PHARMACOTHERAPY OF INFECTIONS

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  • Antimicrobial drugsChemotherapy: The use of drugs to treat a disease.Antimicrobial drugs: Interfere with the growth of microbes within a host.Antibiotic of biological origin: Produced by a microbe, inhibits other microbes.Today distinction blurred many newer "antibiotics" are biological products that areChemically modified or Semi synthesised.

  • Different types of antimicrobial drugs:

    Antibacterial drugsAntiviral drugsAntifungal drugsAntiprotozoan drugsAntihelminthic drugs

  • Features of antimicrobial drugs Most modern antibiotics come from species of microorganisms that live in the soil.

    To commercially produce antibiotic:Select strain and grow in brothWhen maximum antibiotic concentration reached, extract from mediumPurifyChemical alter to make it more stable

  • Features of Antimicrobial Drugs: Spectrum of ActivityAntimicrobial medications vary with respect to the range of microorganisms they kill or inhibit.

    Some kill only limited range : Narrow-spectrum antimicrobial

    While others kill wide range of microorganisms: Broad-spectrum antimicrobial.

  • Mechanisms of action of Antibacterial DrugsInhibit cell wall synthesisInhibit protein synthesisInhibit nucleic acid synthesisInjury to plasma membraneInhibit synthesis of essential metabolites

  • Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: PenicillinNatural and semisynthetic penicilins contain -lactam ring.

    Natural penicillins produced by Penicillium are effective against Gram + cocci and spirochetes.

    Semisynthetic penicillins: made in laboratory by adding different side chains onto -lactam ring penicillinase resistant and broader spectrum of activity .

  • Penicillinase (-lactamase): Bacterial enzyme that destroys natural penicillins.

    Penicillinase resistant penicillins: Methicilin replaced by Oxacilin and Nafcilin due to MRSA

    Extended-spectrum penicilins: Ampicilin, Amoxicilin; new: Carboxypenicilins and Ureidopenicillins (also good against P. aeruginosa)

  • More stable to bacterial -lactamases than penicilinsBroader spectrum used against penicillin-resistant strains

  • First-generation: Narrow spectrum, gram-positive. Example Cefadroxyl, Cephalexin.Second-generation: Extended spectrum includes gram-negative.ExampleCefuroxime, Cefaclor.Third-generation: Includes pseudomonads; mostly injected, some oral. ExampleCefexime, Ceftriaxone.

  • Fourth-generation: Most extended spectrum ExampleCefepime, Cefpirome.

    Fifth-generation: Specifically target against resistant strains of bacteria. Example Ceftobiprole.

  • Glycopeptide from StreptomycesInhibition of cell wall synthesisUsed to kill MRSAEmerging Vancomycin resistance: VRE and VRSA

  • Polyenes, such as nystatin and amphotericin B, for systemic fungal infections. Inhibition of ergosterol synthesis fungicidal NephrotoxicGriseofulvin from Penicillium. Systemic/oral. Binds to tubulin For Tineae

  • They are smallest infective agents consisting essentially of nucleic acid (either DNA or RNA) enclosed in a protein coat or capsid.

  • Pox viruses (Smallpox) Herpes viruses (chicken pox, herpes etc) Adeno viruses (sore throat, conjunctivitis) Hepadna viruses (serum hepatitus) Papilloma viruses (Warts)

  • RNA VIRUSES Orthomyxo Viruses (Influenza) Paramyxo Viruses (Measules, Mumps) Rubella Viruses (German Measules) Rhabdo Viruses (Rabies) Picorna Viruses (Colds, Meningitis, Poliomyelitis) Retro Viruses (AIDS,T-Cell leukemia) Arena Viruses (Meningitis, Lassa fever) Arbo Viruses (Arthopod-borne encephalitis, Yellow Fever)

  • Replication of a DNA virus in a host cell

  • Mechanism Action of Antiviral drugs Inhibition of penetration of host cell. Amnatadin and rimnatadin inhibit uncoating and are effective against influenza A viruses. Gammaglobulins neutralize viruses.

  • Inhibition of Nucleic acid SynthesisInhibition of Nucleic acid Synthesis-IAcyclovir- Selectively inhibit viral DNA polymerases.Example: Herpes viruses.

    Gancyclovir-Supressing the replication of DNA.

  • Inhibition of Nucleic acid Synthesis-II

    Vidarabine- Selectively inhibit viral DNA polymerases.Example : Varicella zoaster.

