1.

Bactericidal
drugs kill the target bacterium or fungus and are more effective. You would use these types of drugs to treat endocarditis, meningitis, osteomyelitis, and other invasive bacterial infections. Hosts with low immune systems should also be treated with bactericidal drugs. These drugs include - Lactams, aminoglycosides, and fluoroquinolones.

2.

Bacteriostatic
drugs inhibit growth and can be helpful cuz they let the normal host defenses to destroy the microorganisms. You would use these to treat infections such as cystitis. These drugs includetetracycline, sulfonamides, clindamycin, and chloramphenicol. Some organisms require 2 agents for killing such as entercocci.

We can classify antibiotics by their mode of action.

1.

Cell Wall Inhibitors:

These include the Glycopeptides (ex vancomycin), Bacitracin, Cycloserin, Fosfomycin, and the lactams (penicillins, cephalosporines, monobactams, carbapenems) that are important to know because if someone is allergic to penicillin you cant give them a different -lactam. Antibiotic agents usually diffuse easily through Gram +ve cell walls, but in Gram ve they need to go through narrow walls and its harder. Peptidoglycan is the critical attack site in cell wall inhibition because it is not found in eukaryotes, and its loss = cell death. It is a crosslinked complex of polysaccharides and peptides, which has been discussed, in earlier lectures (see bacteriology). The cross linked structure is the reason for its great strength. It is synthesized in 3 stages:

UDP-NAM-pentapeptide and UDP-NAG are synthesized in the cytosol {inhibitors here = fosfomycin and cycloserine this is not used because it is also toxic to the nervous system)

precursor molecules are transferred to phosphorylated undecaprenyl alcohol (a lipid carrier in the cytoplasmic membrane) and are transported to the outside surface. Bacitracin interacts with the carrier and so prevents precursor transport.Transglycosylases and transpeptidases reticulate the peptidoglycan units. lactams inactivate transpeptidases because they bind them so D-ala-D-ala cant. Glycopeptides inhibit both transglycosylases and transpeptidases by binding to the D-ala-Dala termini, preventing anything else from binding there.

linking the new peptidoglycan strand into the existing molecule. These enzymes are calledPenicillin Binding Proteins (PBP) because they were discovered by labeling with radioactive penicillin G. They are membrane bound and structurally resemble serine proteases. Bacteria make 4 types of PBP numbered according to molecular weight; letters are used to differentiate PBPs of similar weight (so you can PBP 2a, PBP 2b etc.) PBPs differ in affinities for lactams, amounts and function in cell walls, and enzymes are different in Gram + vs. Gram vs. anaerobic bacteria. Which PBP a lactam binds to affects how the bacteria will look, for example binding to PBP 3 causes bacteria to grow into long filaments and die, while binding to PBP 1 results in bulgeing and bursting of the cell wall. With PBPs inhibited, the autolysins are unopposed which can also contribute to the antibacterial effect. lactamases are PBPs that inactivate the drug by catalyzing hydrolyses of the lactam ring.

Cell Membrane Inhibitors:

These cause disorganization of the membrane. Antibacterials polymyxin, Antifungals Polyenes (amphotericin), Imidazoles (fluconazole , itraconazole , and vorconazole). We can divide these into cationic, anionic, and neutral agents. 1. Polymyxin B and colistin (polymyxin E) : these are low molecular weight octapeptides that inhibit Gram ve bacteria with vely charged lipids on the surface. Allow nucleic acid and cations to leak out of the cell so the cell dies. Cant be used systemically because they are toxic to the kidney and nervous system (except in cases of extreme need), but are used topically.

2. Polyene antibiotics fungal membranes have sterols while bacterial membranes dont. Polyene antibiotics bind to the sterols and make a pore in the membrane and the contents leak out. This does not work in prokaryotes.

