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Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / Contents:No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Subject Contents Concept of antibiotics and their classification Antibiotics Classification of antibiotics Classes of antibiotics 1. Inhibitors of cell wall synthsis Classification of inhibitors of cell walls synthesis B-lactam antibiotics Inhibitors of proteins synthesis:Aminoglycosides (AGs) Tetracyclines Chloramphenicol: Macrolides: Lincosamides : Plasma membrane inhibitors Nucleic acid inhibitors Rifamycins Quinolones Ciprofloxacin, Norfloxacin, Ofloxacin, Moxifloxacin, and trovafloxacin. Metronidazole Antimetabolites Sulfonamides Trimethoprim Antifungal drugs Antiviral drugs Antiprotozoan drugs Antihelminthic drugs Pharmacology Page No. 1 2 2 4 7 12 13 15 20 20 23 26 29 31 33 34 35 37 37 39 40 40 40 42 43 44 44 45 4 th year )1( Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )2( Concept of antibiotics and their classification Antibiotics:means "against life" defines are soluble compounds that are derived from certain M.O that can inhibit the growth of bacteria or even destroy (kill) them and other M.O, such as bacteria, fungi or protozoa, can differ from one another in the following ways: a) Chemical properties. b) Mechanism of action. c) Pharmacokinetics. d) Spectrum of activity. e) Therapeutic uses. f) Untoward effects. The term originally referred to any agent with biological activity against living organisms, however, "antibiotic" now is used to refer to substances with antibacterial, antifungal, or anti-parasitical activity. The first widely used antibiotic compounds used in modern medicine were produced and isolated from living organisms, such as the penicillin class produced by fungi in the genus penicillium or streptomycin from bacteria of the genus streptomyces. With advances in organic chemistry many antibiotics are now also obtained by chemical synthesis, such as the Sulfa drug. Many antibiotics are relatively small molecules with a molecular weight less than 2000 Da. Antibiotics are specific products of metabolism, or their modifications with high physiological activity against individual groups of M.O (Viruses, Bacteria, Streptomyces, Fungi, Algea, Protozoa) or against malignant tumours, that can selectively slow down or completely inhibit their growth. In contrast to some other metabolites, antibiotics are characterized by the following two properties: I: Unlike organic acids alcohols or the like compounds antibiotics are biologically active against organisms sensitive to them. This means that an antibiotic substance has a high physiological effect even in low concentrations. Penicillin for example, in the conc. Of 0.000001 gm/ml produces a pronounced bactericidal effect on bacteria sensitive to this antibiotic. II: The antibiotic action is selective, which means that each antibiotic is potent biologically only against certain organisms, or groups of organisms, without affecting appreciably other living organisms. Penicillin G for example inhibits the growth of only Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )3( certain gram +ve bacteria (cocci, streptococci, etc.) and has no effect on G-ve bacteria, fungi, or other organisms. The antibiotics are not intermediate but final products of metabolism. They are accumulated inside the cell or released by the cell in to the medium. Antibiotics are formed in quantities smaller than organic acids alcohols, etc., but they are physiologically most active products of metabolism. Antibiotics were further developed in Britain following the re-discovery of penicillin in 1928 by Alexander Fleming. Fleming was studying Staphylocci at St. Mary's College in London when he noticed a zone of inhibition surrounding a penicillium contaminant in one of his cultures. The penicillium was initially identified as P. rubrum but was later determined to be P. natatum Definitions: Antimicrobial, antimicrobic: any substances with sufficient antimicrobial activity that it can be used in the treatment of infectious diseases. Anti-infective agents: are chemical substances that kill or suppress the growth of M.O. Bactericidal antibiotics: an antimicrobial that not only inhibits growth but is lethal to bacteria. Bacteriostatic antibiotic: an antimicrobial that inhibits growth but does not kill the organisms. Chemotherapeutics: a broad term that encompasses antibiotics, antimicrobials, and drugs used in the treatment of cancer. In the context of infectious diseases, it implies the agent is not an antibiotic. Minimum inhibitory conc. (MIC): a laboratory term that defines the lowest conc. (µg/ml) able to inhibit growth of the M.O. Resistant: organism that are not inhibited by clinically achievable concentration of an antimicrobial agent. Sensitive: term applied to M.O indicating that they will be inhibited by conc of the antimicrobic that can be achieved clinically. Spectrum: an expression of the categories of M.O against which an antimicrobial is typically active. A narrow spectrum agent has activity against only a few organisms. A Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )4( broad spectrum agent has activity against organisms of diverse types (ex: G +ve and –ve bacteria). Susceptible: term applied to M.O indicating that they will be inhibited by conc of the antimicrobic that can be achieved clinically. Selective toxicity: Clinically effective antimicrobial agent all exhibit selective toxicity toward the parasite rather than the host (more damage to parasite than host), a characteristic that differentiates them from the disinfectants in most cases, selective toxicity is explained by action on microbial processes or structures that differ from those of mammalian cells, for example, some agents act on bacterial cell wall synthesis, and other on functions of the 70 S bacterial ribosome but not the 80 S eukaryotic ribosome, some antimicrobial agents, such as penicillin, are essentially non toxic to the host, unless hypersensitivity has developed. Selective toxicity: is based on the ability of an antimicrobial agent to attack a target present in bacteria but not humans. Type of antibiotics: 1. Natural antibiotics : A number of natural products this substances secretions of fungi or soil M.O. Soils are complex ecosystems, and it is not surprising that it is inhabitants have evolved chemical defenses against each other. For example: Penicillin. 2. Semi-synthetic antibiotics: there are natural antibiotics (products) that have been chemically modified in the laboratory (and pharmaceutical facility) to a. Improve the efficacy of the natural product. b. Reduce it is side effects. c. Circumvent developing resistance by the targeted bacteria. d. Expand the range of bacteria that can be treated with it. 3. Synthetic antibiotics: completely synthetic products, the sulfa drugs are examples. Classification of antibiotics: I: Classification of antibiotics by the mechanism of their biological action: 1. Antibiotics inhibiting synthesis of the cell wall (ex: Penicillins, Bacitracin, Vancomycin, Cephalosporins, cycloserin, …etc) 2. Antibiotics causing membrane dysfunction (ex: nystatin, trichomycin, endomycin, gramicidins,…etc) 3. Antibiotics inhibiting selectively the synthesis (metabolism) of nucleic acids Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )5( a. Inhibiting synthesis of RNA (ex: griseofulvin, canamycin, olivomycin, novobiocin, neomycin, actinomycin) b. Inhibiting synthesis of DNA (ex: ciprofloxacin, norfloxacin, sarcomycin, actidion, brunemycin) 4. Antibiotics inhibiting the synthesis of purins and pyrimidins (ex: Sarcomycin, decoinin, asaserin) 5. Antibiotics inhibiting the synthesis of protein (ex: gentamicin, tetracycline, tobramycin, erythromycin, chloramphenicol,…..etc) 6. Antibiotics inhibiting respiration (ex: patulin, pyocynine, usnic acid,….etc) 7. Antibiotics inhibiting oxidative phosphorylation (ex: colicins, oligomycin, gramicidins) 8. Antibiotics having antimetabolic properties these antibiotics acts as antimetabolites of amino acids, vitamins, and nucleic acids. (ex: trimethoprime, sulfamides, cotrimexazole) II. Classification of antibiotics by the spectrum of their biological action: 1. Antibacterial antibiotics of narrow spectrum, active mostly against G+ve or G-ve organisms. Ex: against G-ve bacteria: polymyxin , against G+ve bacteria: Penicillin 2. Broad spectrum antibacterial antibiotics, active mostly against G+ve and G –ve bacteria ex: tetracycline, Aminoglcosides, chloramphenicol. 