Antibiotics• antibiotics are agents that inhibits or kill

the bacteria

History

• The term antibiotics coming from the word ”antibiosis” which mean against life,

• Antibiosis were first described in 1877 by the French “ Louis Pasteur”, then was renamed as antibiotics by the American “Selman Waksman” in 1942.

Classification:

1.chemical/biosynthetic

• natural: e.g. aminoglycosides

• synthetic: e.g. sulfonamides

• semisynthetics: e.g. beta lactam

Classification (cont)

• II. biological activity:

• -bactericidal: kills the bact.

• -bacteriostatic: slow or stall bacterial growth

Bacteriocidal:

• The beta-lactams Which interfere with cell wall homeostasis,

• quinolones which are topoisomeraseinhibitors.

Beta lactam:

• contain four rings in which steric constrains or chemical substituents activate the beta-lactambond,

• Mechanism of Action:

• Beta-lactams act mainly by blocking the synthesis of peptidoglycan, a component of the cell wall formed of parallel glycase strands cross-linked by peptides. Peptidoglycan synthesis includes cytoplasmic rections to form precursors, catalyzed transglycolase, and cross-linking of peptide components catalyzed

Mechanism of Action (cont)

• by transpeptidase. The transpeptidase step is specifically and irrevrsibly inhibited by beta-lactams. They attack multiple targets called penicillin binding proteins (PBPs), of which transpeptidase is the main example.

Mechanisms of resistance against the beta lactams

• include altered PBPs and production of beta-lactamases. PBPs in Streptococcus pneumoniae, methicillin-resistant Staph. aureus, Enterococcusfaecium and E. hirae often bind pooly to beta-lactamase (50% of the strains may be resistant). Production of beta-lactamases in the primary mechanism of resistant in S. aureus, Moraxellacatarrhalis and Neisseriagoonorrhea.

Beta lactam classification:

• The beta-lactams are classified according to their chemical structures as either penicillins or cephalosporins.

• -The penicillins include penicillin G, penicillin V, nafcillin, amoxicillin and ampicillin.

• -The cephalosporins include cefazolin, ceftazidine, ceftriaxoneand imipenem

Pencillins indication:

• -Parenteral penicillin G is indicated to tret S. pneumoniae, non-penicillinase strains of S. aureus, oral anaerobes, Neisseria meningitidis, and Treponema pallidum

• -Parenteral nafcillin is indicated to treat penicillinase-producing S. aureus.

• Oral penicillin V is indicated to treat S. pneumoniae, non-penicillinase strains of S. aureus, and Enterococci.

• -Oral amoxicillin is indicated to treat B. fragilis (in combination wit clavulanic acid), H. influenzae(alone or in combination with clavulanic acid), and P. mirabilis (in combination with clavulanic acid. Clavulanic acid is a beta-lactamase inhibitor that potentiates the action of amoxicillin against beta-lactamase producing strains

Cephalosporins indication:

• Parenteral cefazolin is indicated to treat Escherichia coli, Klebsiella pneumoniae and P. mirabilis

• Parenteral ceftazidine is indicated to treat E. coli, K. pneumoniae, P. mirabilis and P aeruginosa.

• Parenteral ceftriaxone is indicated to treat S. pneumoniae, N. meningitidis, N. gonorrhea, H. influenzae, E. coli, K. pneiumoniae, Enterobacter, and P. mirabilis.

Side effects:

• GI irritation is common with the amoxicillin/clavulanic acid combination.

• Oral penicillin V& Amoxicillin may block estrogen, thus antagonizing oral contraceptives.

• biliary sludging (pain, nausea, vomoting) with ceftriaxone

Quinolone

• The representative quionolone agents are nalidixic acid, ciproflaxin and levoflaxin the last 2 drugs contain a fluorine atom attached to the reactive quinolone ring.

Mechanism of action:

• are bactericidals of rapid effectys that inhibit baterial topoisomerases II and IV. Topoisomerase II is the primary target, promoting double-strand breaks in bacterial DNA. By inhibitin topoisomerase IV, ecadenation of daughter bacterial cells is blocked. The quinolones will also inhibit mammalian topoisomerases I and II, but at much higher concentration than needed to inhibit baterial topoisomerases.

Quinolone indications:

• -Nalixilic acid is an older agent that does not differentiate much between bacterial and hosts targets, and is useful only to treat urinary infections (where it accumulates).

• -Ciproflaxin and levoflaxin are indicated for urinary track infections, pneumonia and bronchitis caused by gram-negative aerobes.

• -Ciproflaxin is also indicated in N. gonorrhea and Pseudomonas.