3. Imidazoles : inhibit ergosterol synthesis.

3 Nucleic Acid Synthesis Inhibitors

Inhibitors of DNA replication: Quinolones and Nitroimidazoles. Fluoroquinolones block the action of DNA gyrase and DNA topoisomerase IV that control and modify the topological states of DNA in cells. They do this by relieving supercoils, which can form during the unwinding of DNA for replication or transcription. Positive supercoils are when the front segment of DNA crosses over the back from left to right. There are a few types of topoisomerases: Type 1: makes transient single stranded breaks in DNA and removes supercoils one at a time. In eukaryotes both topo 1 and 2 can remove both + and supercoils. In bacteria topo 1 can only remove supercoils.

Type 2: makes transient double stranded breaks and removes supercoils 2 at a time, and is more efficient but requires energy from ATP hydrolysis. Bacterial topo II is also called DNA gyrase and has 2 functions (a) to remove +ve supercoils during DNA replication, and, (b) to introduce ve supercoils so the DNA molecule can be packed into the cell. It is made of two A and two B subunits. BacterialTopo IV can only relax supercoils, it cant make supercoils. Topo IV has 2 subunits, ParC and ParE.

Quinolones block topoisomerases by binding to DNA gyrase and DNA. Nitroimidazoles nitro group is reduced by an electron transport protein in anaerobic bacteria, this causes the DNA strand to break. Host cells are unharmed because they dont have the enzyme required.

1. Inhibitors of RNA polymerase Rifamycins. Rifampin binds to a -subunit of RNA polymerases and prevents initiation of DNA transcription. Mammalian mitochondrial RNA synthesis is not impaired significantly.

2. Inhibitors of nucleotide metabolism Acyclovir inhibits viruses by being converted to a tiphosphate and inhibiting the thymidine kinase and DNA polymerase of the herpes viruses, AZT (viruses) inhibits the incorporation of DATP into DNA, Flucytosine (fungi) inhibits yeast by being converted to 5-fluorouracil which inhibits thymidylate synthetase so there are not enough thymine nucleotides to replicate DNA.

4 Protein Synthesis Inhibitors

I am sure you all know the steps of protein synthesis so I wont go into the long explanation she gave. Instead Ill just name the steps formation of the initiation complex elongation of the polypeptide chain termination. 1. Inhibitors of 30S subunit Aminoglycosides bind to specific ribosomal proteins and to a major deep grove in the rRNA. Streptomycin was the first studied and it has a different mechanism from other aminoglycosides. It binds to the S12 protein and causes the ribosome to misread the genetic code. Others also bind the L6 protein of the 50S ribosome. Eukaryotes are relatively unaffected but ribosomes in the mitochondria are sensitive to their effects.

Tetracyclines inhibit binding of aminoacyl-tRNA into the A site of the bacterial ribosome, this is a bacteriostatic drug. 1. Inhibitors of 50S subunit 1. Macrolides, Ketolides, Lincinoids have large lactone rings, bind to the peptidyl side of the 50S subunit. Impair peptidyltransferase and interferes with the translocation of the peptide chain from A to P site, and promotes dissociation of peptidyl-tRNA from the ribosomes.

2. Chloramphenicol bacteriostatic, binds to a peptidyltransferase enzyme on the 50S ribosome.

3. Fusidic acid Streptogramin relatives of macrolides, binds to 50S

Oxazolidinones binds to 50S near the 30S interface which prevents the 30S initiation complex from forming the 70S complex, blocking initiation of protein synthesis. Bacteriostatic

5 Metabolic Inhibitors
Folate inhibitors bacteria make folic acid while humans take it in from their diet. Sulfonamides and trimethoprim block the biosynthesis of tetrahydrofolate, which is a carrier of 1C fragments and is necessary for DNA, RNA, and cell wall synthesis.