3. Antituberculosis antibiotics, active mostly against M. tuberculosis Ex: Rifampin, streptomycin, cycloserin, canamycin 4. Antifungal antibiotics (ex: Nystatin, griseofulvin, candicin, trichothecin, levorin) 5. Antitumour antibiotics (ex: actinomycin C, mitomycin C, olivomycin, bruneomycin, rubomycins) 6. Antiamoebic antibiotics (ex: metronidazole, fumagillin) 7. Bacteriostatic antibiotics (ex: chloramphenicol, sulfonamides) Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )6( 8. Bactericidal antibiotics (ex: penicillin, Aminoglcosides, ciprofloxacin, cefotaxime) III. Classification of antibiotics by the spectrum of their biological origin: 1. Antibiotics produced by M.O of the order Eubacterials. a. Antbiotics formed by representatives of the genus Pseudomonas: Pyocyanin P. aeroginosa Viscosin P. viscose b. Antbiotics formed by representatives of genera micrococcus, streptococcus, diplococcus, chromobacterium, Escherichia, proteus Nicin S. lactis Diplomycin Diplococcus x-5 Prodigiosin Chromobacterium prodigiosum (Serratia marcescens) Coliformin E. coli Protaptins P. vulgaris c. Antbiotics formed by genus Bacillus Gramicidins B. brevis Subtilin B. subtilis Polymyxins B. polymyxa Colistatin Bacillus unidentified sporous aerobe 2. Antibiotics formed by M.O belonging to the order streptomycetales: Streptomycin S. griseus Tetracyclin S. aureofaciencs, S. rimosus Novobiocin S. spheroids Actinomycins S. antibioticus 3. Antibiotics formed by imperfect fungi Penicillin P. chrysogenum Griseofulvin P. griseofulvum Trichothecin Trichothecium roseum 4. Antibiotics formed by fungi of the basidiomycete and ascomycete classes Thermophillin Basidiomycete Lenzites thermophila Lenzitin Lenzites septaria Chetomin Chaetomium cochloides (ascomycete) Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )7( 5. Antibiotics formed by Lichens, algae, and lower plants Usnic (Usninic) acid Lichen Chlorellin Chlorella vulgaris 6. Antibiotics formed by higher plants Allicin Allium sativum Raphanin Raphanus sativum Phytoalexins Pisatin in peas (Pisum sativum) Phaseolin in true beans (Phaseolus vulgaris) 7. Antibiotics of animal origin Lysozyme, ecmolin, cruzin (Tripanosoma cruzi), Interferone Classes of antibiotics At the highest level, antibiotics can be classified as either bactericidal or bacteriostatic. Bactericidal kill bacteria directly where bacteriostatic prevent them from dividing. However, these classifications are based on laboratory behavior; in practice, both of these are capable of ending a bacterial infection. Generic Name Amikacin Gentamicin Kanamycin Neomycin Netilmicin Streptomycin Tobramycin Paromomycin Antibiotics[6] Brand Names Common Uses Aminoglycosides Amikin Infections caused by Gram-negative Garamycin bacteria, such as Kantrex Escherichia coli and Klebsiella Netromycin particularly Pseudomonas aeruginosa. Nebcin Effective against Aerobic bacteria (not Humatin obligate/facultative anaerobes). Possible Side Effects Hearing loss Vertigo Kidney damage Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )8( Ansamycins Experimental, as antitumor antibiotics Geldanamycin Herbimycin Carbacephem Loracarbef Lorabid Cefadroxil Cefazolin Cefalotin or Cefalothin Carbapenems Invanz Bactericidal for both Gram-positive and Finibax Gram-negative Primaxin organisms via inhibition of cell wall synthesis and therefore useful for empiric broadMerrem spectrum antibacterial coverage. (Note MRSA resistance to this class.) Cephalosporins (First generation) Duricef Ancef Keflin Cefalexin Keflex Ertapenem Doripenem Imipenem/Cilastatin Meropenem Cefaclor Cefamandole Cefoxitin Cefprozil Cefuroxime Cefixime Cefdinir Cefditoren Cefoperazone Cefotaxime Cefpodoxime Cephalosporins (Second generation) Ceclor Mandole Mefoxin Cefzil Ceftin, Zinnat Cephalosporins (Third generation) Suprax Omnicef Spectracef Cefobid Claforan Gastrointestinal upset and diarrhea Nausea Seizures Headache Rash and Allergic reactions Gastrointestinal upset and diarrhea Nausea (if alcohol taken concurrently) Allergic reactions Gastrointestinal upset and diarrhea Nausea (if alcohol taken concurrently) Allergic reactions Gastrointestinal upset and diarrhea Nausea (if alcohol taken concurrently) Allergic reactions Dr. Zahra Muhsin Ali Ceftazidime Ceftibuten Ceftizoxime Ceftriaxone Cefdinir / Lectures of antibiotics / Biology dep. / 4 th year )9( Fortaz Cedax Rocephin Cephalosporins (Fourth generation) Cefepime Maxipime Gastrointestinal upset and diarrhea Nausea (if alcohol taken concurrently) Allergic reactions Glycopeptides Teicoplanin Vancomycin Vancocin Macrolides Azithromycin Clarithromycin Dirithromycin Erythromycin Roxithromycin Troleandomycin Telithromycin Zithromax, Sumamed, Zitrocin Biaxin Ketek Streptococcal infections, syphilis, respiratory infections, mycoplasmal infections, Lyme disease Pneumonia Nausea, vomiting, and diarrhea (especially at higher doses) Jaundice Visual Disturbance, LIVER TOXICITY. This medication's approval in the U.S. was controversial, and one doctor went to jail in followup attempts to ascertain its safety because she falsified the results of her part of the testing precisely because it seemed to cause liver problems, including liver failure, to a greater extent than would be expected of a common-use antibiotic.[7] Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )10( Antimetabolite, Anticancer Monobactams Spectinomycin Aztreonam Penicillins Amoxicillin Ampicillin Azlocillin Carbenicillin Cloxacillin Dicloxacillin Flucloxacillin Mezlocillin Meticillin Nafcillin Oxacillin Penicillin Piperacillin Ticarcillin Novamox Wide range of infections; penicillin used for streptococcal infections, syphilis, and Lyme disease Polymyxin B Enoxacin Gatifloxacin Levofloxacin Lomefloxacin Moxifloxacin Norfloxacin Ofloxacin Trovafloxacin Polypeptides Eye, ear or bladder infections; usually applied directly to Kidney and nerve damage the eye or inhaled (when given by injection) into the lungs; rarely given by injection Quinolones Bacitracin Colistin Ciprofloxacin Gastrointestinal upset and diarrhea Allergy with serious anaphylactic reactions Brain and kidney damage (rare) Ciproxin, CiploxESTECINA Urinary tract Tequin Levaquin Avelox NOROXIN Ocuflox Trovan infections, bacterial prostatitis, community-acquired Nausea (rare), tendinosis pneumonia, (rare) bacterial diarrhea, mycoplasmal infections, gonorrhea Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )11( Sulfonamides Mafenide Prontosil (archaic) Sulfacetamide Sulfamethizole Sulfanilimide (archaic) Sulfasalazine Sulfisoxazole Trimethoprim TrimethoprimSulfamethoxazole (Cotrimoxazole) (TMPSMX) Urinary tract infections (except sulfacetamide and mafenide); mafenide is used topically for burns Bactrim Nausea, vomiting, and diarrhea Allergy (including skin rashes) Crystals in urine Kidney failure Decrease in white blood cell count Sensitivity to sunlight Tetracyclines Demeclocycline Doxycycline Minocycline Oxytetracycline Vibramycin Minocin Terracin Tetracycline Sumycin Arsphenamine Salvarsan Chloramphenicol Chloromycetin Clindamycin Cleocin Lincomycin Ethambutol Fosfomycin Fusidic acid Furazolidone Fucidin Syphilis, chlamydial infections, Lyme disease, mycoplasmal infections, acne rickettsial infections Others Spirochaetal infections (obsolete) acne infections, prophylaxis before surgery acne infections, prophylaxis before surgery Antituberculosis Gastrointestinal upset Sensitivity to sunlight Staining of teeth (especially in children) Potential toxicity to mother and fetus during pregnancy Dr. Zahra Muhsin Ali Isoniazid Linezolid Metronidazole Mupirocin Nitrofurantoin / Lectures of antibiotics / Biology dep. / 4 th year Antituberculosis Zyvox Flagyl Bactroban Macrodantin, Macrobid Giardia Platensimycin Pyrazinamide Quinupristin/Dalfopristin Syncercid Antituberculosis Rifampin or Rifampicin Binds to the β subunit of "RNA polymerase" to Reddish-orange sweat, inhibit transcription tears, and urine of mostly "Grampositive" and "mycobacteria" Tinidazole Generic Name )12( Brand Names Common Uses Possible Side Effects 1. Inhibitors of cell wall synthsis Peptidoglycan a vital component of the bacterial cell wall (Fig. 1) is a compound unique to bacteria and therefore provides an optimum target for selective toxicity. Synthesis of peptidoglycan precursors starts in the cytoplasm, wall subunits are then transported across the cytoplasmic membrane and finally inserted in to the growing peptidoglycan molecule. Several different stages are therefore potential targets for inhibition Fig. (2) The peptidoglycan (murein sac) component of the bacterial cell wall gives it is shape and rigidity. This giant molecule is formed by weaving the linear glycans N-acetylglucosamine and N-acetylmuramic acid into a basket-like structure. Mature peptidoglycan is held together by cross-linking of short peptide side chains hanging off the long glycan molecules. This cross linking process is the target of two of the most important groups of antimicrobics, the B-lactams and the glycopeptides (vancomycin and teicoplanin). Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )13( Fig. (1) Structure of the Bacterial Cell Wall Classification of inhibitors of cell walls synthesis A) Inhibitor of cell wall synthesis B-lactam antibiotics other antibiotics (1. vancomycin,2. Bacitracin) Dr. Zahra Muhsin Ali Penicillin / Lectures of antibiotics / Biology dep. / Cephalosporins Carbapenems a) Imipenem b) Cilastatin 4 th year Monobactams Aztreonam B) B-lactamase inhibitors 1. Sulbactam 2. Tazobactam 3. Clavulanic acid I: Classification of Penicillin A) Natural penicillin 1. Benzylpenicillin PG 2. Phenoxymethylpenicillin PV B) Semisynthetic penicillin 1. B-lactmase resistance a. methicillin, b. oxacillin, c. cloxacillin, d. flucloxacillin 2. Extended spectrum a. aminopenicillin (ampicillin, amoxicillin, tatampicillin, pivampicillin, bacampicillin) b. Amidiniopenicillin (pivamecillinam, mecillinam c. carboxypenicillins (carbenicillin, ticacillin, piperacillin, mezlocillin, azlocillin) II: Classification of Cephalosporins 1. 1st generation Cephalosporins including: Cefadroxil, Cefzolin, Cefalexin, Cephalothin, Cephradine 2. 2nd generation Cephalosporins including: Cefaclor, Cefamandole, Cefmetazole, Cefonicid, Cefotetan, Cefprozil, Cefuroxime 3. 3rd generation Cephalosporins including: Cefdinir, Cefditoren, Cefoperazone, Cefpodoxime, Cefotaxime, Ceftazidime,Ceftriaxone. Ceftizoxime )14( Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )15( 4. 