INTRODUCTION TO ANTIBIOTICS

An antibiotic is a chemical substance produced by one organism that is destructive to another. The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which means a process by which life could be used to destroy life. Antibiotics are used to treat infections caused by bacteria. Bacteria are microscopic organisms, some of which may cause illness. Illnesses as syphills, tuberclosis salmonella, and some forms of meningitis are caused by bacteria. Some bacteria are harmless, while others are good for us. Before bacteria can multiply and cause symptoms, the body's immune system can usually destroy them. We have special white blood cells that attack harmful bacteria. Even if symptoms do occur, our immune system can usually cope and fight off the infection. There are occasions, however, when it is all too much and some help is needed.....from antibiotics.

HISTORY OF ANTIBIOTICS
The ancient Egyptians, the Chinese, and Indians of central America all used molds to treat infected wounds. However, they did not understand the connection of the antibacterial properties of mold and the treatment of diseases. In the early 1920s, the British scientist Alexander Fleming reported that a product in human tears could lyse bacterial cells. Flemings finding, which he called lysozyme, was the first example of an antibacterial agent found in humans. Like pyocyanase, lysozyme would also prove to be a dead end in the search for an efficacious antibiotic, since it typically destroyed nonpathogenic bacterial cells. Flemings second discovery, though, would change the course of medicine. In 1928, Fleming serendipitously discovered another antibacterial agent. Returning from a weekend vacation, Fleming looked through a set of old plates that he had left out. On one such plate, he found that colonies of Staphylococcus, which he had streaked out, had lysed. Fleming observed that bacterial cell lysis occurred in an area adjacent to a contaminant mold growing on the plate and hypothesized that a product of the mold had caused the cell lysis. While Fleming generally receives credit for discovering penicillin, in fact technically Fleming rediscovered the substance. In 1896, the French medical student Ernest Duchesne originally discovered the antibiotic properties of Penicillium, but failed to report a connection between the fungus and a substance that had antibacterial properties, and Penicillium was forgotten in the scientific community until Flemings rediscovery. Through follow-up work, Fleming showed experimentally that the mold produced a small substance that diffused through the agar of the plate to lyse the bacteria. He named this substance penicillin after the Penicillium mold that had produced it. By extracting the substance from plates, Fleming was then able to directly show its effects. Important to its discovery was the penicillin had destroyed a common bacterium, Staphylococcus aureus, associated with sometimes deadly skin infections.

HOW ANTIBIOTICS WORK

1. 2. 3. 4. 5. Inhibition of Cell Wall Synthesis (most common mechanism) Inhibition of Protein Synthesis (Translation) (second largest class) Alteration of Cell Membranes Inhibition of Nucleic Acid Synthesis Antimetabolite Activity

1. Inhibition of cell wall synthesis Beta-Lactams ---> Inhibition of peptidoglycan synthesis (bactericidal) Resistance ---> (1) fails to cross membrane (gram negatives) (2) fails to bind to altered PBPs (3) hydrolysis by beta-lactamases Vancomycin ---> Disrupts peptidoglycan cross-linkage Resistance ---> (1) fails to cross gram negative outer membrane (too large) (2) some intrinsically resistant (pentapeptide terminus) Bacitracin ---> Disrupts movement of peptidoglycan precursors (topical use) Resistance ---> fails to penetrate into cell Antimycobacterial agents ---> Disrupt mycolic acid or arabinoglycan synthesis (bactericidal) Resistance ---> (1) reduced uptake (2) alteration of target sites

2. Inhibition of protein synthesis 30S Ribosome site Aminoglycosides ---> Irreversibly bind 30S ribosomal proteins (bactericidal) Resistance ---> (1) mutation of ribosomal binding site (2) decreased uptake (3) enzymatic modification of antibiotic Tetracyclines ---> Block tRNA binding to 30S ribosome-mRNA complex (b-static) Resistance ---> (1) decreased penetration (2) active efflux of antibiotic out of cell (3) protection of 30S ribosome 50S Ribosome site Chloramphenicol ---> Binds peptidyl transferase component of 50S ribosome, blocking peptide elongation (bacteriostatic) Resistance ---> (1) plasmid-encoded chloramphenicol transferase (2) altered outer membrane (chromosomal mutations) Macrolides ---> Reversibly bind 50S ribosome, block peptide elongation (b-static) Resistance --->