What are Antibiotics? The word "antibiotics" comes from the Greek anti ("against") and bios ("life"). Antibiotics are drugs that either destroy bacteria or prevent their reproduction. Antibiotics that kill bacteria are called "bactericidal" and the ones that stop the growth of bacteria are called "bacteriostatic". Since penicillin's introduction during the 1940s, scientists developed numerous other antibiotics. Today, over 100 different antibiotics are available. About 90%

of antibiotics are made from living organisms such as bacteria, others are produced synthetically, either in whole or in part. Antibiotics classification Although there are several classification schemes for antibiotics, based on bacterial spectrum (broad, narrow) or route of administration (injectable, oral, topical), or type of activity (bactericidal, bacteriostatic), the most useful is based on chemical structure. Antibiotics within a structural class will generally have similar patterns of effectiveness, toxicity, and allergic potential. Most commonly used types of antibiotics are: Penicillins, Fluoroquinolones, Cephalosporins, Macrolides, and Tetracyclines. While each class is composed of multiple drugs, each drug is unique in some way. Penicillins The penicillins are the oldest class of antibiotics. Penicillins have a common chemical structure which they share with the cephalopsorins. Penicillins are generally bactericidal, inhibiting formation of the cell wall. There are four types of penicillins: 1. The natural pencillins are based on the original penicillin-G structure. Penicillin-G types are effective against gram-positive strains of streptococci, staphylococci, and some gram-negative bacteria such as meningococcus. Penicillinase-resistant penicillins are active even in the presence of the bacterial enzyme that inactivates most natural penicillins. Extended spectrum penicillins which are effective against a wider range of bacteria. Aminopenicillins such as ampicillin and amoxicillin have an extended spectrum of action compared with the natural penicillins.

2. 3. 4.

Penicillins side effects

Penicillins are among the least toxic drugs known. The most common side effect of penicillin is diarrhea. Nausea, vomiting, and upset stomach are also common. In rare cases penicillins can cause immediate and delayed allergic reactions specifically, skin rashes, fever, and anaphylactic shock. Penicillins are classed as category B during pregnancy. Cephalosporins Cephalosporins have a mechanism of action identical to that of the penicillins. However, the basic chemical structure of the penicillins and cephalosporins differs in other respects, resulting in some difference in the spectrum of antibacterial

activity. Like the penicillins, cephalosporins interfere with synthesis of the bacterial cell wall and so are bactericidal. Cephalosporins are among the most diverse classes of antibiotics, they are grouped into "generations" by their antimicrobial properties. Each generation has a broader spectrum of activity than the one before. The first generation cephalosporins include: cephalothin, cefazolin, cephapirin, cephradine, cephalexin, cefadroxil. Their spectrums of activity are quite similar. They possess generally excellent coverage against most gram-positive pathogens and variable to poor coverage against most gram negative pathogens. The second generation cephalosporins include: cefaclor, cefamandole, cefonicid, ceforanide, cefuroxime. In addition to the gram-positive spectrum of the first generation cephalosporins, these agents have expanded gram-negative spectrum. Cefoxitin and cefotetan also have good activity against Bacteroides fragilis. The third generation cephalosporins have much expanded gram-negative activity. However, some members of this group have decreased activity against grampositive organisms. The third generation cephalosporins include: cefcapene, cefdaloxime, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpodoxime, ceftibuten, ceftriaxone. They have the advantage of convenient dosing schedules, but they are expensive. The fourth generation cephalosporins are extended-spectrum agents with similar activity against gram-positive organisms as first-generation cephalosporins. They also have a greater resistance to beta-lactamases (bacterial enzymes that may destroy antibiotic before it can do its work) than the third generation cephalosporins. Many fourth generation cephalosporins can cross blood brain barrier and are effective in meningitis. The fourth generation cephalosporins include: cefclidine, cefepime, cefluprenam, cefozopran, cefpirome, cefquinome. Cephalosporin side effects Cephalosporins generally cause few side effects. Common side effects associated these drugs include: diarrhoea, nausea, mild stomach cramps or upset. Approximately 510% of patients with allergic hypersensitivity to penicillins will also have cross-reactivity with cephalosporins. Thus, cephalosporin antibiotics are contraindicated in people with a history of allergic reactions (urticaria, anaphylaxis, interstitial nephritis, etc) to penicillins or cephalosporins. Cephalosporin antibiotics are classed as pregnancy category B. Fluoroquinolones Fluoroquinolones are the newest class of antibiotics. Their generic name often contains the root "floxacin". They are synthetic antibiotics that belong to the family of antibiotics called quinolones. The older quinolones are not well absorbed and are used to treat mostly urinary tract infections. The newer fluoroquinolones are broad-spectrum bacteriocidal drugs that are chemically unrelated to the

