Antimicrobial Drugs Ch 20 Notes PDF

Ch. 20 Antimicrobial Drugs Did you know that a hundred years ago in the U.S., one out of every three children was expected to die of an infectious disease before the age of 5?  History of syphilis In 1495 an epidemic of a new and terrible disease broke out among...

Ch. 20 Antimicrobial Drugs Did you know that a hundred years ago in the U.S., one out of every three children was expected to die of an infectious disease before the age of 5?  History of syphilis In 1495 an epidemic of a new and terrible disease broke out among the soldiers of Charles VIII of France when he invaded Naples in the first of the Italian Wars, and its subsequent impact on the peoples of Europe was devastating – this was syphilis, or the “great pox”. Although it didn’t have the horrendous mortality of the bubonic plague, its symptoms were painful and repulsive Etiological agent: Treponema pallidum (bacterium)  Modern treatment of syphilis ▪ Today, syphilis is easy to cure in its early stages. ▪ A single intramuscular injection of long acting Benzathine penicillin G (2.4 million units administered intramuscularly) will cure a person who has primary, secondary or early latent syphilis. ▪ Treatment will kill the syphilis bacterium and prevent further damage, but it will not repair damage already done. ▪ http://www.cdc.gov/std/syphilis/stdfact-syphilis-detailed.htm © 2013 Pearson Education, Inc. The Birth of Modern Chemotherapy ▪ Chemotherapy is the chemical treatment of a disease. ▪ Term is broad and does not apply only to chemicals used to treat cancers ▪ Antimicrobial drugs: interfere with the growth of microbes within a host ▪ Two types of chemotherapeutic agents (antimicrobial drugs) are: ▪ 1) synthetic drugs (chemically prepared in the laboratory) ▪ 2) antibiotics (substances produced naturally by bacteria and fungi that, in small amounts, inhibit the growth of other microorganisms). © 2013 Pearson Education, Inc. The First Synthetic Drugs ▪ Quinine [quy”-nyne] from tree bark was long used to treat malaria ▪ Paul Ehrlich speculated about a “magic bullet” that could destroy a pathogen without harming the host ▪ 1910: Ehrlich developed a synthetic arsenic drug, “salvarsan” [sal”-ver-san], to treat syphilis ▪ 1930s: sulfonamides were synthesized © 2013 Pearson Education, Inc. Penicillium – discovery of antibiotics ▪ Alexander Fleming observed that the Penicillium fungus inhibited the growth of a bacterial culture (S. aureus). He named the active ingredient penicillin (1928). ▪ Penicillin has been used clinically as an antibiotic since the 1940s. ▪ 1940s: Penicillin was tested clinically and mass produced ▪ Very effective treatment for syphilis and other bacterial infections © 2013 Pearson Education, Inc. The discovery of penicillin. Normal bacterial colony Area of inhibition of bacterial growth Penicillium colony © 2013 Pearson Education, Inc. Microbes produce antibiotics ▪ Antibiotics are substances naturally produced by microbes, in order to kill other microbes ▪ Are common metabolic products of aerobic bacteria and fungi ▪ Bacteria in genera such as Streptomyces and Bacillus ▪ Molds in genera Penicillium and Cephalosporium ▪ By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients and space © 2013 Pearson Education, Inc. Laboratory Bacterial colonies producing antibiotics observation of antibiosis; examples of bacterial inhibition by antibiotics produced by bacteria Table 20.1 Representative Sources of Antibiotics Insert Table 20.1 Principles of Antimicrobial Therapy ▪ Challenge: to administer a drug to an infected person that destroys the infective agent without harming the host’s cells ▪ Selective toxicity: killing harmful microbes without damaging the host ▪ Antimicrobial drugs are produced either: ▪ naturally (by organisms) or ▪ synthetically (in laboratory) © 2013 Pearson Education, Inc. Interactions Between Drug and Microbe ▪ Antimicrobial drugs should be selectively toxic – drugs should kill or inhibit microbial cells without simultaneously damaging host tissues ▪ As the characteristics of the infectious agent become more similar to the vertebrate host cell, complete selective toxicity becomes more difficult to achieve and more side effects are seen © 2013 Pearson Education, Inc.  