antibiotics

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Thiazolidine ring β-Lactam ring Secondary amino group

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It´s an antibiotic, discovered by Sir Alexander Fleming. 1928, Nobel Prize Penicillium notatum Manly effective against Staphylococcal and Streptococcal infection

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Penicillins (eg, penicillin G) These have the greatest activity against gram-positive organisms, gram-negative cocci, and non- β -lactamase-producing anaerobes. However, they have little activity against gram-negative rods. They are susceptible to hydrolysis by β-lactamases. Antistaphylococcal Penicillins (eg, nafcillin) These penicillins are resistant to staphylococcal lactamases. They are active against staphylococci and streptococci but inactive against enterococci, anaerobic bacteria, and gram-negative cocci and rods. Extended-Spectrum Penicillins (Ampicillin and the Antipseudomonal Penicillins) These drugs retain the antibacterial spectrum of penicillin and have improved activity against gram negative organisms, but they are destroyed by β-lactamases.

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Penicillin, like all –β-Lactam antibiotics, inhibit bacterial growth by interfering with a specific step in bacterial cell wall synthesis. The cell wall is a rigid outer layer that is not found in animal cells. It completely surrounds the cytoplasmic membrane , maintaining the shape of the cell and preventing cell lysis from high osmotic pressure. The cell wall is composed of a complex cross linked polymer, peptidoglycan (murein, mucopeptide), consisting of polysaccharides and polypeptides. The polysaccharide contains alternating amino sugars, N-acetylglucosamine and N-acetylmuramic acid. A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine. Penicillin-binding proteins (PBPs) catalyze the transpeptidase reaction that removes the terminal alanine to form a crosslink with a nearby peptide, which gives cell wall its structural rigidity. β -Lactam antibiotics are structural analogs of the natural D-Ala-D-Ala substrate and they are covalently bound by PBPs at the active site. After a β–lactam antibiotic has attached to the PBP, the transpeptidation reaction is inhibited, peptidoglycan synthesis is blocked, and the cell dies. Penicillins and cephalosporins are bactericidal only if cells are actively growing and synthesizing cell wall.

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A highly simplified diagram of the cell envelope of a gram-negative bacterium. The outer membrane, a lipid bilayer, is present in gram-negative but not gram-positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic access to the cytoplasmic membrane. The peptidoglycan layer is unique to bacteria and is much thicker in gram-positive organisms than in gram-negative ones. Together, the outer membrane and the peptidoglycan layer constitute the cell wall. Penicillin-binding proteins (PBPs) are membrane proteins that cross-link peptidoglycan. β-lactamases, if present, reside in the peri plasmic space or on the outer surface of the cytoplasmic membrane, where they may destroy -lactam antibiotics that penetrate the outer membrane.

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N-acetylglucosamine Nacetylmuramic acid. A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar.

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Semisynthetic Penicillins. The discovery that 6-aminopenicillanic acid could be obtained from cultures of P. chrysogenum, to the development of the semisynthetic penicillins. Side chains can be added that alter the susceptibility of the resulting compounds to inactivating enzymes (b-lactamases) and that change the antibacterial activity and the pharmacological properties of the drug. 6-Aminopenicillanic acid is now produced in large quantities with the aid of an amidase from P. chrysogenum The variety of side chains that have been added to 6-aminopenicillanic acid to produce the medicinal penicillins in current use. Classification of antibiotics 1) Acid – resistant alternative to penicillin G Phenoxymethyl penicillin (Penicillin –V) 2) Penicillinese-resistant Penicillins Methacillin Cloxacillin 3. Extended Spectrum Penicillins Aminopenicillin –Ampicillin, Becampicillin,amoxicillin Carboxypenicillins- Carbenicillin Ureidopenicillins-Pepracillin Beta – Tactamase Inhibitors Clavulanic Acid Salbactum, Tazobactum

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Penicillin G Penicillin G has activity against a variety of species of gram-positive and gram-negative bacteria and few others. Cocci: streptococci ( except viridans, enterococci) are highly sensetive, so are many pneumococci, staph. aureus, through origanally very sensitive, has acquired resistance to such an extent that it must be counted out of PnG spectrum. Gram negative cocci--- Neisseria gonorrhoeae and N.meningitidis are susceptible PnG, through increasing number of gonococci have developed partial and others high degree resistance. Bacilli :- Gram-positive bacilli—majority of B.anthracis, corynebacterium diphtheria, and particularly all clostridia, listeria are highly sensitive, so are sperochetes ( treponema pallidum) but bacteroides fragilis is largely resistant. Actinomyces israelii is only moderately sensetive. Majorty of gram-negative bacilli (except a few E.Colli, proteus), mycobacrieum tuberculosis, rickecttsiae,protozoa, fungi and viruses are totally insensitive to PnG.

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Bacterial resistance- Development of high-molecular-weight PBPs that have decreased affinity for the antibiotic. Altered PBPs with decreased affinity for b-lactam antibiotics are acquired by homologous recombination between PBP genes of different bacterial species. Ex-Streptococcus pneumoniae isolates have decreased affinity for b- lactam antibiotics as a result of interspecies homologous recombination events. The number and size of pores in the outer membrane vary among different gram-negative bacteria. An extreme example is P. aeruginosa, which is intrinsically resistant to a wide variety of antibiotics because it lacks the classical high-permeability porins. Active efflux pumps serve as another mechanism of resistance, removing the antibiotic from its site of action before it can act.