• -Levoflaxin is indicated for community-aquiredpneuminia.

Side effect of quinolones

• As ciproflaxin distributes to the CNS ,the main adverse reactions are due to CNS stimulation: headache, dizziness, insomnia and nervousness. Seizures are rare but may occur in sensitive patients or those using alcohol or theophilline.

• Pain, nausea, vomiting, tendonitis and tendon rupture are also common.

• Unpredictable acute liver failure is associated with certain quinolones.

• Renal impairment as they are eliminated mostly in urine.

Drug interaction

Drug interaction:

-The beta lactam group have many drug interactions.

-Bacteriostatic antibiotics (chloramphenicol, macrolidesand tetracyclines) interfere with the action of beta-lactams.

- The aminoglycoside antibiotics have synergistic antibacterial action but are chemically incompatible with the beta-lactams.

-

Drug interaction:

Low pH and destroxe solution inactivates beta lactams.

-Probenecid bloks their excretion thus prolonging effective blood levels of most beta-lactams(excepts a few cephalosporins).

- Drugs containing metals decrease the absorption of quinolones

- Warfarinm may havee greater anticoaguant effects with fluoroquinolones

Bacteriostatic

• bacteriostatic antibiotics include • the macrolides,

• tetracyclines,

• aminoglycosides

• chloramphemnicol

• and clindamycin

Mode of action

• They inhibit bacterial protein synthesis by acting on bacterial ribosomal units. In addition to the bacteriostatic activity.

• Each drug class has other characteristic mechanisms:

• Macrolides: accumulate in gram-positive bateria and some mammalian cells

• Tetracyclines: pumped into bacterial cells

• Aminoglycosides and Aminociclitols: are also bactericidal

• Chloramphenicol: also affects mitochondrial protein synthesis

• Clindamycin: passively enters bacteria and concentrates in macrophages

Indication

• Macrolides: they include azithromycin and erythromycin

• They are indicated to treat atypical pneumonias caused by Mycoplasma pneumoniae and Legionellapneumoniae. Other patogens like Streptococcus pneumonia, H. influenzae and M. avium readily develop resis

• Azithromycin is also indicated to treat H. influenzae, bronchitis and Chlamydia tance by either increasing drug eflux from bacterial cells or by altering drug binding targets.

• Erythromycin is also indicated to treat otitis media in combination with sulfisoxazole.

Indications (cont)

• Chloramphenicol is indicated to treat H. influenzae, Salmonella, Ricketsia, Chlamydia and anaerobic absesses, especially in the brain, or meningitis.

• Clindamycin isindicated in anaerobic bacteria or sites, like bone and abdomen. Other indications are against gram-positive bateria and Pneumocystiscarinni (in combination with primaquine).

•

• Tetracyclines: they are indicated to treat Rickettsia, Chlamydia, Mycoplasma, Lyme disease, relapsing fever, and selected gram-positive and gram-negative bacteria

• Aminoglycosides and Aminocyclitols: they include; amikacin, gentamycin, kanamycin, netilmycin, streptomycin, neomycin and paromomycin. The only amynociclitol in use is spectinomycin.

Indications (cont)

-These agents are indicated against gram-negative aerobic bacteria like E. coli, Enterobacter, Proteus and Klessiella. Anmikacin, gentamicin, netlmicin and tobramycin are active against Ps. aeruginosa.

-They are also used against gram-positive aerobicbacteria like Strep. viridans, Strep. agatactae and Enterococus. Aminoglycosides are used in combination with beta-lactamsto treat serious gram-positive infections.

- Streptomycin is indicated against M. tuberculosis and spectinomycin against N. gonorrhea.

Indications (cont)

Side effects:

• The macrolides concentrate in tissue and inflammatory cells, but CNS levels are too low to be effective. They are metabolized in the liver and excreted primarily in bile. May cause stomach cramps, nausea, vomiting and diarrhea by overstimulation of the GI muscles

• The tetracyclines are contraindicated in children less than 9 years old and pregnant women because they interfere with bone and teeth development. They are also contraindicated in patients with renal impairment.

• The aminoglycosides cause dose-dependent ototoxicity (may be permanent), renal toxicity and neuromuscular blockade due to atypical absortion.

• Chloramphenicol will cause reversible bone marrow supression (dose-related), aplastic anemia (rare and fatal, not dose related, may occur weeks or months after therapy), and gray baby syndrome.

• Clindamycin may cause diarrhea, antibiotic associated colitis and pseudomembramous colitis

Drug interaction:

- Chloramphenicol and clindamycin antagonize the antibiotic effect of macrolides.