Activity So first of all, to develop a drug that targets only the bacterial pathogens, list characteristics that you would find in: Prokaryotic cells but not in Eukaryotic cells 13  Bactericidal KNOW THIS TABLE Kill microbes directly Bacteriostatic 14 Prevent microbes from growing KNOW THIS TABLE 15 KNOW THIS TABLE 16 KNOW THIS TABLE 17 The Spectrum of an Antimicrobic Drug ▪ Spectrum – range of activity of a drug ▪ Narrow-spectrum – effective on a small range of microbes − Target a specific cell component that is found only in certain microbes ▪ Broad-spectrum – greatest range of activity − Target cell components common to most pathogens (e.g., ribosomes) © 2013 Pearson Education, Inc. Table 20.2 The Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs Mechanisms of Drug Action 1. Antimicrobial Drugs That Affect the Bacterial Cell Wall ▪ Inhibition of cell wall synthesis 2. Antimicrobial Drugs That Disrupt Cell Membrane Function ▪ Breakdown of cell membrane structure or function 3. Drugs That Affect Nucleic Acid Synthesis ▪ Inhibition of nucleic acid synthesis, —> (DNA or RNA) structure or function 4. Drugs That Block Protein Synthesis ▪ Inhibition of protein synthesis —> ribosomes 5. Drugs that Affect Metabolic Pathways ▪ Blocking enzymes in key metabolic pathways © 2013 Pearson Education, Inc. Major Action Modes of Antimicrobial Drugs. 1. Inhibition of cell wall synthesis: penicillins, 2. Inhibition of protein synthesis: chloramphenicol, cephalosporins, bacitracin, vancomycin erythryomycin, tetracyclines, streptomycin DNA mRNA Protein Transcription Translation Replication Enzyme 4. Injury to plasma membrane: polymyxin B 5. Inhibition of essential metabolite synthesis: sulfanimide, trimethoprim 3. Inhibition of nucleic acid replication and transcription: quinolones, rifampin 22 23 Major Action Modes of Antimicrobial Drugs. 24 1. Antimicrobial Drugs That Affect the Bacterial Cell Wall ▪ Most bacterial cell walls contain peptidoglycan ▪ Protects bacteria in a hypotonic environment from bursting ▪ Penicillins and cephalosporins (both groups of antibiotics produced by molds in the genera Penicillium and Cephalosporium) block synthesis of peptidoglycan by binding and blocking peptidases that cross-link the glycan molecules, causing the cell wall to lyse ▪ Lysis = The disintegration of a cell resulting from destruction of its membrane ▪ Active only on young, growing cells, because older cells are not producing peptidoglycan. © 2013 Pearson Education, Inc. Peptidoglycan 26 Bacterial cell walls. N-acetylglucosamine (NAG) Tetrapeptide side chain N-acetylmuramic acid (NAM) Peptide cross-bridge Side-chain amino acid Cross-bridge amino acid NAM Peptide Carbohydrate bond “backbone” NAG Structure of peptidoglycan in gram-positive bacteria. Effects of Antibiotics on bacterial cell walls. Continued next slide… 28 Effects of Antibiotics on bacterial cell walls. 29 The inhibition of bacterial cell synthesis by penicillin. Rod-shaped The bacterial cell bacterium before lysing as penicillin penicillin. weakens the cell wall. 1. Antimicrobial Drugs That Affect the Bacterial Cell Wall (cont.) ▪ Penicillins that do not penetrate the outer membrane are less effective against gram-negative bacteria (which have outer membranes and less peptidoglycan). © 2013 Pearson Education, Inc. Gram (+) and Gram (-) Cell Walls Insert figure 4.12 Comparative cell envelopes 32 1. Antimicrobial Drugs That Affect the Bacterial Cell Wall (cont.) ▪ Broad spectrum, semisynthetic penicillins and cephalosporins have been chemically altered so that they can cross the cell walls of gram-negative bacteria. © 2013 Pearson Education, Inc. Table 20.3 Antibacterial Drugs (Part 1 of 3) More specifics about Antibacterial Drugs that act on the Cell Wall ▪ "Beta-lactam" antimicrobials [lak'-tam] ▪ Beta-lactam is a highly reactive chemical compound made of carbon and nitrogen; primary mode of action is to interfere with proteins involved in the synthesis of cell wall by binding and blocking peptidases that cross-link the glycan molecules of peptidoglycan ▪ Greater than ½ of all antimicrobic drugs are "beta- lactams" ▪ Penicillins and cephalosporins are the most prominent beta-lactams (penicillins and cephalosporins are antibiotics) © 2013 Pearson Education, Inc. Penicillin and Its Relatives - Large diverse group of compounds ▪ Can be synthesized in the laboratory from raw materials, but more economical