4th generation Cephalosporins including: Cefepime, Cefpirome * Cephalosporins have been classified as first, 2nd, 3rd, and 4th generation largely on this basis of 1. Bacterial Susceptibility, 2. Resistance to B-lactamases B-lactam antibiotics Beta lactams contain a beta lactam ring and inhibit cell wall synthesis by binding to penicillin binding proteins (PBP). Beta lactams comprise a very large family of different groups of bactericidal compounds all containing the beta lactam ring. The different groups with in the family are distinguished by the structure of the ring attached to the beta-lactam ring in penicillins this is a five-membered ring in cephalosporins a sixmembered ring and by the side chains attached to these ring Fig. (3), PBP are membrane proteins (ex: Carboxypeptidases, Transglycosylases, and Transpeptidases) capable of binding to penicillin (hence the name PBP) and are responsible for the final stages of cross linking of the bacterial cell wall structure, various bacteria differ in their number and type of PBP as different B-lactams have variable affinity for different PBP bacteria have differing B-lactam susceptibility. . Fig. (4): The structure of B-lactam Beta lactam ring Chemistry: The structure of B-lactam consists of a thiazolidine ring (1) connected to a B-lactam ring (2), which is attached to a side chain ®, the various penicillins differ in their side chain structure Fig. (4) The basic structure of all B-lactams consists of a four membered Blactam ring, the type and structure of the side chain defines the class and pharmacokinetics of the drugs. * Mechanism of action Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )16( Inhibition of one or more of these essential enzymes results in an accumulation of precursor cell wall units leading to activation of the cells autolytic system and cell lysis Fig (5). B-lactam antimicrobics are usually highly bactericidal, but only to growing bacteria synthesizing new cell wall. Killing involves attenuation and disruption of the developing peptidoglycan "corset" liberation or activation of autolytic enzymes that further disrupt weakened areas of the wall, and finally osmotic lysis from passage of water through the cytoplasmic membrane to the hypertonic interior of the cell. As might be antipated, cell wall-deficient organisms, such as Mycoplasma or L forms are unaffected , are not susceptible to B-lactam antimicrobics. The action of antimicrobics on peptidoglycan synthsis. The glucan backbone and the amino acid side chains of peptidoglycan are shown. The transpeptidase enzyme catalyzes the cross linking of the amino acid side chains. Penicillin and other B-lactames bind to the transpeptidase, preventing it from carrying out its function. Vancomycin binds directly to the amino acids, preventing the binding of transpeptidase. The spectrum of activity and therapeutics uses of B-lactams varies widely Different B-lactams have different clinical uses, but are not active against species that lack a cell wall (ex: Mycoplasma) or those with very impenetrable walls such as Mycobacteria, or intacellular pathogens such as Brucella, Legionella and Chlamydia. 1. Penicillin covers a narrow spectrum of bacteria where as the Carbapenems and some penicillins (ex: Piperacillin/Tazobactam) have a very broad spectrum of coverage. 2. Penicillins cover most Streptococcal infections although some resistance has emerged (ex: Penicillin resistant S. pneumoniae). 3. Meropenem, imipenem, Piperacillin, and Ceftazidime have good P. aeroginosae coverage. 4. Cloxacillin, Cefazolin, Piperacillin/Tazobactam, and imipenem have good S. aureus coverage. 5. The third generation Cephalosporins, Piperacillin, imipenem have good gram negative coverage. 6. Some Enterococci are sensitive to amoxicillin, piperacillin, imipenem. 7. Aztreonam is active essentially only against aerobic gram –ve Bacilli. 8. Piperacillin use to P. aeroginosa infection and carbenicillin and ticarcillin active against P. aeroginosa called it antipsudomonadal infections. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )17( 9. Cloxacillin, oxacillin, methicillin is used to treatment of infection caused by Staphylococci including skin and soft tissue infections, pneumonia, osteomylitis, endocarditis, and septicemia st 10. 1 generation Cephalosporins activity against Proteus mirabilis, E. coli, K. pneumonia, Staphylococci and Streptococci nd 11. 2 generation Cephalosporins activity against H. influnzae, some Enterobacter aerogenes, some Neisseria spp., Klebsiella, E. coli, Proteus, Streptococc i rd 12. 3 generation Cephalosporins effective against Serratia marcescens, Meningitis, P. aeroginosa th 13. 4 generation Cephalosporins activity against Staphylococci and Streptococci and Enterobacter, Enterobactereciae, E. coli, K. pneumonia, Proteus mirabilis, P. aeroginosa, H. influenzae, Nesseria 14 Penicillin therapy is still the first choice for all types of a) Gonococcal infections b) Anthrax (B. anthrax) c) Gas gangrene d) Actinomycosis e) Listeria infections 15. syphilis: PG is the most effective treatment for all stages of syphilis, since Treponema pallidum, the M.O causing syphilis is very sensitive to PG. Dverse effects (Side effect): 1. B-lactams are generally well tolerated and are considered relatively non toxic. 3. Allergic and hypersensitivity reactions are the most frequent adverse drug effect. 4. Uncommon side effects include drug induced fever, serum sickness, interstitial, nephritis, hepatic toxicity, neutropenia and seizures. 5.Allergic manifestations including (a. Urticaria, angioedema, drug fever, Maculopapuar rash, Serum sickness). 6. Adisulfira like effect including (Thrombocytopenia, neutropenia, interstitial nephritis) Absorption, distribution, & excretion of B-lactam: After intramuscular or intravenous administration, absorption of most penicillins is rapid and complete. After oral administration, only 5-30% of the dose is absorbed, depending on acid stability, binding to food, presence of buffers, etc. After absorption penicillins are widely distributed in tissues and body fluids. Protein binding is 40-60% for PG , ampicillin, and methecillin, 90% for nafcillin, and 95-98% for oxacillin and Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )18( dicloxacillin. For most rapidly absorbed penicillins, a parenteral dose of 3-6 gm/24h yields serum levels of approximately 1-6 µg/ml, in many tissues, penicillin concentrations are similar to those in serum. Lower levels occur in joints, eye, and the central nervous system. However in meningitis penetration is enhanced and levels of 0.2 µg/ml occur in the cerebrospinal fluid with a daily parenteral dose of 12 gm. Most of the absorbed penicillin is rapidly excreted by the kidneys. The simultaneous administration of probenecid or para-aminohippuric acid and procain are prolongs the duration of penicillin in the body this state called depot preparation because probenecid and procain are blocks the transport of penicillin in the proximal tubule (kidneys) this preparation of penicillin provides an alternative means for maintaining high plasma levels of penicillin. Antimicrobial activity: All penicillins and cephalosporins have the same mode of action, B-lactams are bactericidal, they bind to PBP and inhibit bacterial cell wall synthesis,they may also activate endogenous autolytic enzymes resulting in bacterial cell lysis. PG and P V are often measured in units (1million units=0.6gm), but the semisynthetic penicillins are measured in grams. Whereas 0.002-1µg/ml of penicillin G is lethal for a majority of susceptible G+ ve organisms, 10-100 times more is required to kill G-ve bacteria (except neisseriae). The activity of penicillin also varies with their protein binding, which ranges from 40% to more than 95% for different drugs. Resistance to Beta lactams may involve one or more of the three possible mechanisms 1. Resistance by alteration in target site: Some bacteria synthesize an additional PBP which has a much lower affinity for Blactams than normal PBP and is therefore able to continue cell wall synthesis when the other PBP are inhibited, the gene which codes for the additional PBP is present on the chromosome in all cells of a resistant population. 2. Resistance by alteration in access to the target site This mechanism is found in gram –ve cells where B-lactams gain access to their PBP by diffusion through protein channels (porins) in the outer membrane. Mutations in porin genes result in a decrease in permeability of the outer membrane and hence resistance. Strains resistant by this mechanism may exhibit cross resistance to unrelated antibiotics that use the same porins. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )19( 3. Reistance by production of B-lactamases Bete-lactamases are enzymes that catalyze the hydrolysis of the B-lactam ring to yield microbiologically inactive products. Genes encoding these enzymes are widespread in the bacterial kingdom and are found on the chromosome and plasmids. The B-lactamase of G+ve bacteria are released into the extracellular environment (Fig 5a) and resistance will only be manifest when a large population of cells is present. The B-lactam of G-ve cells however remain within the periplasm (Fig. 5b). Bacterial resistance production penicillinase and cephalosporins are a B-lactamase which is produced by a number of bacteria. It can hydrolyze the B-lactam ring of penicillin to form penicilloic acid and cephalosporinic acid a substance that has no antibacterial activity. Microorganisms that are capable of producing penicillinase and cephalosporins (Blactamase) including : S. aureus, Bacillus spp., Bacteroids spp., E. coli, proteus spp., P. aeruginosa, Mycobacterium tuberculosis. *Microorganisms can acquire the ability to produce penicillinase and cephalosporins (B-lactamase) through 1. Plasmid acquisition via transduction in G+ve bacteria. 