PHL424 ANTIBACTERIALS Dr. Sarah I bukhari Pharmaceutics microbiology Department College of Pharmacy...

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  • PHL424ANTIBACTERIALSDr. Sarah I bukhariPharmaceutics microbiology DepartmentCollege of PharmacyKing Saud UniversityPHL424 DNA inhibitors**

    PHL424 DNA inhibitors

  • ANTIBIOTIC CLASSESInhibit cell wall synthesis-lactamsGlycopeptidesBacitracinFosfomycincycloseineInhibit protein biosynthesisAminoglycosidesMacrolides & LincosamidesOxazolidinones & StreptograminsTetracyclines & ChloramphenicolAct on cell membranePolymyxinsLipopeptides (Daptomycin)Inhibit DNA synthesisSulfonamidesTrimethoprim QuinolonesMetronidazole and NitrofurantoinRifamycins*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • *PHL424*

    PHL424

  • A-QuinolonesMECHANISM OF ACTIONQuinolone Target: 2 essential bacterial enzymesDNA gyrase (The main target in Gram negative bacteria)Topoisomerases IV (The main target in Gram +ve bacteria)DNA gyrase is responsible for supercoiling of DNAComposed of 2 GyrA & GyrB subunits, encoded by gyrA & gyrB.Quinolones interfere with DNA gyrase and prevent conversion of relaxed DNA to super-coiled DNA.Topoisomerase IV decatenates or removes the interlinking of daughter chromosomes.Composed of 2 subunits, ParC & ParE encoded by parC & parEQuinolones interfere with topoisomerse II & prevent decatenation of DNA*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • *PHL424*

    PHL424

  • MECHANISM OF RESISTANCEChromosomal mediatedAlterations in the targets of quinolonesSingle step mutation in DNA gyrase & topoisomerase IVHigh level of resistance was resulted due to Mutation in QRDR of DNA gyrase and topoisomerase II Decreased accumulations of drug inside bacteriaImpermeability of the membrane and/orDecrease in level of expression of OmpF in E. coliAn over-expression of efflux systems.

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • MECHANISM OF RESISTANCEPlasmid mediated quinolone resistance (PMQR)responsible for low level of resistance.PMQR detected only in EnterobacteriacaeThree known PMQR mechanisms to date:Qnr determinants (qnrA, qnrB, qnrS, qnrD, qnrC)Protect DNA gyrase & topoisomerase IV from quinolone inhibition.(inhibit DNA binding)Aminoglycoside acetyltransferase (AAC(6)-Ib-cr).AAC(6)-Ib-cr is a variant of AAC(6)-Ib and is responsible for reduced susceptibility to ciprofloxacin or norfloxacin by N-acetylation of a piperazinylamineQepA (quinolone efflux pump)*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • Correlation between MIC and QRDR mutationsSingle mutation in gyrA results in high-level resistance to nalidixic acid & reduce susceptibility to FluoroquinolonesTo obtain high levels of resistance to fluoroquinolones, the presence of additional mutation(s) in gyrA and/or in another target such as parC is requiredMIC of nalidixic acid could be used as a generic marker of resistance for the quinolone in Gram-negative bacteriaThe most frequent mutation observed in quinolone-resistant E. coli is at codon 83 followed by 87 of gyrAIn the parC gene of E. coli the most common substitutions occur at codons 80 and 84

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • *PHL424 DNA inhibitors*Pipemidic acid

    PHL424 DNA inhibitors

  • Classification of quinolones1st generations (Narrow spectrum)Nalidixic acid, oxolinic acid and pipemidic acidNalidixic acid was introduced in 1962.Active against aerobic G -ve (Enterobacteriaceae).Pipemidic acid has extra activity against Ps. aeruginosaDisadvantagesNo activity against G +ve or anaerobic bacteria.Limited spectrum and poor tissue penetrationTheir use is restricted to treatment of UTIToxicity especially to CNS and GITRapid emergence of resistance*PHL424*