to obtain natural penicillin through microbial fermentation and modify it to semi-synthetic forms ▪ Penicillium chrysogenum – species of mold that serves as major source ▪ Some bacteria produce penicillinases or beta- lactamases, which are enzymes that destroy the beta- lactam rings of penicillins and render the drug ineffective. ▪ This is one type of antibiotic resistance. © 2013 Pearson Education, Inc. Penicillin and Its Relatives – (cont.) ▪ All penicillins consist of a: ▪ Beta-lactam ring ▪ Variable side chain: − Can be added to the beta-lactam ring to modify the drug and give it certain characteristics (semisynthetic drugs) − Dictates microbial activity of the penicillin drug, and can be synthetically added to give the drug additional attributes such as: − 1. acid resistance − 2. penicillinase resistance − 3. giving drug a broader spectrum (such as by helping it move across the outer membrane of gram- neg cell walls) © 2013 Pearson Education, Inc.  Side chains Beta-lactams 38 39 Cephalosporins ▪ Account for one-third of all antibiotics administered ▪ Also have a beta-lactam structure, which is synthetically altered ▪ Relatively broad-spectrum, resistant to most penicillinases, and cause fewer allergic reactions ▪ Drug names often begin with cef, ceph, or kef ▪ Examples: cephalothin [sěf'ə-lə-thĭn'], cefazolin [si- faz'-ə-lən], Keflex [kef’-leks] © 2013 Pearson Education, Inc. Cephalosporins Beta lactam ring 41 Some Cell Wall Inhibitors are not Beta- lactams ▪ Some drugs inhibit the elongation of peptidoglycan in other ways ▪ One particular drug works by interfering with mycolic acid synthesis, a necessary component of the cell wall of acid-fast organisms ▪ Used to treat infections with Mycobacterium tuberculosis ▪ Mycolic acid is the substance that has high affinity for carbolfuchsin, the primary stain in the acid-fast stain, which resists decolorization by the acid-alcohol used in this staining technique. © 2013 Pearson Education, Inc. Acid-fast stain. M. bovis © 2013 Pearson Education, Inc. 2. Antimicrobial Drugs That Disrupt Cell Membrane Function ▪ A cell with a damaged membrane dies from: ▪ disruption in metabolism, or: ETC is found in prokaryotes ▪ lysis ▪ These drugs usually have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes © 2013 Pearson Education, Inc. Cell Membrane and various lipid molecules 45 A sterol Phospholipids - membrane molecules micelle [my-sel'] = particle formed by an aggregate of molecules and occurring in certain electrolyte solutions; hydrophilic heads/hydro- phobic tails 46 2. Antimicrobial Drugs That Disrupt Cell Membrane Function (cont.) ▪ Anti-Bacterial drugs ▪ Some antibiotics interact with phospholipids and cause leakage out of the bacteria of important cell constituents, particularly in gram-negative bacteria ▪ Anti-Fungal drugs ▪ Some antibiotics form complexes with sterols on fungal cell membranes which causes leakage © 2013 Pearson Education, Inc. Effects of polymyxin on the bacterial cell membrane = leaky 48 Injury to the plasma membrane of a yeast cell caused by an antifungal drug. Table 20.3 Antibacterial Drugs (Part 2 of 3)  3. Drugs That Affect Nucleic Acid Synthesis ▪ May block synthesis of nucleotides, inhibit replication, or stop transcription ▪ Chloroquine [klawr'-uh-kwin], an antimalarial/ antiprotozoan drug, binds and cross-links the double helix; quinolones (antibiotics) inhibit DNA helicases (how would this affect the bacteria?) ▪ Antiviral drugs that are analogs of nitrogenous bases insert in viral nucleic acid, preventing replication © 2013 Pearson Education, Inc. Table 20.3 Antibacterial Drugs (Part 3 of 3) 4. Drugs That Block Protein Synthesis ( Translation ) ▪ Because ribosomes of eukaryotes differ in size and structure from prokaryotes, the antimicrobics usually have a selective action against prokaryotes (protects eukaryotic host cell); however, some may also damage the mitochondria of eukaryotic cells, which contains prokaryote-like ribosomes.