Chemotherapeutics & antibiotics

Chemotherapeutics Chemicals which are used within the body tissues to kill or inhibit the growth of pathogenic organisms

The Spectrum of antimicrobial Activity **it is easy to find or develop drugs that effective against prokaryotic cells ,& that do not affect the eukaryotic cells of humans **the problem is difficult when the pathogen is eukaryotic (fungus, protozoan, helminthes) **viral infection more difficult to treat

The Spectrum of antimicrobial Activity Prok.**-differ in cell wall -differ in fine structure of their ribosome -details of their metabolism Euk.**resemble the human cell **the virus is within the human cells

antibiotics

Antibiotics=are a metabolic products or a constituent of a microorganism which kills or inhibit the growth of another microorganism Nowadays used are semi synthetic (Ampicillin) or synthetic (Sulfa drugs) (produced wholly or partly by chemical synthesis) Low concentrations inhibit the growth of m.o.

Characteristics of a good chemotherapeutic or antibiotic 1-it must kill or inhibit the growth of the pathogenic organism 2-it must cause no damage to the host (it must have selective toxicity) 3-it must cause no allergic reaction 4-it must be stable in solid or dissolved state 5-it must remain in the desired tissue for the sufficient length of time (pharmacokinetics) 6- it must kill the pathogenic organism quickly before it mutates and becomes resistant to the drug

Pharmacokinetics have to be desirable (absorption, disintegration) selective toxicity = toxic for the pathogenic organism and not toxic for the host == defined by the therapeutic index max. tolerated dose (toxic to the host) -------------------------------------------------------------- min. curative dose (effective therapeutic dose) The high the therapeutic index the better the antibiotic is

Drug Dosage (per Kg Body Weight) Therapeutic Index = Toxic Dose/Therapeutic Dose Drug Dosage (per Kg Body Weight) Toxic Therapeutic Small Ratio (dangerous) Moderate Ratio High Ratio (safe) Most desirable.

Antibiotics activity

The Spectrum of antimicrobial Activity Narrow spectrum = affect only select group of microorganisms e.g Penicillin G affects Gram positive bacteria Broad spectrum = affect a broad range of Gram positive or Gram negative bacteria = affect a more diverse range of microbes e.g. Chloramphenicol.

Antibiotics activity

The type of activity Bactericidal : direct killing of microorganisms = kill microorganisms directly (Streptomycin) Bacteriostatic = inhibit their growth = prevent microorganism from growth (chloramphenicol) #*#* =Host defenses usually destroy microorganisms by phagocytosis & antibody production

Combination of

Mechanisms of Antimicrobial Action Bacteria have their own enzymes for Cell wall formation Protein synthesis DNA replication plasma membrane Synthesis of essential metabolites

Bacterial protein synthesis inhibitors ## initiation of protein synthesis ## elongation (=interfere with elongation factors) Fusidic acid Bacteriostatic Gm+ve bacteria only

initiation of protein synthesis inhibitors Antimicrobial that bind to the 50S ribosomal subunit Antimicrobial that bind to the 30S ribosomal subunit bacteriostatic Tetracyclines bacteriostatic broad spectrum Tetracyclin, Minocycline Doxycycline Aminoglycosides Bactericidal Many gm.-ve bacteria &some gm+ve. Bacteria Streptomycin Kanamycin Gentamycin Neomycin Tobramycin Chloramphenicol – broad rang Lincomycin Clindamycin Restricted range Macrolides Gm+ve bacteria & Mycoplasma Erythromycin

Inhibitors of nucleic acid synthesis & function Inhibitors of RNA (DNA dependent RNA polymerase) Inhibitors of DNA (DNA gyrase) Rifampin Rifamycin Rifampicin Bactericidal Wide spectrum Tuberculosis Quinolones Nalidixic acid Ciprofloxacin Bactericidal Gm+ve bacteria urinary tract infection

Bacterial cell wall synthesis inhibitors

Bacterial cell wall synthesis inhibitors (bactericidal)

penicillins Bactericidal Narrow range Effected by Stomach acidity=intramuscularly Susceptible to penicillinase (b lactamase) = are enzymes produced by many bacteria (Staph.) that clave the b lactam ring

Methicillin Oxacillin Ampicillin & amoxacillin & Mezlocillin=broad spectrum Carbapenems & Monobactam =broad Cephalosporins=gm-ve Vancomycin Bacitracin =gm+ve

++ anti mycobacterial agents Mycobacterium tuberculosis Antibiotics that interfere with mycolic acid synthesis or incorporation Isoniazid (INH) Administerd simultaneously with other drug (rifampin=rifampicin)