2. R factor acquisition during conjugation in G-ve bacteria. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )20( Inhibitors of proteins synthesis:1. Although protein synthesis proceeds in an essentially similar manner in prokaryotic and eukaryotic cells its possible to exploit the differences (ex: 70 S vs. 80 S ribosome) to achieve selective toxicity. The bacterial ribosome consists of a 70 S particle, that has 2 subunits: the 50 S (large) and the 30 S (Small): (Surprisingly: 50 S + 30 S=70 S). There are 5important types of antibiotics that inhibit the function of bacterial ribosome this group including: 1. Aminoglycosides (Including: Gentamicin, Amikacin, Streptomycin, Neomycin, Tobramycin, Netilmicin, Spectinomicin, Framycetin, paramomycin, etc). 2. Chloramphenicol. 3. Tetracyclines (Including: Chlorotetracycline, Demethylchlorotetracycline, Doxycyclin, Oxytetracycline). 4. Erythromycin. 5. Lincomycin. 1. Aminoglycosides (AGs) Chemistry The aminoglycosides are compounds containing characteristic amino sugars joined a hexose nucleus in glycosidic linkage, all members of aminoglycosides group of antibiotics have a six member aminocyclitol ring with attached amino sugars. The individual agents differ in terms of the exact ring structure and the number and nature of the amino sugar residues. Mechanism of action: Aminoglycosides acts by binding to specific proteins in the 30 S ribosomal subunit, where they interfere with the binding of formylmethionyl-transfer RNA (fmet-tRNA) to the ribosome (Fig.33.16), and therapy preventing the formation of initiation complexes from which protein synthesis proceeds. Aminoglycosides cause misreading of mRNA codons and tend to break a part functional polysomes (Protein synthesis by multiple ribosomes tandem attached to a single mRNA molecule) in to nonfunctional monosomes. Pharmakinetics Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )21( 1. All of AGs are poorly absorbed after oral administration because of their polycatioic structure. 2. All the AGs are more active in an alkaline environment. 3. Streptomycin, gentamicin, tobramycin, amikacin, kanamycin, and netilmicin are absorbed rapidly after intramuscular or subcutaneous administration. a. It is distributed in all extra cellular fluid. b. It crosses the blood brain barrier only if the meninges are inflamed. c. It is excreted by glomerular filtration. 4. Neomycin is also poorly absorbed following oral administration. It is most often applied topically. Preparations and administration: 1. Streptomycin a. Intramuscular injection is the most common rate of administration. b. To avoid the development of bacterial resistance, streptomycin therapy rarely is extended beyond 10 days except in tuberculosis and subacute bacterial endocarditis. 2. Gentamycin a. This drug can be administrated intramuscularly (Im.), intravenously (IV.), or as an ointment or cream. b. When renal function is impaired, peak and through serum conc. of gentamicin are measured intermittently to allow optimal guidance for adjusting dosage and renal function is monitored by means of the serum creatinine level. 3. Tobramycin, amikacin, and netilmicin can be given IV. or Im., kanamycin can be give Im., IV., or orally. 4. Neomycin a. This drug is available in the form of creams, ointments, and sprays, both alone and in combination with polymyxin, bacitracin, other antibiotics, and corticosteroids. b. It is also available for oral and parenteral administration, although it is rarely used parenterally Side effect of aminoglycosides All of the aminoglycoseds are : 1. Ototoxicity and nephrotoxicity are the most serious side effects. 2. Dysfunction of the optic nerve can occur with streptomycin producing scotomas. 3. Neuromuscular junction blockade may when an AGs is given at high doses and in combination with curariform drugs. 4. Hypersensitivity reactions can occur. 5. Super infection and intestinal malabsorption can occur following oral administration of neomycin. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )22( 6. Directly toxic to both components of the 8th cranial nerve leading to deafness, vertigo and ataxia which may be irreversible. Avoid in patients with hearing loss. 7. Toxicity increases with age, pre-existing renal failure, volume depletion, duration of therapy, high dose, and use in combination with certain nephrotoxic drugs. 8. AGs should generally not be used in pregnancy because of a risk of congenital deafness, but can be given to breast feeding women because of minimal excretion in breast milk or oral absorption by the infant in breast milk or oral absorption by infant. Spectrum of activity 1. Gentamicin: against (proteus, pseudomonas, serratia, some strains S. aureus and etc.). Gentamicin and tobramicin are major AGs they have an extended spectrum, which includes staphylococci, enterobacteriacea, and of particular importance P. aeroginosa. 2. Amikacin and streptomycin are now primarily used in combination with other antibiotics in the therapy of tuberculosis and other mycobacterium diseases. Streptomycin is effective against the organisms that cause Yersinia pestis and tularemia (Francisella tularensis). Therapeutic use UTI and RTI, peritonitis, and bacterial meningitis. 3. Kanamycin has also been largely superseded by less toxic, more effective agents. Against pseudomonas and most G+ve organism. 4. Netilmicin: active against bacteria that are resistant to gentamicin, P. aeroginosa, Serratia, enterobacter and Klebsiella. 5. Neomycin is effective against many G-ve spp and is also effective G+ve (ex: S. aureus). Note: Because of its serious effects when absorbed systemically is used most frequently in dermatologic and ophthalmic ointments. In addition, neomycin can be used orally as a bowel preparation for surgery or for the management of hepatic coma. Resistance bacteria of AGs: 1. Resistance to AGs antibiotics may occur by alteration of the 30s ribosomal target protein (ex: a single amino acid change in the p12 protein prevents streptomycin binding). Resistance may be also a rise through alterations in cell wall permeability or in the energy dependent transport a cross the cytoplasm membrane. 2. Production of Aminoglycoside modifying enzymes (Adenylases, acetylases, phosphorylases) are the principal cause of resistance to AGs is most important mechanism of acquired resistance. The genes for these enzymes are often plasmid Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )23( mediated, located on transposons, and transferable from one bacterial species to another. The enzymes alter the structure of the AGs molecules, thus inactivating the drug. 2. Tetracyclines: 1. The tetracyclines are a large family of antibiotics that were discovered as natural products of Streptomyces bacteria beginning in the late 1940s, the group of tetracyclines and the related compounds that are formed during their synthesis by only three microorganisms (1. Str. aureofaciens , 2. Str. rimosus, 3. Nocardia sulphurea) several semisynthetic preparations were obtained from the metabolites of these microorganisms. They are used in medicine as well. 2. Common members of the tetracycline group of antibiotics are: • Oxytetracycline is a commonly used form of tetracycline that is also known as Terramycin. • Chlortetracyline is another commonly used form of tetracycline that is also known as Aureomycin. • Doxycycline is a semisynthetic form of tetracycline that has a longer-lasting effect than the natural form of tetracycline. • Minocyline is a semisynthetic form of tetracycline. 3. Some newly discovered members of the tetracycline family (e.g. chelocardin) have been shown to act by inserting into the bacterial membrane, not by inhibiting protein synthesis. 4. However, most bacteria possess an active transport system for tetracycline that will allow intracellular accumulation of the antibiotic at concentrations 50 times as great as that in the medium. This greatly enhances its antibacterial effectiveness and accounts for its specificity of action, since an effective concentration cannot be accumulated in Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )24( animal cells. Thus a blood level of tetracycline which is harmless to animal tissues can halt protein synthesis in invading bacteria. 