- Tetracyclines antagonize the antibiotic effects of penicillins

-The beta-lactams and aminoglycosides inactivate each other in sdolution but act synergistically when used sequentially.

-clindamycin and may interact with anesthetics, neuromuscular blockers (enhance block), antidiarrheals(block absorption), and will antagonize the antibiotic effects of chloramphenicol and the macrolides.

Chemotherapy

• The word "chemotherapy" without a modifier usually refers to cancer treatment.

• The first modern chemotherapeutic agent was arsphenamine, an arsenic compound discovered in 1909 and used to treat syphilis.

Sidney Farber, M.D. - founder of Children's Hospital Cancer Research Foundation in the 1950's and 1960's.

Sidney Farber is regarded as the father of modern chemotherapy.

Mechanism of action

• Most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells.

• As these drugs cause damage to cells, they are termed cytotoxic.

• Some drugs cause cells to undergo apoptosis (so-called "self-programmed cell death").

• Drugs affect "younger" tumors (i.e., more differentiated) more effectively, because mechanisms regulating cell growth are usually still preserved.

• With succeeding generations of tumor cells, differentiation is typically lost, growth becomes less regulated, and tumors become less responsive to most chemotherapeutic agents.

• Near the center of some solid tumors, cell division has effectively decreased, making them insensitive to chemotherapy. Another problem with solid tumors is the fact that the chemotherapeutic agent often does not reach the core of the tumor.

Solutions to this problem include radiation therapy ( brachytherapy & teletherapy) and surgery.

Cancer cell they fight back!

• Over time, cancer cells become more resistant to chemotherapy treatments.

• Recently, scientists have identified small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside.

• Research on p-glycoprotein and other such chemotherapy efflux pumps is currently ongoing.

• Medications to inhibit the function of

p-glycoprotein are undergoing testing as of 2007 to enhance the efficacy of chemotherapy.

Mechanisms of resistance

• One way is to pump drugs out of cells by increasing the activity of efflux pumps, such as ATP-dependent transporters.

• Resistance can occur as a result of reduced drug influx a mechanism reported for agents that 'piggyback' on intracellular carriers or enter the cell by means of endocytosis.

• In cases in which drug accumulation is unchanged, activation of detoxifying proteins, such as cytochrome P450 mixed-function oxidases, can promote drug resistance. Cells can also activate mechanisms that repair drug-induced DNA damage.

• Finally, disruptions in apoptotic signaling pathways (e.g. p53 or ceramide) allow cells to become resistant to drug-induced cell death.

Depending on your type of cancer and how advanced it is, chemotherapy can:

• Cure cancer - when chemotherapy destroys cancer cells to the point that your doctor can no longer detect them in your body and they will not grow back.

• Control cancer - when chemotherapy keeps cancer from spreading, slows its growth, or destroys cancer cells that have spread to other parts of your body.

• Ease cancer symptoms (also called palliative care) - when chemotherapy shrinks tumors that are causing Pain or pressure.

Other uses

• Certain chemotherapeutic agents also have a role in the treatment of other conditions, including

• ankylosing spondylitis,

• multiple sclerosis,

• Crohn's disease,

• psoriasis, psoriatic arthritis,

• rheumatoid arthritis,

• and scleroderma.

Chemotherapy may be given in many ways.• Injection. The chemotherapy is given by a

shot in a.

• Intra-arterial (IA). The chemotherapy goes directly into the artery that is feeding the cancer.

• Intraperitoneal (IP). The chemotherapy goes directly into the peritoneal cavity.(Ovarian tumor)

• Intravenous (IV). The chemotherapy goes directly into a vein.

• Topically. The chemotherapy comes in a cream that you rub onto your skin.(BCC)

• Orally. The chemotherapy comes in pills, capsules, or liquids that you swallow. (Tamoxifen)

• Traditional chemotherapeutic agents act by killing cells that divide rapidly, (one of the main properties of most cancer cells.)

• This means that chemotherapy also harms cells that divide rapidly under normal circumstances:

• cells in the bone marrow,

• digestive tract,

• and hair follicles.

• Newer anticancer drugs (for example, various monoclonal antibodies) are not indiscriminately cytotoxic, but rather target proteins that are abnormally expressed in cancer cells and that are essential for their growth.

• Such treatments are often referred to as targeted therapy (as distinct from classic chemotherapy) and are often used alongside traditional chemotherapeutic agents in antineoplastictreatment regimens.

Types

• The majority of chemotherapeutic drugs can be divided in to

• alkylating agents( Cisplatin and carboplatin),

• Antimetabolites(azathioprine, mercaptopurine),

• anthracyclines,

• plant alkaloids,

• topoisomerase inhibitors,

• and other antitumor agents.