—> 70s ribosomes © 2013 Pearson Education, Inc. 4. Drugs That Block Protein Synthesis (cont.) Enzymes !! ▪ Antibiotics such as streptomycin and gentamycin insert on specific sites of the ribosome and cause misreading of mRNA Amino acids!! ▪ Tetracyclines (antibiotics) block attachment of tRNA to the ribosome and stop further protein synthesis. © 2013 Pearson Education, Inc. Blocking protein synthesis 55 The inhibition of protein synthesis by antibiotics. Protein Growing synthesis polypeptide site Tunnel Growing polypeptide 50S 5′ Chloramphenicol Binds to 50S portion and inhibits formation of peptide bond 30S 50S 3′ portion mRNA Three-dimensional detail of the protein synthesis site showing the 30S and 50S Protein synthesis site subunit portions of the 70S prokaryotic ribosome tRNA Messenger RNA 30S portion Direction of ribosome movement Streptomycin Tetracyclines 70S prokaryotic Changes shape of 30S portion, ribosome Interfere with attachment of causing code on mRNA to be tRNA to mRNA–ribosome read incorrectly Translation complex Diagram indicating the different points at which chloramphenicol, the tetracyclines, and streptomycin exert their activities Table 20.3 Antibacterial Drugs (Part 2 of 3) Streptomycin, Gentamicin, Tetracyclines!! Table 20.3 Antibacterial Drugs (Part 2 of 3) 5. Drugs that Affect Metabolic Pathways /A\ —>/B\—>/C\—>/D\ 1. 2. 3. Product ▪ Some drugs block enzymes required for synthesis of folic acid, which is needed for DNA and RNA synthesis ▪ Competitive inhibition – drug competes with normal substrate for enzyme’s active site Additive ▪ Some of these type drugs are administered together to produce a synergistic effect, in which the effects of a combination of antibiotics are greater than the sum of the effects of the individual antibiotics − Ex: trimethoprim and sulfamethoxazole are often administered together, broadening the spectrum and greatly reducing the emergence of resistant strains. © 2013 Pearson Education, Inc. Enzyme inhibitors. Action of Enzyme Inhibitors Competitive inhibitor Altered active site Noncompetitive Allosteric inhibitor site Sulfa drugs The sulfonamides are synthetic antimicrobial agents Wide spectrum: most gram-positive and many gram- negative. First efficient treatment to be employed systematically for the prevention and cure of bacterial infections. © 2013 Pearson Education, Inc. Sulfa drugs Compete with para-aminobenzoic acid (PABA), which is needed to synthesize folic acid. The action of sulfonamides illustrates the principle of selective toxicity Difference between mammal cells and bacterial cells: All cells require folic acid for growth. Folic acid (a vitamin acquired from food) diffuses or is transported into human cells. However, folic acid cannot cross bacterial cell walls by diffusion or active transport. For this reason bacteria must synthesize folic acid from PABA.—> substrate © 2013 Pearson Education, Inc. Inhibiting the enzyme that catalyzes production of folic acid with a sulfa drug The sulfa drug competitively inhibits the PABA molecule (para-aminobenzoic acid, the substrate) from binding the active site. 63 Inhibiting the Synthesis of Essential Metabolites: using Sulfa drugs as analogs (i.e., “analogous” to…) Mimics Normal anabolic reaction producing folic acid: Sulfa drug competitively inhibiting PABA: Table 20.3 Antibacterial Drugs (Part 3 of 3) Survey of Major Antimicrobial Drug Groups ▪ About 260 different antimicrobial drugs are classified in 20 drug families ▪ Antibacterial drugs: ▪ Antifungal drugs ▪ Antiprotozoan drugs ▪ Antiviral drugs ▪ Antihelminth drugs © 2013 Pearson Education, Inc. Antibacterial drugs: ▪ Antibiotics (NOTE: only effective against BACTERIA!) ▪ Synthetic or semisynthetic drugs © 2013 Pearson Education, Inc. Antifungal drugs: Agents to Treat Fungal Infections ▪ Problem: fungal cells are eukaryotic; a drug that is toxic to fungal cells is often also toxic to human cells ▪ Five antifungal drug groups have been developed, which often damage the cell membranes ▪ Some antibiotics form complexes with sterols on fungal cell membranes which causes leakage © 2013 Pearson Education, Inc. Antiviral drugs: Antiviral Chemotherapeutic Agents ▪ Challenge: Ideal selective toxicity is almost impossible due to obligate intracellular parasitic nature of viruses ▪ Modes of Action include: ▪ 1. Block penetration into host cell ▪ 2. Block replication, transcription, or translation of viral genetic material − Example: Nucleotide analogs − Used in drugs that treat herpesviruses and HIV ▪ 3. Prevent maturation of viral particles − Example: Protease inhibitors (protease clips viral proteins into functional pieces) − Used in drugs that treat HIV © 2013 Pearson