5.The tetracyclines have a remarkably low toxicity and minimal side effects when taken by animals. The combination of their broad spectrum and low toxicity has led to their overuse and misuse by the medical community and the wide-spread development of resistance has reduced their effectiveness. Nonetheless, tetracyclines still have some important uses, such as the use of doxycycline in the treatment of Lyme disease. a. Chemistry: Tetracyclins are four-ring molecules with five different sites for substitution, therapy giving rise to a family of molecules with different substituents at different sites. Members of the family differ more in their pharmacologic properties than in their spectrum of activity. b. Mechanism of action: Tetracyclines are primarily bacteriostatic, inhibiting protein synthesis by binding to 30 S ribosomes at a point that blocks attachment of aminoacyl-tRNA to the acceptor site on the mRNA ribosome complex. Unlike the aminoglycosides, their effect is reversible; they are bacteriostatic rather than bactericidal. c. Pharmakinetics of tetracyclines: The tetracyclines are absorbed orally. The tetracyclines are chelated by divalent cations, and their absorption and activity are reduced. Thus, they should not be taken with dairy products or many antacid preparations. Tetracyclines are excreted in the bile and urine in active form. d. Side effects of tetracyclines: Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )25( 1. The tetracyclines have a strong affinity for developing bone and teeth, interference with bone development and brown staining of teeth occurs in the fetus and children. Systemic administration may cause liver damage. The drugs are deposited in the teeth and bones because of their chelating properties and the formation of a tetracyclinecalcium orthophosphate complex. To which they give a yellowish color, and they are avoided in children up to 8 years of ago. 2. Common complications of tetracyclines therapy are gastrointestinal disturbance due to alteration of the normal flora, predisposing to superinfection with tetracyclineresistant organisms and vaginal or oral candidiasis (thrush) due to the opportunistic yeast Candida albicans. Tetracyclines suppress diarrhea and encouraging overgrowth by resistant and undesirable bacteria (ex: S. aureus) and fungi (ex: Candida). 3. Hypersensitivity reactions can occur. 4. When tetracyclines are administered orally, gastrointestinal irritation is common. 5. High doses of tetracyclines can produce hepatic dysfunction. This reaction is exacerbated during pregnancy. e. Preparations and administration: Tetracyclines are available in formulations suitable for oral, IV, and Im administration, they are also available for topical use, including ophthalmic solutions. f. Spectrum of activity 1. Tetracycline is a broad-spectrum antibiotic that attacks both gram-positive and gram-negative bacteria. Tetracyclines are able to combat pathogens that invade cells because they can enter body tissues. They are used against urinary tract infections, rickettsial infection, and chlamydial infections. Tetracyclines are also used as the secondary treatment for gonorrhea and syphilis, Pseudomonas aeruginosa is less sensitive but is generally susceptible to tetracycline concentrations that are obtainable in the bladder. 2. Doxycycline is frequently used to treat chronic prostatitis, sinusitis, syphilis, Chlamydia, pelvic inflammatory disease, acne and rosacea. In addition, it is used in the treatment and prophylaxis of anthrax and in prophylaxis against malaria. It is also effective against Yersinia pestis (the infectious agent of bubonic plague) and is prescribed for the treatment of Lyme disease, ehrlichiosis and Rocky Mountain spotted fever. Because doxycycline is one of the few medications that is effective in treating Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )26( Rocky Mountain spotted fever (with the next best alternative being chloramphenicol), it is indicated even for use in children for this illness. 3. Mycoplasmal infections. Tetracyclines may be beneficial in the treatment of acne. 3. Chloramphenicol: Ehrlich and his collaborators isolated from cultivated soil of Venezuela in 1947 the strain of a Streptomyces species that produced an antibiotic with a broad antimicrobial spectrum. The antibiotic was chloramphenicol, and the organism that produced it, Str. venezuelae. Chloramphenicol was originally discovered and purified from the fermentation of a Streptomyces species, but currently it is produced entirely by chemical synthesis. a. Chemistry Chloramphenicol is a relatively simple molecule containing a nitrobenzene nucleus, which is responsible for some of the toxic problems associated with the drug. Other derivatives have been produced, but none is in widespread clinical use. Fig. (1): Chemical structure of chloramphenicol b. Mechanism of action of chloramphenicol: Chloramphenicol has affinity for the large (50S) ribosomal subunit where it blocks the action of peptidyl transferase, therapy preventing peptide bond synthesis (Fig. 33.16.). Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )27( the drug has some inhibitory activity on human mitochondrial ribosomes (which are also 70 S) which may account for some of the dose-dependent toxicity to bone marrow. c. Pharmakinetics of chloramphenicol: 1. Chloramphenicol is absorbed rapidly from the gastrointestinal tract. 2. Chloramphenicol is widely distributed in body fluids and reaches therapeutic levels in CSF fluid, it is also present in bile, milk, and aqueous humor. 3. Chloramphenicol is metabolized in the liver by conjugation with glucuronic acid to yield a microbiologically inactive form that is excreted by the kidneys. 4. It is metabolites are excreted in the urine. d. Preparations and administration: Chloramphenicol is well absorbed when given orally, but be given IV if the patient cannot take drugs by mouth. Topical preparations (ophthalmic solutions and ointments) are also available. It is well distributed in the body and penetrates host cells. e. Side effects of chloramphenicol: Nitrobenzene is a bone marrow suppressant, and the structurally similar chloramphenicol molecule has similar effects. This toxicity takes two forms: a. dose-dependent bone marrow suppression, which occurs if the drug is given for long periods and is reversible when treatment is stopped. b. an idiosyncratic reaction causing aplastic anemia, which is not dose dependent and irreversible. It can occur after treatment has stopped, but is fortunately very rare, occurring in about 1-30000 patients treated. 1. Hypersensitivity reactions can occur. 2. Chloramphenicol was once a highly prescribed antibiotic and a number of deaths from anemia occurred before its use was curtailed. 3. Bone marrow depression resulting in panocytopenia. 4. Superinfections can occur, including oropharyngeal candidiasis and acute staphylococcal enterocolitis. 5. Gray baby syndrome: Chloramphenicol is also toxic to neonates, particularly premature babies whose liver enzyme systems are incompletely developed. This can result in gray baby syndrome Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )28( a. this condition is seen in neonates, especially premature infants, who have been given relatively large doses of Chloramphenicol. b. Cyanosis, respiratory irregularities, vasomotor collapse, abdominal distention, loose green stools, and an ashen-gray color characterize this often fetal syndrome. c. The condition develops because of the immature hepatic conjugating mechanism and the inadequate mechanism for renal excretion in neonates. 5. Chloramphenicol is an antibiotic of last resort because it inhibits formation of blood cells, causing aplastic anemia. 6. The eucaryotic cells most likely to be inhibited by chloramphenicol are those undergoing rapid multiplication, thereby rapidly synthesizing mitochondria. Note: Now it is seldom used in human medicine except in life-threatening situations (e.g. typhoid fever). f. Spectrum of activity: Chloramphenicol is a broad-spectrum antibiotic that is small enough to effect areas of the body that are too small for other antibiotics to enter. Is a protein synthesis inhibitor that has a broad spectrum of activity but it exerts a bacteriostatic effect. It is effective against intracellular parasites such as the rickettsiae. The drug achieves satisfactory concentrations in the CSF, topical preparations are used variety of bacterial species, both G-ve and G+ve, aerobes and anaerobes, including intracellular organisms. 1. Chloramphenicol is the drug of choice for typhoid fever. 2. Chloramphenicol has been used in the treatment of bacterial meningitis caused by (particularly H. influenzae) is effectively treated. 3. Rickettsial diseases and brucellosis can be treated with chloramphenicol; however, tetracyclines are the preferred agents. Chloramphenicol use is now restricted to treatment of rickettsial or ehrlichial infections in which tetracyclines cannot be used because of hypersensitivity or pregnancy. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )29( In some developing countries Chloramphenicol use is more extensive because of its low cost and proven efficacy in diseases such as typhoid fever and bacterial meningitis. g. Resistance bacteria of Chloramphenicol The most common mechanism of Chloramphenicol resistance involves the inactivation of the drug by a plasmid mediated enzymatic mechanism which is easily transferred with in G-ve bacterial populations. Chloramphenicol acetyl transferases produced by resistant bacteria are intracellular, but capable of inactivating all Chloramphenicol in the immediate environment of the cell. Acetylated Chloramphenicol fails to bind to the ribosomal target. 4. Macrolides: 1. The investigators study intensely the antibacterial products of metabolism of various streptomycetes a high molecular weight, Woodward (1957) gave the name of macrolides to these compounds, also as the product of metabolism of Str. erythreus. Macrolide antibiotics are characterized by the presence in their molecules of the macrocyclic lactone ring connected with one or several carbohydrate residues, these are usually amino sugars. Chemistry: Macrolides contain a lacton ring and one or more deoxy sugars. Fig (1): The chemical structure of a macrolide antibiotic. Azithromycin: Is a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics. It is s derived from erythromycin, but it differs chemically from Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )30( erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15-membered. Azithromycin is used to treat certain bacterial infections, most often bacteria causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia and sinusitis. It is also effective against certain sexually transmitted diseases, such as non-gonococcal urethritis and cervicitis. The chemical structure of Azithromycin: 2. The most important members of the group are erythromycin, clarithromycin, and azithromycin . 