the drug of choice for MRSA (methicillin resistant staph. aureus ) MOA: Inhibit cell wall synthesis at a site different from the -lactams  Pharmacokinetics of Vancomycin It is poorly absorbed from the GIT- usually given IV Oral treatment is only for pseudomembraneous colitis where it has to reach the site of infection in the colon Widely distributed into body tissues and eliminated by the kidneys It exhibits time-dependent bacteria killing Therapeutic Drug Monitoring may be necessary in pt receiving concomitant Aminoglycosides, pt with renal impairment, pt on hemodialysis  Adverse Effects of Vancomycin Ototoxicity (tinnitus & deafness)and Nephrotoxicity at high plasma levels Ototoxicity maybe reversed if drug is stopped Rapid IV infusion may cause vasodilatation (rash) and hypotension due to histamine release (‘Red man’ syndrome) - therefore must be infused slowly (1 hr) in a diluted solution others: fever, rash and pain at injection site  INHIBITION OF PROTEIN SYNTHESIS Aminoglycosides Macrolides Tetracyclines Chloramphenicol Clindamycin  Aminoglycosides Aminoglycosides inhibit protein synthesis at the level of the 30s ribosome – result in abnormal proteins which are fatal to the microbe They are bactericidal They exhibit concentration-dependent bacterial killing – must achieve relatively high plasma concentration for effective killing They have broad spectrum of activity but with low activity against anaerobes Good substitute antibiotic for pt allergic to penicillins Pharmacokinetics of Aminoglycosides They are usually administered IV or IM – poor absorption in GIT Eliminated unchanged in the urine Regular TDM is necessary – more frequently in pt with renal impairment Distributed mainly to the extracellular fluids, poor transfer to CSF Single daily dose regimen is equally effective and cause less oto- and nephrotoxicity  Adverse Effects of Aminoglycosides Toxicity increases with high dose and long duration, renal insufficiency, dehydration or co-administered with other nephrotoxic drugs Ototoxicity – hearing loss, vertigo and tinnitus, serious ototoxicity can occur with topical application, including ear drops Nephrotoxicity – usually reversible; low BP, loop diuretics and advanced age  risk Neuromuscular blockade – C/I in Myasthenia Gravis Others: rash, hemolytic anemia and bleeding  Examples of Aminoglycoside Gentamicin Tobramycin Streptomycin Neomycin Netilmicin Amikacin Framycetin Drug Interactions of Aminoglycosides When administered concurrently with Penicillins, the effect of Aminoglycosides are greatly decreased – should be given several hours apart Effects of anticoagulants such as Warfarin can increase when taken together with Aminoglycosides  Macrolides Macrolides are broad spectrum antibiotics MOA: Macrolides bind to the 50s ribosomal subunits and inhibit protein synthesis Macrolides typically display bacteriostatic activity, but may be bactericidal when present at high concentrations against very susceptible organisms Exhibit time-dependent killing ROA: oral or IV; not IM because it is too painful IV infusion should be slow and diluted in NS or D5W to avoid pain  Examples of Macrolides Erythromycin (base, stearate, ethylsuccinate, estolate) Azithromycin (Zithromax) Clarithromycin (Klacid  ) sensitiveto the Azithromycin & Clarithromycin have longer duration and improved resistance to acid degradation in the stomach – less frequent dosing , less GI S/E and better absorption 5 todayonly  Pharmacokinetics of Macrolides Gastric acid destroys Erythromycin; therefore acid resistant salts are added e.g. can' ethylsuccinate, stearate, estolate or enteric- eve coated to decrease dissolution in the stomach Normally food does not affect the absorption of acid resistant Macrolides They are excreted in the bile, feces and urine; only a small amount is excreted in urine, so renal insufficiency is not a contraindication  Adverse Effects of Macrolides Most common S/E: GI disturbance such as N/V, diarrhea, abdominal cramp Hepatotoxicity can occur with Erythromycin and Azithromycin are taken in high doses with other hepatotoxic drugs such