Plasma membrane= phospholipids & protein Polymixin B interfere with phospholipids of plasma membrane Bactericidal Gm. – ve bacteria

Antimetabolite antimicrobials ++ Inhibitors of folic acid synthesis (bacteria cannot use pre-formed folic acid, they synthesize their own folic acid)

bacteriostatic

antifungal

Antifungal chemotherapeutics Fungi Fungi are Eukaryotes They may be unicellular ( yeast) or multicellular (mold). Cell wall compose of chitin Sterols in plasma membrane = ergosterol

Macrolide Polyenes Antifungals Azole Allylamine Amphotericin B –mimic lipids, most versatile & effective, topical & systemic treatments Nystatin – topical treatment Azole Synthetic azoles – broad-spectrum; ketoconazole, clotrimazole, miconazole (topical treatment of athlets foot) Allylamine Recently developed antifungal=inhibit ergosterols

Antifungal drugs Flucytosine – analog of cytosine; coetaneous mycoses or in combination with amphotericin B for systemic mycoses **interfere with RNA biosynthesis 44

Antiviral drugs

Antiviral drugs Attachment Penetration Uncoating Nucleic acid synthesis (polymerases inhibitors) Assembly release

Nucleoside & nucleotide analoges (acyclovir, ribavirin, lamavudine) Lamavudine ==nucleoside analog=cytidine Hepatitis B virus Reverse transcriptase inhibitor==HIV

Antiviral drugs Acyclovair=Zovirax=acycloguanosine=ACV Guanosine analogus **Herpes simplex virus infection (Genital, oral & eye) **varicilla zoster virus (Shingles & Chickenpox in immunocompromised patients) ###viral thymidine kinase phosphorelate the drug ==this inactivate DNA polymerase @@activity only inside virally infected cells@@

Ribavirin==guanosin analoge stop viral RNA synthesis & mRNA ===nucleoside inhibitor ***hepatitis C virus ***respiratory syncytial virus

HIV inhibitors Amantadine ==symmetrel ***uncoating of influenza virus Tamiflue…..neuraminidase HIV inhibitors Reveres transcriptase enzyme inhibitors=retrovirus= nucleoside analoge Protease inhibitors (Indinavir, saquinavir, ritonavir) Zidovidine=rv.tr. inhibitor

Antiviral Drugs Interferon=protein(cytokines) produced by virally infected cells, that inhibit spread of the virus & protect other cells ***by the activation of the cell to produce certain enzyme ==prevent viral protein synthesis ==kill virally infected cells ==the same way in which cancer cells be killed (cancers) (Viral hepatitis)

Anti protozoa chemotherapeutics Protozoa are unicellular Eukaryotic microbes Have variety of shapes, Lives free or as parasite They absorb or ingest organic compounds from their environment

Anti malaria Malaria is an entirely preventable & treatable disease treatment==rapid & complete elimination of the parasite ------chronic & anemia prevention== of the spread & emerging resistance

Drugs used for malaria prophylaxis can work in one of three ways: Kill parasites in the liver Causal prophylaxis primaquine ++++ malarone ++ Kill asexual parasites in RBCs Suppressive prophylaxis chloroquine ++++ malarone ++++ mefloquine ++++ doxycycline ++++ Mosquito Human Kill sexual parasites (gametocytes) in RBCs Gametocytocidal prophylaxis primaquine ++++ 56

Antihelminthic Drugs Praziquantel Albendazole Surgery Helminths are macroscopic multicellular eukaryotic organisms: tapeworms, roundworms, pinworms, hookworms 57 57

Clinical uses of antimicrobial drugs

Clinical uses of antimicrobial drugs Inappropriate Antimicrobial Use Prescription not taken correctly Antibiotics for viral infections Antibiotics sold without medical supervision Spread of resistant microbes in hospitals due to lack of hygiene

**-the identity of the pathogen **-potential toxicity to the patient Proper selection of antimicrobial agent is based on a number of factors **-the identity of the pathogen **-potential toxicity to the patient **-pharmacokinetics & pharmacodynamics of the agent **-site of infection **-rout of administration **-drug resistance **-possible drug interaction **-host factors **-cost

Drug selection should be based on it’s activity against infecting pathogen pathogen may be predictably susceptible to a particular drug Therefore lab. guidance is essential for safe prescribing Culture & sensitivity test

Susceptibility Tests Agar diffusion = disk-diffusion test (cont’d) Agar diffusion = disk-diffusion test  Kirby-Bauer Disk Diffusion Test Sensitive Intermediate resistant 62

Minimal Inhibitory Concentration (MIC)=the lowest concentration of drug capable of preventing bacterial growth vs. Minimal Bactericidal Concentration (MBC)=the lowest concentration of chemotherapeutic agent that kills bacteria 32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml Sub-culture to agar medium MIC = 8 ug/ml MBC = 16 ug/ml

Minimum inhibitory concentration (MIC) is determined when **a patient does not respond to treatment **thought to be adequate, **relapses while being treated **when there is immunosuppression.