Education, Inc. 71 Health care workers’ risk of exposure to HIV ▪ CDC reports that health care workers who are exposed to a needlestick involving HIV-infected blood at work have a 0.23% risk of becoming infected. In other words, 2.3 of every 1,000 such injuries, if untreated, will result in infection. ▪ CDC report (2015): ▪ 58 confirmed occupational transmissions of HIV and 150 possible transmissions have been reported in the United States (as of December 31, 2013). − Of these, only one confirmed case has been reported since 1999. © 2013 Pearson Education, Inc. Post-exposure prophylaxis (PEP) ▪ Healthcare workers have a high risk of occupational exposure (more so in developing countries, with high incidence of blood borne diseases and prevalence of unsafe practices). ▪ Among the various blood borne diseases, the most common and important ones are HIV infection, hepatitis B, and hepatitis C. ▪ Most of the occupational transmission can be prevented and the "standard precaution" has been shown to reduce exposures and hence the transmission of infection. ▪ Healthcare workers have to be educated about post-exposure prophylaxis and each institution needs to adopt a clear protocol. © 2013 Pearson Education, Inc. Post-exposure prophylaxis (PEP) ▪ Healthcare workers have a high risk of occupational exposure (more so in developing countries, with high incidence of blood borne diseases and prevalence of unsafe practices). ▪ Among the various blood borne diseases, the most common and important ones are HIV infection, hepatitis B, and hepatitis C. ▪ Most of the occupational transmission can be prevented and the "standard precaution" has been shown to reduce exposures and hence the transmission of infection. ▪ Healthcare workers have to be educated about post-exposure prophylaxis and each institution needs to adopt a clear protocol. © 2013 Pearson Education, Inc. Post-exposure prophylaxis (PEP) ▪ Post-exposure prophylaxis (PEP) involves taking anti-HIV medications as soon as possible (within 72 hours, but preferably within 24-36 hours) after you may have been exposed to HIV to try to reduce the chance of becoming HIV positive. PEP is a month-long course of emergency medication taken to try to keep HIV from making copies of itself and spreading through your body. ▪ PEP is used by health care workers who have been exposed to HIV- infected fluids on the job or anyone who may have been exposed through unprotected sex, needle-sharing injection drug use, or sexual assault. ▪ If you think you were exposed to HIV, go immediately to an Infectious Disease Physician, a clinic, or an emergency room and ask for PEP. © 2013 Pearson Education, Inc. Post-exposure prophylaxis (PEP) ▪ PEP must begin within 72 hours of exposure, before the virus has time to make too many copies of itself in your body. The sooner the better! Preferably within the first 36 hours! ▪ PEP consists of 2-3 antiretroviral medications and must be taken for 28 days. ▪ PEP is not always 100% effective, but still indicates a high success rate; it does not guarantee that someone exposed to HIV will not become infected with HIV, but can greatly reduce the risk. © 2013 Pearson Education, Inc. Post-exposure prophylaxis (PEP) ▪ Healthcare workers are evaluated for PEP if they are exposed after: − Getting cut or stuck with a needle that was used to draw blood from a person who may have HIV infection − Getting blood or other body fluids that may have lots of HIV in their eyes or mouth − Getting blood or other body fluids that may have lots of HIV on their skin when it is chapped, scraped, or affected by certain rashes © 2013 Pearson Education, Inc. Pre-Exposure Prophylaxis (PrEP) ▪ “PrEP” stands for Pre-Exposure Prophylaxis. PrEP is a way for people who don’t have HIV but who are at very high risk of getting it to prevent HIV infection by taking a pill every day. ▪ The pill approved by the U.S. Food and Drug Administration (FDA) for daily use as PrEP for people at very high risk of getting HIV infection is called Truvada®. ▪ Truvada® is a combination of two HIV medications (tenofovir and emtricitabine). ▪ These medicines work by blocking important pathways that HIV uses to set up an infection. © 2013 Pearson Education, Inc. Mode of Action of Nucleoside Reverse Transcriptase Inhibitors (Helper T cell) Interferons (INF) can be used as drugs ▪ Human-based glycoprotein produced primarily by fibroblasts and leukocytes ▪ Therapeutic benefits include: ▪ Reduces healing time and some complications of infections (mainly herpesviruses) ▪ Prevents or reduces symptoms of cold and papillomavirus (warts) ▪ Slows the progress of certain cancers, leukemias, and lymphomas ▪ Treatment of hepatitis C (viral liver infection), genital warts © 2013 Pearson Education, Inc.  