3. Mechanism of action of Macrolides: Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. Binding inhibits elongation of the protein by peptidyl transferase or prevents translocation of the ribosome or both. Macrolides are bacteriostatic for most bacteria but are cidal for a few Gram-positive bacteria. 4. Pharmacokinetics: a. All forms of erythromycin are absorbed following oral administration and diffuse in to most body tissues and fluids except CSF fluid. b. Macrolides are concentrated in the liver and is excreted primarily in bile and feces. 5. Preparations and administration: a. Oral macrolides base is supplied as enteric coated tablets. b. Macrolides ethylsuccinate, is available as granules or powder for oral suspension, other available oral salts are stearate, and estolate. c. Sterile macrolides gluceptate is available for parenteral administration. d. Macrolides base is available in topical formulations. 6. Side effects of Macrolides: Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )31( a. Cholestatic hepatitis has occurred in adults treated for a week or longer with the estolate form. Hepatitis can also occur with the ethylsuccinate, and possibly with the stearate. The hepatitis is uncommon and is reversible. b. Epigastric distress can occur. c. A high incidence of thrombophlebitis occurs when erythromycin is administered intravenously even when the drug is dissolved in a large fluid volume. d. Superinfection can occur. e. Transient deafness has been reported, especially with higher doses. f. Erythromycin causes nausea and vomiting after oral administration in a significant number of patients. Jaundice is associated with some formulations of the drug. 7. Spectrum of activity: a. This drug is effective against G+ve organism, including some strains of S. aureus that are penicillin G resistance. b. Neisseria species, some strains of H. influenzae, and Bordetella, Legionella, Treponema, Mycoplasma species are sensitive to erythromycin. c. In general, it is not very active against most G-ve bacilli. d. Macrolide antibiotics can be administered orally, making them the choice for treating children who have streptococcal and staphylococcal infections. The most commonly used macrolide is Erythromycin, which is used to treat legionellosis, mycoplasmal pneumonia, and streptococcal and staphylococcal infections. e. Clarithromycin is also active against mycobacterium. In addition, both azithromycin and clarthromycin have demonstrated efficacy against Borrelia burgdorferi , the causal agent of lyme disease and the protozoan parasite Toxoplasma gondii, which causes toxoplasmosis. 5. Lincosamides : 1. The antibacterial products of metabolism of various streptomycetes, the product of metabolism of Str. lincolnesis . including clindomycin and lincomycin. Chemistry: Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )32( Clindomycin is the 7-deoxy,7-chloro derivative of the parent drug, lincomycin, which it has essentially replaced. The chemical structure of Lincosamides 2.Pharmakinetics a. Although it is well absorbed following oral administration, clindomycin most often is administered parenterally. b. The drug is widely distributed in body fluids and tissues but does not pass readily into CSF fluid. c. Most of the drug is metabolized to the inactive sulfoxide form, which then is excreted in the bile and urine. 2. Mode of action: Lincosamides is chemically unrelated to the macrolides but has a similar mode of action and spectrum, are a miscellaneous group of protein synthesis inhibitors with activity similar to the macrolides. 3. Spectrum activity: Lincomycin has activity against Gram-positive bacteria and some Gram-negative bacteria (Neisseria, H. influenzae). Clindamycin is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria. It is a common topical treatment for acne, and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. The most severe common adverse effect of clindamycin is Clostridium difficile-associated diarrhea (the most frequent cause of pseudomembranous colitis). Although this side-effect occurs with almost all antibiotics, including beta-lactam antibiotics, it is classically linked to clindamycin use. 4. Side effect: Pseudomembranous colitis can occur, resulting in diarrhea, abdominal pain, fever, and mucus and blood in the stools. At one time, this condition was often fatal, but now that the causative organism is known to be C. difficile, it can treated with vancomycin. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )33( 5.Resistance bacteria of Macrolides and clindamycin a. Altered accumulation (Minimal outer membrane penetration, efflux pump) b. Altered target (methylation of rRNA). c. Enzymatic inactivation (phosphotransferase, esterase). 3. PLASMA MEMBRANE INHIBITORS 1. Plasma membrane inhibitors are antibiotics that interfere with the functionally of the plasma membrane of a pathogen. 2. The commonly used plasma membrane inhibitor antibiotic is Polymyxin B, which combats gram-negative bacteria such as Pseudomonas. Today, when combined with neomycin, it is used in nonprescription topical antibiotics for superficial infections. a. The plasma membranes that encompass all kinds of living cells perform a variety of vital functions. The structure of these membranes in bacterial cells differs from that in mammalian cells and allows the application of some selectively toxic molecules, but these are few in number compared with those acting at other target sites. The most important are the polymyxins, which act on the membranes of G-ve bacteria, the polyene antifungal agents (amphotericin B, nystatin) also act by inhibiting membrane function. b. Polymyxins: The group of polymyxins includes antibiotics substances of the polypeptide nature produced by various strains of B. polymyxa and B. circulans that differ in amino acid composition , five various polymyxins were first differentiated: polymyxin A (aerosporin), polymyxin B, C, D, E (Colistin), and M. Polymyxin B and E are the most common members of the family still in clinical use. The chemical structure of polymyxin Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )34( c. Polymyxins are bacteriocidal cyclic polypeptides that disrupt the structure of cell membranes. The free amino groups of polymyxins act as cationic detergents, disrupting the phospholipids structure of the cell membranes. d. This antibiotics inhibiting membrane bound protein (enzyme) permeases which is involved in transport processes (active and passive osmosis), in this state the antibiotics is bacteriocidal, these biologically active compounds effect wall permeability in cells sensitive to them. Cell permeability is known to depend in the first instance on the cytoplasmic membrane. 8. Polymyxins act selectively on G –ve bacteria , Pseudomonas aeroginosa , fungicidal effects, E. coli, K. pneumoniae, S. typhi, V. cholera, Brucella abortis. 9. Resistance due to chromosomally mediated alterations in membrane structure or antibiotic uptake has been reported. 10. Polymyxins are primarily used topically but have also been for gut decontamination, wounds irrigation and as a bladder washout. 11. In the past they have been used systemically, but due to poor distribution in tissues, nephrotoxicity and neurotoxicity they have been superseded by less toxic agents. 4. NUCLEIC ACID INHIBITORS Some antibiotics and chemotherapeutic agents affect the synthesis of DNA or RNA, or can bind to DNA or RNA so that their messages cannot be read. Either case, of course, can block the growth of cells. The majority of these drugs are unselective, however, and affect animal cells and bacterial cells alike and therefore have no therapeutic application. Two nucleic acid synthesis inhibitors which have selective activity against procaryotes and some medical utility are the quinolones and rifamycins. Nucleic acid inhibitors interfere with the formation of nucleic acids. The commonly used nucleic acid inhibitor antibiotics follow. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )35( 1. Rifamycins 1. Sensi et al., 1959 isolated from the culture of Str. mediterranei , an antibacterial antibiotics which they named rifamycin (rifampin). It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei). Chemistry: Rifamycin belongs to the group of complex macrocyclic antibiotics, it is zwitterionic and is soluble in water at low PH. Fig: The chemical structure of rifampin 2. Mechanism of action: Rifampin inhibits RNA synthesis in bacteria and chlamydiae by binding to DNA-dependent RNA polymerase, which prevents the initiation of RNA synthesis. Selective toxicity is based on the far greater affinity for bacterial polymerases than for the equivalent human enzymes. 3. Pharmacokinetics: Rifampin is well absorbed from the gastrointestinal tract, and it is widely distributed in tissues and is excreted mainly through the liver. Rifamycins can reach the cerebrospinal fluid and enter tissues and abscesses. The disadvantage of rifamycins is that they cause urine, feces, saliva, sweat and tears to appear an orange-red color. It is crosses the blood brain barrier and reaches high concentrations in saliva. 