    Rebavirine- Interefere in viral DNA synthesis.

  • Inhibition of Nucleic acid Synthesis-III

    Foscarnet - inhibits viral DNA polymerase by attaching to the pyrophosphate binding site.

    Zidovidine Inhibits reverse transcriptase and effective in HIV.

  • Antiviral Mechanism of Action

  • Nucleoside analogs inhibit DNA synthesis

    Acyclovir and newer derivatives: Selective inhibition of herpes virus replication. Acyclovir conversion to nucleotide analog only in virus infected cells very little harm to uninfected cells!

  • Examples of Antiprotozoan:Chloroquine: MalariaQuinacrine: GiardiaMetronidazole (Flagyl): Vaginitis, anaerobic bacteria Examples of Antihelminthic: Niclosamide and praziquantel: Tapeworm. Mebendazole: broadspectrum antihelmintic.Ivermectin: nematodes, mites, lice .

  • Agar Disk Diffusion Method determines susceptibility of an organism to a series of antibiotics: Kirby-Bauer test

  • Antimicrobial resistance is the ability of microbes, such as bacteria, viruses, parasites, or fungi, to grow in the presence of a chemical (drug) that would normally kill it or limit its growth. Evolution of drug resistance:Vertical evolution due to spontaneous mutationHorizontal evolution due to gene transfer

  • A variety of mutations can lead to antibiotic resistanceMechanisms of antibiotic resistance :Reduce entry of antibiotics into pathogenEnhanced export of antibiotics by eflux pumpRelease of microbial enymes that destroy the antibioticsAlteration of microbial proteins that transform pro-drug to the effective moietiesAlteration of target proteinsDeviation of alternate pathway to those inhibited by antibiotics Resistance genes are often on plasmids or transposons that can be transferred between bacteria.

  • Resistance to Antibiotics

  • Misuse of AntibioticsMisuse of antibiotics selects for resistance mutants. Misuse includesTreatment of nonresponsive infectionsTherapy of fever of unknown originImproper dosageInappropriate reliance on chemotherapy aloneLack of adequate bacterioligical information

  • PROPHYLAXISProphylaxisPre-empetiveEmpericalDefinitiveSuppresiveNo infectionInfectionSymptomsPathogen isolationResolution

  • Prophlaxis : It involves treating of patients who are not yet infected or not developed the diseaseGoal-To prevent development of potentially dangerous diseaseSingle effective non toxic drug can prevent infectionInfection in which prophylaxis is given includes pnemocystis jiroveci,toxoplasma gonidi,candia species,aspergillus sp,cytomegalovirus etcChemoprophylaxis are also given to prevent infection

  • Pre-emptive therapy

    It is an early targeted therapy in high risk patients who already have a laboratory or other test indicating an asymptomatic patient is infectivePrinciple-Delivery of therapy prior to symptomsShort and defined duration

  • Emperical therapyIt is for symptomatic patient.The 1st consideration in selecting an antimicrobial drug is to determine if the drug is indicatedFor some patiens the cost of waiting a few days is low , these patients can wait for microbioligical evidence of infection without emperical treatmentIn patients were risk of waiting is high emperical therapy is relied on the clinical presentation which may suggest specific microorganism

  • Definitive therapyOnce pathogen has been isolated and susceptibility results are available,therapy should be streamlined to a narrow targeted antibioticsMonotherapy is prefered to decrease the risk of antimicrobial toxicity and selection of antimicrobial resistant pathogenProper antimicrobial dose and dose shedule are crucial to maximize efficacy and minimize toxicity

  • COMBINATION THERAPY When the inhibitory or killing effect of two or more antimicrobial used together are significantly greater than expected from their effects when used individually synergism resultsMECHANISM : Blockade of sequential steps in a metabolic sequenceInhibition of enzymatic inactivationEnhancement of antimicrobial agent uptakeEg:penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter.

  • Other combinations of drugs can be antagonistic.

    MECHANISM : 1)Inhibion of cidal activity by static agent 2)Induction of enzymatic inactivation For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth.

  • Combination therapy is used for : Preventing resistance to monotherapyAccelerating the rapidity of microbial killingEnhancing therapeutic efficacy by use of synergestic interactions or enhancing kill by a drug based on mutation generated by resist to another drugParadoxically reducing toxicity

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