Drug and Antibiotic Resistance © 2013 Pearson Education, Inc. Drug and Antibiotic Resistance ▪ Modern researchers are tackling the problem of drug-resistant microbes, microbes that become resistant to antibiotics/drugs, rendering the drug no longer effective. © 2013 Pearson Education, Inc.  The Acquisition of Drug Resistance Evolution of microbes keeps new-drug developers in business Adaptive response in which microorganisms begin to tolerate an amount of drug that would ordinarily be inhibitory; due to genetic versatility or variation; toleration can be due to the intrinsic (natural state) of a gene, or the acquiring of new genes Acquired genetic resistance can result from: – Spontaneous mutations in critical chromosomal genes – Acquisition of new genes or sets of genes via transfer from another species Originates from plasmids called resistance factors encoded with drug resistance, or transposons ("jumping" segments of DNA that migrate to new locations within the genome) 85 Shows transfers or resistance factors that have occurred and been documented between species 86  Mechanisms of Drug Resistance: result from mutations or acquisition Drug inactivation by acquired enzymatic activity – penicillinases or beta-lactamases, enzymes which some bacteria produce, which destroy the beta-lactam rings of penicillins Decreased permeability to drug or increased elimination of drug from cell – acquired or mutation Change in drug receptors – acquired or mutation Change in metabolic patterns – mutation of original enzyme 87 KNOW EACH OF THESE EXAMPLES 88 KNOW EACH OF THESE EXAMPLES 89  Bacterial Resistance to Antibiotics. 1. Blocking entry Antibiotic 2. Inactivation by enzymes Antibiotic Antibiotic Altered target molecule Enzymatic action 3. Alteration of Inactivated target molecule antibiotic 4. Efflux of antibiotic Natural Selection and Drug Resistance Large populations of microbes are likely to include drug resistant cells due to prior mutations or transfer of plasmids – no growth advantage until exposed to drug, the “selective pressure” If exposed, sensitive cells are inhibited or destroyed while resistance cells will survive and proliferate. Eventually entire population will be resistant – selective pressure – natural selection Worldwide indiscriminate use of antimicrobials has led to explosion of drug resistant microorganisms 91 A model of natural selection for drug resistance 92 The development of an antibiotic-resistant mutant during antibiotic therapy. Antibiotic resistance of bacterial Initiation of population measured by amount of antibiotic therapy antibiotic needed to control growth 108 50 Antibiotic resistance (mg/ml) 107 40 Bacteria (number/ml) 106 30 Bacteria count 105 20 104 10 103 0 1 2 3 4 5 6 7 8 9 10 11 Days Clinical Focus: Antibiotics in Animal Feed Linked to Human Disease after conjugation Cephalosporin- S. enterica S. enterica resistance in E. coli transferred by E. coli conjugation to Salmonella enterica in the intestinal tracts of turkeys. Resistance plasmid  Campylobacter jejuni C. jejuni is now recognized as a serious pathogen. It is the leading cause of bacterial diarrhea illness in the United States. C. jejuni causes the illness Campylobacteriosis, also known as Campylobacter Enteritis or Gastroenteritis. The main food associated with C. jejuni is chicken. Many healthy chickens carry this bacterium in the digestive tracts. If chicken is fully cooked the bacteria dies. Raw milk is another source of the infection. Pasteurized milk contains none of the bacteria. Non-chlorinated drinking water may be another source of the bacteria. Clinical Focus: Antibiotics in Animal Feed Linked to Human Disease; Flouroquinolone-resistant Campylobacter 30 jejuni in the United States, 1986–2008. FQ for FQ for FQ for poultry humans poultry discontinued Percent FQ-resistant Campylobacter 25 20 15 10 5 0 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 Year  Antibiotic