4. Preparations: Rifampin is available as capsules for oral use. 5. Side effects: a. Urine, sweat, tears, and contact lenses may take on an orange color because of rifampin administration, this effect is harmless. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )36( b. Light-chain proteinuria and impaired antibody response may occur. c. Rifampin induces hepatic microsomal enzymes . d. Rashes, gastrointestinal disturbances, and renal damage have been reported. e. Jaundice and severe hepatic dysfunction are occasionally produced. 5. Spectrum activity: Rifampicin (or rifampin) is a bactericidal antibiotic from the rifamycin group. a. They are used to treat tuberculosis and leprosy. A commonly used rifamycin is rifampin, which is used to attack Mycobacterium tuberculosis that causes tuberculosis and leprosy. It has been found to have greater bactericidal effect against M. tuberculosis than other anti-tuberculosis drugs, and it has largely replaced isoniazid as one of the front-line drugs used to treat the disease, especially when isoniazid resistance is indicated. It is effective orally and penetrates the cerebrospinal fluid so it is useful for treatment of bacterial meningitis. b. Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and leprosy; and also has a role in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid. It is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection. It is also used to treat infection by Listeria monocytogenes, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila. 6. Resistance due to chromosomally mediated alterations in target site (Mutant RNA polymerase) Three additional synthetic chemotherapeutic agents have been used in the treatment of tuberculosis: isoniazid (INH), para-aminosalicylic acid (PAS), and ethambutol. The usual strategy in the treatment of tuberculosis has been to administer a single antibiotic (historically streptomycin, but now, most commonly, rifampicin is given) in conjunction with INH and ethambutol. Since the tubercle bacillus rapidly develops resistance to the antibiotic, ethambutol and INH are given to prevent outgrowth of a resistant strain. It must also be pointed out that the tubercle bacillus rapidly develops resistance to ethambutol and INH if either drug is used alone. Ethambutol inhibits incorporation of mycolic acids into the mycobacterial cell wall. Isoniazid has been reported to inhibit mycolic acid synthesis in mycobacteria and since it is an analog of pyridoxine (Vitamin B6) it may inhibit pyridoxine-catalyzed reactions as well. Isoniazid is activated by a mycobacterial peroxidase enzyme and destroys several targets in the cell. PAS is an antifolate, similar in activity to the sulfonamides. PAS was once a primary anti-tuberculosis drug, but now it is a secondary agent, having been largely replaced by ethambutol. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )37( Isoniazid is also called isonicotinyl hydrazine or INH. Isoniazid is a first-line antituberculosis medication used in the prevention and treatment of tuberculosis. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops. 2. Quinolones 1. Quinolones are synthesis agents that interfere with replication of the bacterial chromosome including Nalidixic acid. 2. Quinolones interfere with DNA gyrase (an enzyme), which is involved in DNA replication. 3. Quinolones represent a large family of bacteriocidal synthetic agents which, in a manner similar to the cephalosporins, can be generally grouped in categories or "Generations" based on their spectrum of activity (Fig: 33:26). Nalidixic acid is the first generation prototypes, but the addition of fluorine at position 6 of the main quinolone ring (Fluoroquinolones) (Fig: 33:27) has improved antibacterial activity, leading to the synthesis of many additional compounds, this compound including Ciprofloxacin, Norfloxacin, Ofloxacin, Moxifloxacin, and trovafloxacin. 4. Mechanism of action The antibacterial activity of Quinolones is due to their ability to inhibit the activity of bacterial DNA gyrase enzyme and Topoisomerase II,IV (which is an enzyme necessary to separate replicated DNA, and thereby inhibits cell division), which is essential for DNA replication and allows supercoils to be relaxed and reformed. Binding of the drug inhibits DNA gyrase activity. During replication of the bacterial chromosome, DNA gyrase produces and removes supercoils in DNA ahead of the replication fork to maintain the proper "Tension" required for efficient DNA duplication. Topoisomerase IV similarly acts to remove supercoils and to separate newly formed DNA "Daughter" strand after replication (Fig. 33.28). These enzymes thus act in concert to insure that the DNA molecule has the proper conformation for efficient replication and packaging within the cell. Quinolones are able to interfere with these essential enzymes in bacteria while not affecting their counterparts in mammalian cells. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )38( 5. Resistance to Quinolones is chromosomally mediated a. Mutations which changes the target enzymes in a manner that affects Quinolones binding (changing in DNA gyrase subunits structure resulting in lowered affinity for the drug). b. Changes in cell wall permeability, resulting in decreased uptake, or by efflux. These mechanisms may also lead to cross-resistance to other unrelated agents affected by the same process. 6. Quinolones are primarily administered orally since they are readily absorbed from the gastrointestinal tract, achieving significant serum conc. and good distribution throughout the body compartments. Excretion is mostly in the urine, though a small proportion is excreted in the feces. 7. Spectrum activity: Fluoroquinolones comprise a group of antibiotics that have a broad-spectrum, and are able to enter cells to attack pathogens. a. Nalidixic acid is only active against enterobacteria, and, although occasionally employed in treatment of urinary tract infections, its use has largely been replaced by the newer fluorinated compounds. The compound is unusual in that it is effective against several types of Gram-negative bacteria such as E. coli, Enterobacter aerogenes, K. pneumoniae and Proteus species which are common causes of UTIs. It is not usually effective against Pseudomonas aeruginosa, and Gram-positive bacteria may be resistant. b. Nalidixic acid is a bactericidal agent that binds to the Some quinolones penetrate macrophages and neutrophils better than most antibiotics and are thus useful in treatment of infections caused by intracellular parasites. c. The fluoroquinolone, Cipro. (ciprofloxacin) was recently touted as the drug of choice for treatment and prophylaxis of anthrax, which is caused by a Gram-positive bacillus, Bacillus anthracis. 8. Side effects of Quinolones: a. Gastrointestinal intolerance disturbances are the most common side effect of Quinolones. b. Neurotoxicity and Photosensitivity reaction are less common. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )39( c. The disadvantage of fluoroquinolones is that they may interfere with cartilage development, making them unsafe for pregnant, not used to children because of possible toxic effects on cartilage development. women and children. d. Confusion, dizziness, headache. e. Rushes. 3. Metronidazole: 1. Metronidazole is a nitroimidazole with antiparasitic and antibacterial properties. 2. Mechanism of action: After entry into the microbial cell the molecule is activated by reduction, and the reduced intermediate products are responsible for antimicrobial activity, probably through interaction with, and breakage of the cell's DNA. The reactive intermediates are short-lived and decompose to none toxic inactive end products. Metronidazole is active only against anaerobic organisms because only these can produce the low redox potential necessary to reduce the parent drug. 3. Metronidazole is usually given orally or rectally. It is well absorbed and well distributed in tissues and CSF. The drug is metabolized and most of the parent compound and metabolites are excreted in the urine. 4. Metronidazole is also effective against other protozoan parasites such as Giardia lamblia , Entamoeba coli and E. histolytica. It is an important agent for treatment of infections caused by anaerobic bacteria. 5. Metronidazole resistance is relatively rare and appears to involve either an alteration in uptake or a decrease in cellular reductase activity, therapy slowing the activation of the intracellular drug. 6. The most serious side effects of Metronidazole involved the central nervous system and include peripheral neuropathy. However, these are relatively uncommon and usually seen only in patient on large doses or prolonged treatment. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )40( ANTIMETABOLITES Antimetabolites are a group of drugs that interfere with metabolite, which is a substance (such as an enzyme) that is necessary for cell metabolism. Common antimetabolites follow. 