(1) methylation of 23S ribosomal RNA subunit (2) enzymatic cleavage (erythromycin esterase) (3) active efflux Clindamycin ---> Binds 50S ribosome, blocks peptide elongation; Inhibits peptidyl transferase by interfering with binding of amino acid-acyl-tRNA complex Resistance ---> methylation of 23S ribosomal RNA subunit 3. Alteration of Cell Membranes Polymyxins (topical) ---> Cationic detergent-like activity (topical use) Resistance ---> inability to penetrate outer membrane Bacitracin (topical) ---> Disrupt cytoplasmic membranes Resistance ---> inability to penetrate outer membrane 4. Inhibition of Nucleic Acid Synthesis DNA Effects Quinolones ---> Inhibit DNA gyrases or topoisomerases required for supercoiling of DNA; bind to alpha subunit Resistance ---> (1) alteration of alpha subunit of DNA gyrase (chromosomal) (2) decreased uptake by alteration of porins (chromosomal) Metronidazole ---> Metabolic cytotoxic byproducts disrupt DNA Resistance ---> (1) decreased uptake (2) elimination of toxic compounds before they interact RNA Effects (Transcription) Rifampin ---> Binds to DNA-dependent RNA polymerase inhibiting initiation & Rifabutin of RNA synthesis Resistance ---> (1) altered of beta subunit of RNA polymerase (chromosomal) (2) intrinsic resistance in gram negatives (decreased uptake) Bacitracin (topical) ---> Inhibits RNA transcription Resistance ---> inability to penetrate outer membrane 5. Antimetabolite Activity Sulfonamides & Dapsone ---> Compete with p-aminobenzoic acid (PABA) preventing synthesis of folic acid Resistance ---> permeability barriers (e.g., Pseudomonas) Trimethoprim ---> Inhibit dihydrofolate reductase preventing synthesis of folic acid Resistance ---> (1) decreased affinity of dihydrofolate reductase (2) intrinsic resistance if use exogenous thymidine

ANTIBIOTIC RESISTANCE (SUPERBUGS)

Antibiotic resistance is the ability of bacteria or other microbes to resist the effects of an antibiotic. Antibiotic resistance occurs when bacteria change in some way that reduces or eliminates the effectiveness of drugs, chemicals, or other agents designed to cure or prevent infections. The bacteria survive and continue to multiply causing more harm.

WHY SHOULD WE CONCERN ABOUT SUPERBUGS

Antibiotic resistance has been called one of the world's most pressing public health problems. Almost every type of bacteria has become stronger and less responsive to antibiotic treatment when it is really needed. These antibiotic-resistant bacteria can quickly spread to family members, schoolmates, and co-workers - threatening the community with a new strain of infectious disease that is more difficult to cure and more expensive to treat. Antibiotic resistance can cause significant danger and suffering for children and adults who have common infections, once easily treatable with antibiotics. Microbes can develop resistance to specific medicines. A common misconception is that a person's body becomes resistant to specific drugs. However, it is microbes, not people, which become resistant to the drugs. If a microbe is resistant to many drugs, treating the infections it causes can become difficult or even impossible. Someone with an infection that is resistant to a certain medicine can pass that resistant infection to another person. In this way, a hard-to-treat illness can be spread from person to person. In some cases, the illness can lead to serious disability or even death

WHY ARE BACTERIA BECOMING RESISTANT TO ANTIBIOTICS

Antibiotic use promotes development of antibiotic-resistant bacteria. Every time a person takes antibiotics, sensitive bacteria are killed, but resistant germs may be left to grow and multiply. Repeated and improper uses of antibiotics are primary causes of the increase in drug-resistant bacteria. While antibiotics should be used to treat bacterial infections, they are not effective against viral infections like the common cold, most sore throats, and the flu. Widespread use of antibiotics promotes the spread of antibiotic resistance. Smart use of antibiotics is the key to controlling the spread of resistance. Antibiotics kill bacteria, not viruses.

HOW DO BACTERIA BECOME RESISTANT TO ANTIBIOTICS

Antibiotic resistance occurs when bacteria change in some way that reduces or eliminates the effectiveness of drugs, chemicals, or other agents designed to cure or prevent infections. The bacteria survive and continue to multiply causing more harm. Bacteria can do this through

several mechanisms. Some bacteria develop the ability to neutralize the antibiotic before it can do harm, others can rapidly pump the antibiotic out, and still others can change the antibiotic attack site so it cannot affect the function of the bacteria. Antibiotics kill or inhibit the growth of susceptible bacteria. Sometimes one of the bacteria survives because it has the ability to neutralize or escape the effect of the antibiotic; that one bacterium can then multiply and replace all the bacteria that were killed off. Exposure to antibiotics therefore provides selective pressure, which makes the surviving bacteria more likely to be resistant. In addition, bacteria that were at one time susceptible to an antibiotic can acquire resistance through mutation of their genetic material or by acquiring pieces of DNA that code for the resistance properties from other bacteria. The DNA that codes for resistance can be grouped in a single easily transferable package. This means that bacteria can become resistant to many antimicrobial agents because of the transfer of one piece of DNA.