• All of these drugs affect cell division or DNA synthesis and function in some way.

• Depression of the immune system

• Gastrointestinal distress (Chemotherapy-induced nausea and vomiting (CINV) Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments.

• Hair loss These are most often temporary effects: hair usually starts to regrow a few weeks after the last treatment.

Side effects

• Infertility: Patients may choose between several methods of fertility preservation prior to chemotherapy, including cryopreservation of semen, ovarian tissue, oocytes, or embryos.

• Secondary neoplasm: Development of secondary neoplasiaafter successful chemotherapy and/or radiotherapy treatment can occur. The most common secondary neoplasm is secondary acute myeloid leukemia, which develops primarily after treatment with alkylating agents or topoisomeraseinhibitors.

• Survivors of childhood cancer are more than 13 times as likely to get a secondary neoplasm during the 30 years after treatment than the general population.

• Not all of this increase can be attributed to chemotherapy!

• These include monoclonal antibodies and the new tyrosine kinase inhibitors, which directly targets a molecular abnormality in certain types of cancer

• Eg. (chronic myelogenousleukemia, gastrointestinal stromal tumors).

• In addition, some drugs that modulate tumor cell behaviour without directly attacking those cells may be used. Hormone treatments fall into this category

Newer agents do not directly interfere with DNA.

Newer and experimental approaches

Isolated infusion approaches• Isolated limb perfusion (often used in melanoma), or

isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumours.

• The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases,

• but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases.

• Specially targeted delivery vehicles aim to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This should result in an increased tumor kill and/or reduced toxicity.

• Specially targeted delivery vehicles have a differentially higher affinity for tumor cells by interacting with tumor-specific or tumor-associated antigens.

• Specially targeted delivery vehicles vary in their stability, selectivity, and choice of target, but, in essence, they all aim to increase the maximum effective dose that can be delivered to the tumor cells.

• Reduced systemic toxicity means that they can also be used in sicker patients, and that they can carry new chemotherapeutic agents that would have been far too toxic to deliver via traditional systemic approaches.

Targeted delivery mechanisms

Nanoparticles

• Nanoparticles have emerged as a useful vehicle for poorly soluble agents such as paclitaxel. Protein-bound paclitaxel (e.g., Abraxane) or nab-paclitaxelwas approved by the U.S. Food and Drug

• Administration (FDA) in January 2005 for the treatment of refractory breast cancer. This formulation of paclitaxel uses human albumin as a vehicle

• Nanoparticles made of magnetic material can also be used to concentrate agents at tumour sites using an externally applied magnetic field.

Electrochemotherapy

• Electrochemotherapy is the combined treatment in which injection of a chemotherapeutic drug is followed by application of high-voltage electric pulses locally to the tumor.

• The treatment enables the chemotherapeutic drugs, which otherwise cannot or hardly go through the membrane of cells (such as bleomycin and cisplatin), to enter the cancer cells.

• Clinical electrochemotherapy has been successfully used for treatment of cutaneous and subcutaneous tumors irrespective of their histological origin.

• Recently, new electrochemotherapy modalities have been developed for treatment of internal tumors using surgical procedures, endoscopic routes or percutaneous approaches to gain access to the treatment area.[

Monoclonal antibodies

• Several are in development and a few have been licencedby the FDA:

• Rituximab (marketed as MabThera or Rituxan) targets CD20 found on B cells. It is used in non Hodgkin lymphoma

• Trastuzumab (Herceptin) targets the Her2/neu (also known as ErbB2) receptor expressed in some types of breast cancer

• Cetuximab (marketed as Erbitux) targets the epidermal growth factor receptor. It is used in the treatment of colon cancer and non-small cell lung cancer.

• Bevacizumab (marketed as Avastin) targets circulating VEGF ligand. It is approved for use in the treatment of colon cancer, breast cancer, non-small cell lung cancer, and is investigational in the treatment of sarcoma. Its use for the treatment of brain tumors has been recommended

Never lose Hope

References

• http://en.wikipedia.org/wiki/Antibiotic

• http://scienceaid.co.uk/biology/micro/antibiotics.html

• http://www.angelfire.com/sc3/toxchick/medpharm/medpharm69.html

• http://en.wikipedia.org/wiki/Chemotherapy

• http://www.chemocare.com/whatis/fullstory.sps?iNewsid=43483.

• http://www.clltopics.org/Chemo/chemotherapy%20how%20and%20what.htm.

• http://en.wikipedia.org/wiki/Chemotherapy

• http://www.webmd.com/cancer/questions-answers-chemotherapy