1. Sulfonamides -Sulfonamides or sulfa drugs are used to treat urinary tract infections and control infections in burn patients. These were among the first synthetic antimicrobial drugs used. Commonly used sulfonamides are: • Silver sulfadiazine is used to control infections common in burn patients. • TMP-SMZ is a combination of trimethoprim and sulfamethoxazole and is used to combat intestinal tract and urinary tract gram-negative pathogens. -Many of the synthetic chemotherapeutic agents (synthetic antibiotics) are competitive inhibitors of essential metabolites or growth factors that are needed in bacterial metabolism. Hence, these types of antimicrobial agents are sometimes referred to as anti-metabolites or growth factor analogs, since they are designed to specifically inhibit an essential metabolic pathway in the bacterial pathogen. At a chemical level, competitive inhibitors are structurally similar to a bacterial growth factor or metabolite, but they do not fulfill their metabolic function in the cell. Some are bacteriostatic and some are bactericidal. Their selective toxicity is based on the premise that the bacterial pathway does not occur in the host. -Sulfonamides were introduced as chemotherapeutic agents by Domagk in 1935, who showed that one of these compounds (prontosil) had the effect of curing mice with infections caused by beta-hemolytic streptococci. Chemical modifications of the compound sulfanilamide gave rise to compounds with even higher and broader antibacterial activity. The resulting sulfonamides have broadly similar antibacterial activity, but differ widely in their pharmacological actions. Bacteria which are almost always sensitive to the sulfonamides include Streptococcus pneumoniae, beta-hemolytic streptococci and E. coli. The sulfonamides have been extremely useful in the treatment of uncomplicated UTI caused by E. coli, and in the treatment of meningococcal meningitis (because they cross the blood-brain barrier). The sulfonamides (e.g. Gantrisin and Trimethoprim) are inhibitors of the bacterial enzymes required for the synthesis of tetrahydofolic acid (THF), the vitamin form of folic acid essential for 1-carbon transfer reactions. Sulfonamides are structurally similar to para aminobenzoic acid (PABA), the substrate for the first enzyme in the THF pathway, and they competitively inhibit that step. Trimethoprim is structurally similar to dihydrofolate (DHF) and competitively inhibits the second step in THF synthesis mediated by the DHF reductase. Animal cells do not synthesize their own folic acid but Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )41( obtain it in a preformed fashion as a vitamin. Since animals do not make folic acid, they are not affected by these drugs, which achieve their selective toxicity for bacteria on this basis. The chemical structures of sulfanilamide and para-aminobenzoic acid (PABA). In bacteria, sulfanilamide acts as a competitive inhibitor of the enzyme dihydropteroate synthetase, DHPS, which catalyses the conversion of PABA to dihydropteroate, a key step in folate synthesis. Folate is necessary for the cell to synthesize nucleic acids (DNA and RNA), and in its absence, cells will be unable to divide. Hence, sulfanilamide and other sulfonamides exhibit a bacteriostatic rather than bactericidal effect. - Resistance is widespread with plasmid mediated genes coding for an altered dihydropteroate synthtase Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year ANTIFUNGAL DRUGS Antifungal drugs inhibit the growth of fungi. The commonly used antifungal drugs follow: Polyenes Polyenes are a group of antifungal antibiotics that combine with the ergosterol in the plasma membrane of fungi. This causes the plasma membrane to become extremely )42( Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year permeable, ultimately resulting in the death of the fungi. A commonly used polyene is amphotericin B, which is used to treat histoplasmosis, coccidioidomycosis, and blastomycosis. However, amphotericin B is toxic to kidneys. Enclosing amphotericin B in liposomes when administering the drug reduces its toxicity. Imidazoles Imidazoles interfere with fungal ergosterol synthesis. Commonly used imidazoles are: • Clotrimazole is used to treat cutaneous mycoses. Two example are athlete’s foot and vaginal yeast infections. • Miconazole is similar to clotrimazole. Both drugs are used topically and sold without a prescription. Triazoles Triazoles are similar to imidazoles, but are less toxic than other antifungals. Griseofulvin Griseofulvin is an antibiotic used to treat dermatophytic fungal infections of the hair and nails. This includes tinea capitis. Griseofulvin is taken orally and enters the keratin of skin, hair, and nails. Its purpose is to interfere with fungal mitosis, inhibiting reproduction. Tolnaftate Tolnaftate is a topical treatment for athlete’s foot. Its mechanism for action is unknown. ANTIVIRAL DRUGS Antiviral drugs interfere with the replication of viruses. Commonly used antiviral drugs follow. Amantadine Amantadine prevents a virus from entering the cell or from uncoating once the virus enters the cell. It is used (though it has limited usefulness) to prevent influenza A, but has no practical effect once the virus infects the cell. Nucleoside analogs Nucleoside analog antiviral drugs affect the synthesis of viral DNA or RNA. Commonly used nucleoside analogs are: • Acyclovir is used to combat viruses that cause herpes. • Ribavirin is used to treat rotavirus-caused pneumonia in infants. • Ganciclovir is used fight cytomegalovirus infections that are common in transplant patients and patients who have AIDS. • Trifluridine is used to treat the eye infection caused by acyclovir-resistant herpes keratitis. • Zidovudine (AZT) is used in HIV infection. This drug blocks the synthesis of DNA from RNA by the enzyme reverse transcriptase. )43( Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year ANTIPROTOZOAN DRUGS Antiprotozoan drugs are used to combat parasitic infection, such as the disease malaria. Commonly used antiprotozoan drugs follow. Chloroquine Chloroquine is a replacement for quinine, which was the traditional treatment for malaria. Mefloquine Mefloquine is a secondary treatment for malaria when there is a resistance to chloroquine. Quinacrine Quinacrine is used to treat giardiasis. Diiodohydroxyquin Diiodohydroxyquin is used to treat intestinal amoebic diseases. However, diiodohydroxyquin can cause damage to the optic nerve if the dosage is not carefully controlled. Metronidazole Metronidazole combats parasitic protozoa and obligate anaerobic bacteria. It is used to treat vaginitis caused by Trichomonas vaginalis, giardiasis, and amoebic dysentery. Nifurtimox Nifurtimox is used to combat Chagas’ disease. However, nifurtimox can cause side effects, such as nausea and convulsions. ANTIHELMINTHIC DRUGS Antihelminthic drugs are used to combat helminths, which are parasitic flatworms. Commonly used antihelminthic drugs follow. Niclosamide Niclosamide is used to treat tapeworm infections. This drug inhibits ATP production in aerobic conditions. Praziquantel Praziquantel is also used to destroy tapeworm infections and is used to treat schistosomiasis and other fluke-caused diseases. This drug alters the permeability of the organism’s plasma membrane. Mebendazole Mebendazole is used to combat intestinal helminthic infections, such as ascariasis, whipworms, and pinworms. )44( Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )45( Pharmacology: Is study of the biochemical and physiologic a aspect of drug effects including absorption, distribution, metabolism, toxicity, and specific mechanism of drug action. The branches of Pharmacology including: 1. Pharmacognosy. 2. Pharmacodynamics. 3. Pharmacokinetics. 4. Therapeutics. 5. Toxicology. 6. Dosology. 7. Pharmacy. Factors effecting drug absorption: 1. Dosage. 2. Route of administration including: I. Alimentary routes including: a. Orally. b. Rectal. c. Sublingual. * Advantages of Alimentary administration: 1. An Alimentary route is generally the safest route of administration. The delivery of the drug in to the circulation is slow after oral administration, so that rapid high blood levels are avoided and untoward effects are less likely. 2. Alimentary routes allow for convenient dosage forms that do not require sterile technique. ** Disadvantages of Alimentary administration: 1. The rate of absorption is variable. This becomes a problem if only a small range in blood levels separates a drugs desired therapeutic effect from it is toxic effects. 2. Irritation of mucosal surfaces can occur. 3. The compliance of the patient is not ensured. 4. Oral administration of some drugs passages through firstly the liver and the resulting initial hepatic metabolism is avoided by the sublingual route. II. Parenteral routes 1. Intravenous (IV). 2. Intramuscular (IM). 3. Subcutaneous (SC). 4. Intrapertoneal (IP). 5. Epidural injection. 6. Transdermal. Dr. Zahra Muhsin Ali / Lectures of antibiotics / Biology dep. / 4 th year )46( * Advantages of Parenteral administration: 1. There is a rapid response, which may be required in an emergency. 2. The dose can often be more accurately delivered. 3. Parenteral administration provideds an alternative when the alimentary route is not feasible (ex: When the patient is unconscious). **Disadvantages of Parenteral administration: 1. The more rapid absorption can lead to increase in untoward effects. 2. Both a sterile formulation and the use of a septic technique are required. 3. Local irritation may occur at the site of injection. III. Miscellaneous routes 1. Topical administration: is useful in the treatment of local conditions, there is usually little systemic absorption. 2. In halation provides a rapid route of administration it is used for volatile anesthetics and many bronchodilators. Reference: 1. Antimicrobial chemotherapy edited by John M. B. Smith; John E. Payne and Thomas V. Berne. (2000). 2. Antimicrobial Susceptibility testing edited by Richard Schwalbe and Avery C. Goodwin. (2007).