MECHANISM BY WHICH SUPERBUGS CAN BE GENERATED

Selection Pressure The increased prevalence and dissemination of resistance is an outcome of natural selection and should be viewed as an expected phenomenon of the Darwinian biological principle of survival of the fittest. In any large population of bacteria, a few cells will be present which possess traits that enable them to survive in the presence of a noxious substance, in this case the ability to fend off the action of the antimicrobial. Susceptible organisms, those lacking the advantageous trait, will be eliminated, leaving the remaining resistant populations behind. With long-term antimicrobial use in a given environment, the bacterial communities will change dramatically, with more resistant organisms increasing in proportion. This can result in a situation where the next time an antimicrobial is needed , it may not be effective to treat what was once an easily treatable infection. Mechanisms of Antimicrobial Resistance Susceptible bacteria can acquire resistance to antimicrobials by either genetic mutation or by accepting antimicrobial resistant genes from other bacteria. This usually occurs through one of several biochemical mechanisms:

Mutation Destruction or Inactivation And, Efflux

Mutation Mutation is a change in the DNA that can sometimes cause a change in the gene product, which is the target of the antimicrobial. When a susceptible bacterium comes into contact with a therapeutic concentration of antimicrobials, like fluroquinolones, the antimicrobial can bind to the specific enzymes, in this case, DNA gyrase. The DNA gyrase is an essential bacterial enzyme required for DNA replication. The end result is that fluoroquinolones block bacterial DNA replication leading to cell death. However, when spontaneous mutations occur in specific areas of the genes encoding these enzymes, antimicrobials no longer bind efficiently. This allows the bacterium to continue DNA replication.

Destruction or Inactivation Many bacteria possess genes which produce enzymes that chemically degrade or deactivate the antimicrobial, rendering them ineffective against the bacterium. Here the antimicrobial is either degraded or modified by enzymatic activity before it can reach the target site and damage the bacterial cell. Efflux Certain bacteria can often become resistant to antimicrobials through a mechanism known as Efflux. An efflux pump is essentially a channel that actively exports antimicrobial and other compounds out of the cell. The antimicrobial enters the bacterium through a channel termed a porin, and then is pumped back out of the bacterium by the efflux pump. By actively pumping out antimicrobials, the efflux pumps prevent the intracellular accumulation necessary to exert their lethal activity inside the cell.

Genetic Transfer Genetic material can be transferred between bacteria by several means, most often by:

Conjugation Transformation And, Transduction

Conjugation Conjugation is mediated by a particular kind of circular DNA called a plasmid, which replicates independently of the chromosome.Many plasmids carry genes that confer resistance to antimicrobials.When two cells are in close proximity to each other, a hollow bridge-like structure, known as a pilus, forms between two cells.This allows a copy of the plasmid, as it is duplicated, to be transferred from one bacterium to another.This enables a susceptible bacteria to acquire resistance to a particular antimicrobial agent.

Transformation During this process, genes are transferred from one bacterium to another as naked DNA. When cells die and break apart, DNA can be released into the surrounding environment. Other bacteria in close proximity can scavenge this free-floating DNA, and incorporate it into their own DNA. This DNA may contain advantageous genes, such as antimicrobial resistant genes and benefit the recipient cell.

Transduction In this process, bacterial DNA is transferred from one bacterium to another inside a virus that infects bacteria. These viruses are called bacteriophages or phage.When a phage infects a bacterium, it essentially takes over the bacteria's genetic processes to produce more phage.During this process, bacterial DNA may inadvertently be incorporated into the new phage DNA. Upon bacterial death and lysis (or breaking apart), these new phage go on to infect other bacteria.This brings along genes from the previously infected bacterium

HOW CAN WE PREVENT SUPERBUG INFECTION

1. Talk with your healthcare provider about antibiotic resistance: o Ask whether an antibiotic is likely to be beneficial for your illness o Ask what else you can do to feel better sooner 2. Do not take an antibiotic for a viral infection like a cold or the flu. 3. Do not save some of your antibiotic for the next time you get sick. Discard any leftover medication once you have completed your prescribed course of treatment. 4. Take an antibiotic exactly as the healthcare provider tells you. Do not skip doses. Complete the prescribed course of treatment even if you are feeling better. If treatment stops too soon, some bacteria may survive and re-infect. 5. Do not take antibiotics prescribed for someone else. The antibiotic may not be appropriate for your illness. Taking the wrong medicine may delay correct treatment and allow bacteria to multiply. 6. If your healthcare provider determines that you do not have a bacterial infection, ask about ways to help relieve your symptoms. Do not pressure your provider to prescribe an antibiotic.

EXAMPLES OF SUPERBUG