as Paracetamol(high dose), Phenothiazine and Sulfonamides – usually reversible when drug is discontinued  Interactions of Macrolides Erythromycin and other Macrolides are enzyme inhibitors and interfere with metabolism of other drugs e.g. Warfarin, Carbamazepine, Theophylline, Disopyramide and increase their effects Azithromycin peak levels may be reduced by antacids when taken at the same time Azithromycin is usually given once daily for 3 days only – due to its long half-life  Mechanism of Resistance of Macrolides Active Efflux - an efflux pump which pumps the Macrolide out of the cell away from the ribosomes Altered target sites – alteration of the binding site of the Macrolides on the ribosomes  Tetracyclines Tetracycline was the first broad spectrum antibiotic effective against Gram +ve and Gram –ve bacteria and many other organisms MOA: Tetracyclines binds reversibly to bacteria 30s ribosomes and interfere with protein synthesis They are bacteriostatic They are selectively taken up by bacterial transport system not found in mammalian cells  Examples of Tetracyclines Tetracycline = Minocycline (Minocin ) = Doxycycline (Vibramycin ) F Pharmacokinetics of Tetracyclines Tetracyclines are usually given orally, IM injections are painful, IV for severe infection Oral absorption of Tetracycline can be affected by calcium (e.g. milk) , iron, magnesium or aluminium salts (e.g. antacids) – must be taken on empty stomach i.e. 1 hour before or 2 hour after food Absorption of Doxycycline and Minocycline is more rapid and complete They are widely distributed and cross placenta Mostly excreted in the urine – avoid in impaired renal function – Doxycycline & Minocycline preferred because excretion is non-renal  Adverse Effects of Tetracyclines Common side effects are N/V, diarrhea Photosensitivity may occur – advise pt to use sunblock & protective clothing [Pregnant women14 and children&younger than 8 - - years = should not take tetracycline as it can cause discoloration of permanent teeth - Minocycline can cause vestibular disturbance – interference with balance  Other Inhibitors of Protein Synthesis Clindamycin (Dalacin )) Spectrum of activity similar to Erythromycin & Benzylpenicillin Well-absorbed and distributed widely including bones Used for joint, dental & serious intra-abdominal infection Topical preparation used for severe acne Serious adverse effect is antibiotic-associated colitis due to opportunistic pathogens  Other Inhibitors of Protein Synthesis Chloramphenicol It is both bacteriostatic as well as bactericidal depending on bacterial species Broad spectrum of activity – G-ve & G +ve Well distributed including CSF & brain Due to its toxicity, reserved for life-threatening infections; e.g. typhoid fever & meningitis ROA: oral, IV, topical (eye & ear drops) C/I: pregnant women & neonates Blood level monitoring is necessary (esp. neonates & infants)  Other Inhibitors of Protein Synthesis Chloramphenicol (continue) Use of chloramphenicol has been replaced by other safer drugs such as Cephalosporins & Quinolones neonates cannot metabolize Chloramphenicol and ‘gray baby syndrome’ develops (circulatory collapse, pallor, abdominal distention and vomiting) Systemic use of Chloramphenicol cause rare bone marrow damage - even with eye-drops – frequent full blood count to detect Chloramphenicol has a bitter taste, esp when used as eye drops Inhibition of Nucleic Acid Synthesis Fluoroquinolones Sulphonamides/Trimethoprim Metronidazole Nitrofurantoin  Fluoroquinolones MOA: Inhibit DNA gyrase - enzyme which is needed in the synthesis of bacterial DNA They are bactericidal & exhibit concentration dependent bacterial killing play an important role in treatment of serious bacterial infections, especially hospital- acquired infections Well absorbed from the gut and widely distributed in body tissues ROA: oral, IV  Examples of Fluoroquinolones Ciprofloxacin (Ciprobay  ) Moxifloxacin (Avelox ) Levofloxacin (Cravit  ) Ofloxacin (Tarivid  ) Norfloxacin (Noroxin  )  Adverse Effects of Fluoroquinolones GI upset Allergic reactions (rash, pruritis, photosensitivity ) CNS effects may develop with dizziness, headache & confusion – caution against driving Convulsion which is potentiated by NSAIDs– avoid use in epilepsy and pt on NSAIDs Rupture of tendons in elderly & pt on steroids Drug Interactions of Fluoroquinolones Some are potent liver enzyme inhibitors and  metabolism of other drugs; e.g. warfarin, Theophylline, Sulfonylureas and  their effects Mg2+ and Al3+ in antacids  absorption of fluoroquinolones from GIT by forming a chelate complex Fe2+ and Sucralfate also  their absorption they wereable form complex  Mechanisms of Resistance of Fluoroquinolones Some types of efflux pumps can act to decrease intracellular quinolone concentration plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase protecting it from the action of quinolones Mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones  Sulfonamides MOA: Inhibit growth of bacteria by inhibiting the synthesis of folic acid - Folic acid is required for biosynthesis of RNA, DNA & proteins Bacteria, unlike mammals must synthesis their own folate from PABA Sulfonamides are structurally similar to PABA - and compete with it for the enzymes -- Dihydrofolate synthetase and prevent DNA - - synthesis They are bacteriostatic -  Sulfonamide-Trimethoprim - = Combination (Bactrim) Sulfonamides are seldom used alone Combination with Trimethoprim give synergistic - effect against most susceptible bacteria nu Trimethoprim acts at the subsequent step in folate synthesis by inhibiting the Dihydrofolate reductase enzyme Trimethoprim is also bacteriostatic g Resistance is common due to production of enzymes that have reduced affinity for the drugs Mechanism of Action of Bactrim®  Examples of Sulfonamides i', Sulfamethoxazole + Trimethoprim (Bactrim) - Sulfasalazine + Trimethoprim = Sulfadiazine + Trimethoprim Silver sulfadiazine – used topically for prophylaxis and treatment of infected burns, leg ulcers and pressure sores - Pharmacokinetics of Sulfonamides Oral dose are rapidly absorbed from the gut - Well distributed to body tissues including the - hey brain -Metabolism is in the liver Excretion is mainly byD u kidneys Sulfanomides are relatively insoluble and can u cause crystalluria u Very useful in treating kidney infections since mini they achieve a high concentration in the mem kidneys -  Adverse Effects of Sulfonamides S/E include skin rash and itching we un Stevens-Johnson syndrome, a severe systemic - reaction with a rash on the skin and mucous - - - membranes - Prolonged use at2 high doses can cause blood disorders such as-D - - hemolytic anemia, aplastic At anemia, low platelets andA white blood cell u Photosensitivity – excessive m reaction to sunlight – avoid - excessive UV light -Crystalluria – increase fluid intake - Cross sensitivity can occur with different #sulfonamides - - (Contraindications&forCSulfonamides( Drug allergy to sulfa drugs mem m muse nee Pregnant women – possible teratogenic Infants younger than 2 months of age – - increase risk of kernicterus Breast feeding -  Metronidazole  (Flagyl ) Metronidazole is bactericidal to both - - => anaerobic bacteria ( incl. bacteroides & - - Clostridium) and protozoa - It-can be given orally, IV or by rectal - suppository - It is well absorbed after oral administration - and widely distributed in tissues, penetrate - well into CSF & brain - It is metabolised in the liver - accumulate in - You hepatic insufficiency - ability-  Metronidazole (Flagyl) Indications: treatment of anaerobic or mixed intra-abdominal infections, vaginitis, pseudomembranous colitis and brain abscess Adverse-effects: nausea, diarrhoea, stomatitis and peripheral neuropathy with prolonged use, metallic taste May caused a Disulfiram-like reaction when taken with alcohol – pt should be advised to avoid alcohol  Nitrofurantoin Nitrofurantoin is bactericidal against Gram+ve and Gram –ve bacteria that cause acute lower urinary tract infections - It is administered orally and is rapidly excreted in the urine – contraindicated in renal failure – high plasma level causes toxicity Because of its low plasma concentration, its