penicillins or the cephaloprosins. Because of their excellent absorption fluoroquinolones can be administered not only by intravenous but orally as well. Commonly used fluoroquinolones include ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, sparfloxacin, clinafloxacin, gatifloxacin, ofloxacin, trovafloxacin. Fluoroquinolones side effects Fluoroquinolones are well tolerated and relatively safe. The most common side effects include nausea, vomiting, diarrhea, abdominal pain. Other more serious but less common side effects are central nervous system effects (headache, confusion and dizziness), phototoxicity (more common with lomefloxacin and sparfloxacin). All drugs in this class have been associated with convulsions. Fluoroquinolones are classed as pregnancy category C. Tetracyclines Tetracyclines got their name because they share a chemical structure that has four rings. They are derived from a species of Streptomyces bacteria. Tetracycline antibiotics are broad-spectrum bacteriostatic agents, that inhibit bacterial protein synthesis. Tetracyclines may be effective against a wide variety of microorganisms, including rickettsia and amebic parasites. Tetracyclines are used in the treatment of infections of the respiratory tract, sinuses, middle ear, urinary tract, skin, intestines. Tetracyclines also are used to treat Gonorrhoea. Their most common current use is in the treatment of moderately severe acne and rosacea. The most commonly prescribed tetracycline antibiotics are: tetracycline, doxycycline, minocycline, oxytetracycline. Tetracycline side effects Drugs in the tetracycline class become toxic over time. Expired drugs can cause a dangerous syndrome resulting in damage to the kidneys. Common side effects associated with tetracyclines include cramps or burning of the stomach, diarrhea, sore mouth or tongue. Tetracyclines can cause skin photosensitivity, which increases the risk of sunburn under exposure to UV light. This may be of particular importance for those intending to take on holidays longterm doxycyline as a malaria prophylaxis. Rarely, tetracyclines may cause allergic reactions. Very rarely severe headache and vision problems may be signs of dangerous secondary intracranial hypertension. Tetracycline antibiotics should not be used in children under the age of 8, and specifically during periods of tooth development. Tetracyclines are classed as pregnancy category D. Use during pregnancy may cause alterations in bone development.

Macrolides The macrolide antibiotics are derived from Streptomyces bacteria, and got their name because they all have a macrocyclic lactone chemical structure. The macrolides are bacteriostatic, binding with bacterial ribosomes to inhibit protein synthesis. Erythromycin, the prototype of this class, has a spectrum and use similar to penicillin. Macrolide antibiotics are used to treat respiratory tract infections (such as pharyngitis, sinusitis, and bronchitis), genital, gastrointestinal tract, and skin infections. The most commonly prescribed macrolide antibiotics are: erythromycin, clarithromycin, azithromycin, roxithromycin, troleandomycin. Macrolides side effects Side effects associated with macrolides include nausea, vomiting, and diarrhea; infrequently, there may be temporary auditory impairment. Azithromycin has been rarely associated with allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions. Oral erythromycin may be highly irritating to the stomach and when given by injection may cause severe phlebitis. Macrolide antibiotics should be used with caution in patients with liver dysfunction. Pregnancy category B: Azithromycin, erythromycin. Pregnancy category C: Clarithromycin, dirithromycin, troleandomycin.