**-circulating & tissue phagocyte activity Host factors play an important part in proper selection of antimicrobial drug **-age **-circulating & tissue phagocyte activity e.g. hematological malignancy=acute leukemia Bactericidal= amino glycosides broad spectrum penicillins cephalosporin quinolones

Pharmacological factors By achieving satisfactory drug concentration at the site of infection Standard pharmacokinetics =absorption distribution metabolism excretion Oral---- G.I. absorption should be satisfactory interaction with food vomiting (surgery) ***Parenteral agent will be required

Site of infection ---lipid solubility of the drug Amino glycosides are poorly lipid –soluble =penetrate CSF poorly (bacterial meningitis) Meningeal inflammation also affect drug penetration into the tissues Beta-lactam agents achieve satisfactory concentration within CSF but the inflammation subsides drug concentration

super infection Normal flora (skin & mucous membrane) Microbial overgrowth of resistant pathogen Oral & vaginal candidiasis Broad spactrum-(ampicillin or tetracycline) Pseudo-membranous colitis Toxin-producing strain of clostridium Following the use of clindamycin Managed by oral vancomycin surgery

**-the identity of the pathogen **-potential toxicity to the patient Proper selection of antimicrobial agent is based on a number of factors **-the identity of the pathogen **-potential toxicity to the patient **-pharmacokinetics & pharmacodynamics of the agent **-site of infection **-rout of administration **-drug resistance **-possible drug interaction **-host factors **-cost

Drug resistance Intrinsic= inherent properties of bac. are responsible for preventing antibiotic action ==always chromosomally mediated 0r Acquired= occurs when bac. which were previously susceptible then become resistance == occur by mutation in the chromosome or by acquisition of genes coding for resistance from external source (plasmid)

Plasmid mediated resistance has been recognized among Gm. -ve bact Plasmid mediated resistance has been recognized among Gm.-ve bact.== can code for multiple resistant ##cephalosporins, chloromphinicol, amino glycosides ==enzymatic inactivation hospitals & intensive care units

Multi-drug resistance Methicillin resistant Staph.aureus (MRSA) =resist to many antibiotics Hospitals, intensive care units, burn ,cardiothoracic units Glycopeptides , vancomycin

Mechanisms of Antibiotic Resistance Enzymatic destruction of drug (B lactamase) Drug inactivation – penicillinases Prevention of penetration of drug to its target site within the bacteria (tetracycline resistance) Decreased permeability to drug or increased elimination of drug from cell 74 74 74

Mechanisms of Antibiotic Resistance Alteration of drug's target site(a.a changes in the ribosome) Change in metabolic patterns Rapid ejection of the drug Change in drug receptors Efflux pump= antibiotic is rapidly extracted from the cell by an energy-dependent mechanism ( tetracyclines & macrolides)

++ Inpaired cell wall or cell envelope penetration ++ Enzymatic inactivation ++ Altered binding sites ++ Efflux pump= antibiotic is rapidly extracted from the cell by an energy-dependent mechanism( tetracyclines & macrolides)

What Factors Promote Antimicrobial Resistance? Exposure to sub-optimal levels of antimicrobial Exposure to microbes carrying resistance genes 79 79 79

To lower Antimicrobial Resistance Development Use more narrow spectrum antibiotics Use antimicrobial cocktails Effects of combinations of drugs Synergism Penicillin and streptomycin, Sulfa and trimethoprim Antagonism Penicillin and tetracycline Addition 80 80 80

Combination of Drugs For antibiotics “A” and “B” used in combination: Actual killing rate = A + B  Additive Actual killing rate > A + B  Synergistic Actual killing rate < A + B  Antagonistic Typically bacteriostatic agents are antagonistic to bactericidal agents. Bacteriocidal agents can be synergistic (think of the latter as one antibiotic weakens more bacteria than it kills, making the not-killed bacteria more susceptible to additional insult by the second antibiotic). Additive means that the two (or more) antibiotics neither hinder nor help each other’s ability to kill. Also relevant to rates of mutation to resistance. Combination of Drugs 81

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