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Bacteria also can destroy b-lactam antibiotics enzymatically. b-Lactamases are capable of inactivating certain of these antibiotics and may be present in large quantities Bacteria in biofilms produce extracellular polysaccharides and, in part owing to decreased growth rates, are much less sensitive to antibiotic therapy. Pharmacokinetics Absorption. Oral Administration of Penicillin G. About one-third of an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions. Gastric juice at pH 2 rapidly destroys the antibiotic. The decrease in gastric acid production with aging accounts for better absorption of penicillin G from the gastrointestinal tract of older individuals. Absorption is rapid, and maximal concentrations in blood are attained in 30 to 60 minutes.

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Distribution. Penicillin G is distributed widely throughout the body, but the concentrations in various fluids and tissues differ widely. Its apparent volume of distribution is about 0.35 L/kg. Approximately 60% of the penicillin G in plasma is reversibly bound to albumin. Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine. Plasma t1/2 of PnG in healthy adult is 30 min. The pharmacokinetics of PnG is dominated by very rapid renal excretion, about 10% by glomerular filtration and the rest by tubular secretion. Adverse effect. Hypersensitivity Reactions. Hypersensitivity reactions are by far the most common adverse effects noted with the penicillins, and these agents probably are the most common cause of drug allergy. Allergic reactions complicate between 0.7% and 4% of all treatment courses.

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Manifestations of allergy to penicillins include maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxis. The overall incidence of such reactions to the penicillins varies from 0.7% to 10% in different studies. Local irritancy and direct toxicity- Pain at I.M injecstion site, nausea on oral ingestion and thrombophlebitis of injected vein are dose related expression of irritancy. Toxicity to the brain may be manifested as mental confusion, muscular twitching, convulsions and coma, larger dose( >20MU) affect the palette and bleeding processes. Uses of b-lactam antibiotics Streptococcal Infections. Streptococcal Pharyngitis-this is the most common disease produced by S. pyogenes (group A b-hemolytic streptococcus). Penicillin-resistant isolates have yet to be observed for S. pyogenes. The preferred oral therapy is with penicillin, 500 mg every 6 hours for 10 days.

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Pulmonary and periodontal infections usually respond well to penicillin G, Staphylococcal Infections. The majority of staphylococcal infections are caused by microorganisms that produce penicillinase. A patient with a staphylococcal infection who requires treatment with an antibiotic should receive one of the penicillinase-resistant penicillins e.g., nafcillin or oxacillin . Meningococcal Infections. (Pus in cerebrospinal fluid can block brain passages and spinal spaces) Penicillin G remains the drug of choice for meningococcal disease. Patients should be treated with high doses of penicillin given intravenously, as described for pneumococcal meningitis. Syphilis. Sexually transmitted disease caused by the spirochete Treponema pallidum. skin and mucous-membrane rash, lymph node swelling, and bone, joint, eye, and nervous system involvement; Therapy of syphilis with penicillin G is highly effective. Primary, secondary, and latent syphilis .long therapy is required treated with penicillin G.

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Diphtheria. Acute infectious bacterial disease caused by Corynebacterium diphtheriae. The bacterium usually enters through the tonsils, nose, or throat and multiplies there, forming a thick membrane that adheres to the tissues and sometimes blocks the trachea, requiring emergency treatment. There is no evidence that penicillin or any other antibiotic alters the incidence of complications or the outcome of diphtheria; specific antitoxin is the only effective treatment.

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Urticaria kind of skin rash notable for dark red, raised, itchy bumps Maculopapular rash Exfoliative dermatitis Stevens-Johnson syndrome

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The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, (Acremonium is a genus of Fungi in the Hypocreaceae family). History Cephalosporin compounds were first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu. He noticed that these cultures produced substances that were effective against Salmonella typhi, the cause of typhoid fever, which had beta-lactamase. Guy Newton and Edward Abraham at the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C. The cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA), was derived from cephalosporin C and proved to be analogous to the penicillin nucleus 6-aminopenicillanic acid, but it was not sufficiently potent for clinical use. Modification of the 7-ACA side-chains resulted in the development of useful antibiotic agents, and the first agent cephalothin (cefalotin) was launched by Eli Lilly and Company in 1964.

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Mechanism of action Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins) but are less susceptible to penicillinases. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin-binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. Beta-lactam antibiotics mimic this site and competitively inhibit PBP crosslinking of peptidoglycan.

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CLINICAL USE: Cephalosporin's are indicated for the prophylaxis and treatment of infections caused by bacteria susceptible to this particular form of antibiotic. First-generation cephalosporins are predominantly active against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms). Adverse effects The commonly quoted figure of 10% of patients with allergic hypersensitivity (urticaria, anaphylaxis, interstitial nephritis (kidneys ,tubules inflammation ). Pseudomembranous colitis-eosinophil count in the peripheral blood exceeds 450/μl. Hypoprothrombinemia is a blood disorder in which a deficiency of prothrombin (Factor II) results in impaired blood clotting, leading to an increased physiological risk for bleeding, which blocks the enzyme vitamin K epoxide reductase (likely causing hypothrombinemia) and aldehyde dehydrogenase (causing alcohol intolerance).