An antibiotic is a drug that kills or slows the growth of bacteria. Antibiotics are one class of antimicrobials, a larger group which also includes anti-viral, antifungal, and anti-parasitic drugs. Antibiotics are chemicals produced by or derived from microorganisms (i.e. bugs or germs such as bacteria and fungi). The first antibiotic was discovered by Alexander Fleming in 1928 in a significant breakthrough for medical science. Antibiotics are among the most frequently prescribed medications in modern medicine. Some antibiotics are 'bactericidal', meaning that they work by killing bacteria. Other antibiotics are 'bacteriostatic', meaning that they work by stopping bacteria multiplying. Each different type of antibiotic affects different bacteria in different ways. For example, an antibiotic might inhibit a bacterium's ability to turn glucose into

energy, or its ability to construct its cell wall. When this happens, the bacterium dies instead of reproducing. Some antibiotics can be used to treat a wide range of infections and are known as 'broad-spectrum' antibiotics. Others are only effective against a few types of bacteria and are called 'narrow-spectrum' antibiotics. Side effects of antibiotics Antibiotics can literally save lives and are effective in treating illnesses caused by bacterial infections. However, like all drugs, they have the potential to cause unwanted side effects. Many of these side effects are not dangerous, although they can make life miserable while the drug is being taken. In general, antibiotics rarely cause serious side effects. The most common side effects from antibiotics are diarrhea, nausea, vomiting. Fungal infections of the mouth, digestive tract and vagina can also occur with antibiotics because they destroy the protective 'good' bacteria in the body (which help prevent overgrowth of any one organism), as well as the 'bad' ones, responsible for the infection being treated. Some people are allergic to antibiotics, particularly penicillins. Allergic reactions cause swelling of the face, itching and a skin rash and, in severe cases, breathing difficulties. Allergic reactions require prompt treatment. Types of antibiotics There are many different kinds of antibiotics. The type of antibiotics you take depends on the type of infection you have and what kind of antibiotics are known to be effective. The main classes of antibiotics: 1. 2. 3. 4. 5. 6. Aminoglycosides Cephalosporins Fluoroquinolones Macrolides Penicillins Tetracyclines

Macrolides
There are a couple of new relatives of erythromycin (azithromycin and clarithromycin) that work the same way, but kill more bugs and have slightly fewer side effects. The erythromycin-like antibiotics are also known as macrolides. Macrolides belong to the polyketide class of natural products. Macrolide antibiotics are used to treat respiratory tract infections, genital,

gastrointestinal tract, soft tissue infections caused by susceptible strains of specific bacteria. Macrolides bind with ribosomes from susceptible bacteria to prevent protein production. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. Macrolides cause very little allergy problems compared to the penicillins and cephalosporins, the biggest concern with these medicines is that they can irritate the stomach. The most commonly-prescribed macrolides: 1. 2. 3. 4. erythromycin clarithromycin azithromycin roxithromycin

Aminoglycosides
Aminoglycoside antibiotics are used to treat infections caused by gram-negative bacteria. Aminoglycosides may be used along with penicillins or cephalosporins to give a two-pronged attack on the bacteria. Aminoglycosides work quite well, but bacteria can become resistant to them. Since aminoglycosides are broken down easily in the stomach, they can't be given by mouth and must be injected. When injected, their side effects include possible damage to the ears and to the kidneys. This can be minimized by checking the amount of the drug in the blood and adjusting the dose so that there is enough drug to kill bacteria but not too much of it. Generally, aminoglycosides are given for short time periods. The aminoglycosides are drugs which stop bacteria from making proteins. This effect is bactericidal. The most commonly-prescribed aminoglycosides: 1. 2. 3. 4. 5. 6. amikacin gentamicin kanamycin neomycin streptomycin tobramycin

Cephalosporins
Cephalosporins are grouped into "generations" by their antimicrobial properties. Cephalosporins are categorized chronically, and are therefore divided into first,

second, and third generations. Currently, three generations of cephalosporins are recognized and a fourth has been proposed. Each newer generation of cephalosporins has greater gram negative antimicrobial properties than the preceding generation. The later-generation cephalosporins have greater effect against resistant bacteria. Cephalosporins are used to treat pneumonia, strep throat, staph infections, tonsillitis, bronchitis, otitis media, various types of skin infections, gonorrhea. Cephalosporin antibiotics are also commonly used for surgical prophylaxis. Cephalosporins are closely related to the penicillins. Cephalosporins have a bacteriocidal effect by inhibiting the synthesis of the bacteria cell wall.