antibacterial activity is limited to the bladder S/E: GI irritation, nausea, vomiting & diarrhea neuropathy & hemolytic anemia occur in G6PD pt I  Antimicrobial Resistance Antimicrobial resistance: F –The microorganism is no longer affected by a particular antimicrobial that was once effective against that microorganism - Determined via the culture and sensitivity testing - The most important problem associated with infectious disease today is the rapid = - development of resistance to antibiotics  Bacterial Resistance Some bacteria have Inherent resistance – e.g. seem Gram–ve bacteria are naturally resistant to penicillins Bacteria (mutate) develop the ability to produce substances which block the action of antibiotics or change their target or ability to penetrate the cells after repeated exposure to antibiotics -SAcquired - resistance& Resistance genes are often on plasmids that can be transferred between bacteria Cross resistance can occur between antibacterials that have similar actions – e.g Penicillins & Cephalosporins DEVELOPMENT OF RESISTANCE WHAT CAUSES RESISTANCE? Widespread use of antimicrobial drug – e.g. antibiotics prescribed for cold Globalised world – travelers carry resistant bacteria Interrupted or inadequate antimicrobial treatment of infection – inadequate drug levels Type of bacteria – gram-negative strains have higher rates of resistance Re-occurring infections -  use of antibiotics Condition of the host – immunocompromised pt Location – critical care areas – reservoir for bacteria – bacteria can swap genes for resistance  MECHANISMS FOR ACQUIRING RESISTANCE Bacteria use several mechanisms to become antibiotic-resistant: – Inactivation of the antibiotic – Efflux pumping of the antibiotic – Reduced permeability to the antibiotic – Modification of the antibiotic target – Alteration of the pathway  INACTIVATION OF ANTIBIOTIC Inactivation involves enzymatic breakdown of antibiotic molecules. A good example is β-lactamase: – Attacks the antibiotic as it approaches its target – This enzymes breaks up the β-lactam ring of the antibiotic and make it inactive – E.g of lactamase activity in E.coli and S. aureus  EFFLUX PUMPING OF ANTIBIOTIC Efflux pumping is an active transport mechanism. › It requires ATP Efflux pumps are found in: › The bacterial plasma membrane › The outer layer of gram-negative organisms Pumping keeps the concentration of antibiotic below levels that would destroy the cell  REDUCED PERMEABILITY Some bacteria reduce the permeability of their membranes as a way of keeping antibiotics out – They turn off production of porin and other membrane channel proteins. – Seen in resistance to streptomycin, tetracycline, and sulfa drugs  MODIFICATION OF ANTIBIOTIC TARGET Bacteria can modify the antibiotic’s target to escape its activity – e.g. PBP (penicillin binding protein) Bacteria must change structure of the target but the modified target must still be able to function Bacterial ribosomes are a primary target for antibiotics Resistance can be the result of modification of ribosomal RNA so it is no longer sensitive  ALTERATION OF A PATHWAY Some drugs competitively inhibit metabolic pathways Bacteria can overcome this method by using an alternative pathway Resistance to Antibiotics MECHANISMS FOR ACQUIRING RESISTANCE  Combination Antimicrobial Therapy Indications for combination therapy: Broaden the spectrum of coverage for empirical therapy Prevent the development of resistance To obtain potentiation (or synergy) To enable reduction of dose of one component -  toxicity  Adverse Effects of Antibiotic Therapy Normal gut flora are killed, which produces diarrhea and can pave the way for colonization with pathogenic bacteria, possibly even leading to death. – E.g. E. Coli and other organisms help to maintain normal gut function Superinfection – infection with a second (antibiotic resistant) organism that occurs during antibiotic therapy. – In pseudomembranous colitis, the bowel is colonized with Clostridium difficile, producing a severe diarrhea that is sometimes fatal. Allergy – most common with the Penicillins.