Resistance Misuse of antibiotics selects for resistance mutants Misuse includes: – Using outdated or weakened antibiotics – Using antibiotics for the common cold and other inappropriate conditions – Using antibiotics in animal feed – Failing to complete the prescribed regimen – Using someone else’s leftover prescription Why take the entire dose of antibiotic as prescribed? – essentially because if the infection is not completely eliminated and rebounds, then the longer the infection persists, the greater the risks that some of the bacteria will become resistant Complete the full course of the drug. It's important to take all of the medication, even if you are feeling better. If treatment stops too soon, the drug may not kill all the bacteria. You may become sick again, and the remaining bacteria may become resistant to the antibiotic that you've taken. Taking antibiotics for the full duration prescribed is the best way to assure that harmful bacteria causing the infection are completely eradicated. Shortening the course of treatment may only wipe out the least dangerous bacteria while allowing the less sensitive bacteria to survive. This risks a recurrence of the infection, which can sometimes be even more difficult to treat. By not taking the entire course of antibiotics, resistant bacteria may develop that no longer respond to common antibiotics. This has the potential to turn easily treatable infections into serious ones. KNOW THIS TABLE 100 101  Interactions Between Drug and Host Estimate that 5% of all persons taking antimicrobials will experience a serious adverse reaction to the drug – side effects Major side effects: – 1) Direct damage to tissue due to toxicity of drug – 2) Allergic reactions – 3) Disruption in the balance of normal flora- superinfections possible Normal flora can become opportunistic pathogens due to the wider destructive effects of broader-range drugs, which may kill off competitors that are keeping normal microbiota in check (ex: Candida albicans). Superinfection is a term that can also be used to refer to an infection continuing due to an antibiotic-resistant pathogen. 102 Superinfection 103 Table shows major toxic reactions to common drug groups 104 Table shows major toxic reactions to common drug groups 105 Considerations in Selecting an Antimicrobial Drug © 2013 Pearson Education, Inc.  Considerations in Selecting an Antimicrobial Drug Identify the microorganism causing the infection Test the microorganism’s susceptibility (sensitivity) to various drugs in vitro when indicated The overall medical condition of the patient 107  Identifying the Agent Identification of infectious agent should be attempted as soon as possible Specimens should be taken before antimicrobials are initiated 108  Testing for a Pathogen’s Susceptibility to a Drug Essential for groups of bacteria commonly showing resistance Provide profile of drug sensitivity 3 Methods: – 1) Kirby-Bauer disk diffusion test, uses the zone of inhibition to indicate the susceptibility or resistance of the drug to the bacteria – 2) E-test diffusion test, uses a plastic-coated strip to test the MIC – 3) Broth dilution tests – minimum inhibitory concentration (MIC) – smallest concentration of drug that visibly inhibits growth 109 The Kirby-Bauer disk-diffusion method for determining the activity of antimicrobials. Kirby-Bauer Disk Diffusion Test 111 112 E-Test diffusion test, uses a plastic-coated strip to test the MIC 113 MIC Dilution Tests 114 115 The MIC and Therapeutic Index In vitro (ex: lab vessel) activity of a drug is not always correlated with in vivo (inside an actual living organism) effect – If therapy fails, a different drug, combination of drugs, or different administration must be considered Best to choose a drug with highest level of selectivity but lowest level toxicity – measured by therapeutic index – the ratio of the dose of the drug that is toxic to humans as compared to its minimum effective dose (or MIC, “minimum inhibitory concentration”) – assessing risks against benefits – High index is desirable 116 Multiple Drug interactions Sometimes, the use of another drug can cause toxic effects that do not occur when the drug is taken alone. One drug may also neutralize the intended effects of the other. -Ex: a few antibiotics neutralize the effectiveness of contraceptive pills.