The most commonly-prescribed cephalosporins:

1. First generation 1. cephazolin 2. cefadroxil 3. cephalexin 4. cephradine

2.

Second generation

1. 2. 3. 4.

cefaclor cefuroxime cefprozil loracarbef

3.

Third generation

1. 2. 3. 4. 5.

cefotaxime cefixime cefpodoxime ceftazidime cefdinir

4.

Fourth generation

1. 2.

cefepime cefpirome

Fluoroquinolones
Fluoroquinolones are known as broad-spectrum antibiotics, meaning they are effective against many bacteria. Fluoroquinolones are used to treat most common urinary tract infections, skin infections, and respiratory infections (such as sinusitis, pneumonia, bronchitis). Common side effects of fluoroquinolones include mainly the digestive system: mild stomach pain or upset, nausea, vomiting, and diarrhea. These are usually mild and go away over time. Fluoroquinolones should not be given during pregnancy. Fluoroquinolones inhibit bacteria by interfering with their ability to make DNA. This activity makes it difficult for bacteria to multiply. This effect is bacteriocidal. The most commonly-prescribed fluoroquinolones: 1. 2. 3. 4. 5. 6. 7. 8. ciprofloxacin gatifloxacin gemifloxacin levofloxacin moxifloxacin norfloxacin ofloxacin trovafloxacin

Penicillins
Penicillin was the first antibiotic discovered by Alexander Fleming in 1929. Penicillins are used to treat skin infections, dental infections, ear infections, respiratory tract infections, urinary tract infections, gonorrhea. Penicillins are sometimes combined with other ingredients called beta-lactamase inhibitors, which protect the penicillin from bacterial enzymes that may destroy it before it can do its work. Penicillins are usually very safe. The greatest risk is an allergic reaction, which can be severe. People who have been allergic to cephalosporins are likely to be allergic to penicillins. Penicillins block the construction of bacteria cell walls, causing the walls to break down, and eventually killing the bacteria.

The most commonly-prescribed penicillins: 1. 2. 3. 4. 5. amoxicillin ampicillin bacampicillin oxacillin penicillin

Tetracyclines
Tetracyclines are a family of antibiotics used to treat a broad spectrum of bacterial infections. Tetracyclines were discovered in the late 1940s and were extremely popular when they were first discovered. The tetracycline antibiotics have a very broad spectrum of action. Tetracyclines are used to treat mild acne, Rocky Mountain spotted fever, Lyme Disease, upper respiratory tract infections, urinary tract infections, sexually transmitted diseases, typhus. The most commonly-prescribed tetracyclines: 1. 2. 3. tetracycline doxycycline minocycline

Antibiotic resistance
Antibiotics are extremely important in medicine, but unfortunately bacteria are capable of developing resistance to them. Antibiotic-resistant bacteria are germs that are not killed by commonly used antibiotics. When bacteria are exposed to the same antibiotics over and over, the bacteria can change and are no longer affected by the drug. Bacteria have number of ways how they become antibiotic-resistant. For example, they possess an internal mechanism of changing their structure so the antibiotic no longer works, they develop ways to inactivate or neutralize the antibiotic. Also bacteria can transfer the genes coding for antibiotic resistance between them, making it possible for bacteria never exposed to an antibiotic to acquire resistance from those which have. The problem of antibiotic resistance is worsened when antibiotics are used to treat disorders in which they have no efficacy (e.g. antibiotics are not effective against infections caused by viruses), and when they are used widely as prophylaxis rather than treatment. Resistance to antibiotics poses a serious and growing problem, because some infectious diseases are becoming more difficult to treat. Resistant bacteria do not respond to the antibiotics and continue to cause infection. Some of these

resistant bacteria can be treated with more powerful medicines, but there some infections that are difficult to cure even with new or experimental drugs.

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