    PHL424

  • CLASSIFICATION2nd generation (Broad spectrum)Quinolones were a little-used drug class until the early 1980s when introduced 2nd generationfluorination at 6-position Fluoroquinolones (FQ)ring substituent (piperazine, methylpiperazine) at C7FQ modification of other side chains led to:Improved activity against Gram negative (Enterobacteriaceae, Peudomonas, Acinetobacter, Haemophilis, Moraxella & Neisseria)Enhanced anti-Gram-positive activity Improved potency against pneumococcus Improved PK & longer serum half-livesLack activity against anaerobic bacteria*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • CLASSIFICATION2nd generation (Broad spectrum)Nor-, Cipro-, Ofloxacin, Pefloxacin, LomefloxacinNOR is the first 2nd generationconfined for treatment of UTI and STD because of low serum levels and poor tissue penetrationCIPRO is the most common 2nd generationCIPRO is the most potent quinolones against Gram-ve.CIPRO is alternative to parenterally antibiotics for the treatment of osteomyelitis caused by susceptible organisms due to its good penetration into boneOf the 2nd generation, Ofloxacin has the greatest activity againstChlamydia trachomatistreatment of complicated UTI, pyelonephritis, STD, selected pneumonias and skin infections*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • CLASSIFICATION3rd generation (Expanded spectrum)Levo-, Gatifloxacin, Sparfloxacin, Grepafloxacin.In 1990s, 3rd generation was introduced.expanded activity against gram-positive organisms, particularly S. pneumoniaehas activity against mycoplasma, Chlamydia, legionellahas good activity against anaerobic bacteria.less active than ciprofloxacin against Pseudomonas4th generation (Extended spectrum)Trovafloxacin, Moxifloxacin, Gemifloxacin.In 2000s, 4th generation was introduced.Has potent activity against anaerobes and increased activity against pneumococci

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • PHARMACOKINETICStaken orally: well absorbed from GIT-bioavailability of 50% Some FQs are available parenterally/ophthalmicNewer FQs have longer serum half-lives than ciprofloxacin allowing for once daily dosingCIPRO: 500 750 mg q 8-12hLEVO:500-750 mg q24hMOXI: 400mg q24hachieve high intracellular concentrations (e.g. PMNs)widely distributed in body tissues (except CNS).Elimination: most are eliminated by the kidneys (unchanged & as metabolites), although some are eliminated by the liver

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • Approved clinical uses for selected fluoroquinolones.Vincent T. Andriole Clin Infect Dis. 2005;41:S113-S119

  • CLINICAL USEEmpiric therapy of CAP (community-acquired pneumonia)Oral therapy of un-/complicated UTI or RTIOral therapy of serious infections such as osteomyelitis, pneumonia or soft tissue infectionsTreatment of STD: gonorrhea, chancroid, chlamydial urethritisEmpiric therapy of travelers diarrheaTreatment of typhoidTherapy for multidrug-resistant tuberculosis*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • SIDE EFFECTSGenerally very safe antibiotics which do not cause serious or life-threatening adverse reactionsThe most frequent side-effects are:GIT(nausea, dyspepsia, vomiting) CNS reactions such as dizziness, insomnia, headacheShould not be used in children and in pregnancyDrug interactions: absorption: Al3+, Mg2+ and Ca2+ antacidsCYP450 inhibition potential drug interactions for ciprofloxacin(Ex) can increase warfarin exposure (real changes in INR are rare, but monitor)

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • B. Nitroimidazoles and nitrofuransMETRONidazole (Prodrug): 5-nitroimidazole derivative Specifically active against anaerobic organisms.Effective against protozoa: E. histolytica, Giardia lamblia.Mechanism of ActionAntimicrobial action is due to unstable metabolites produced by reduction inside anerobic bacteria after uptakeNitro gp converted to nitrite radical by low redox potential.Metabolites covalently bind to DNA, disturb its helical structure, fragmentation of microbial chromosomeFinally inhibit nucleic acid biosynthesis bacterial deathResistance to metronidazole does not occur.

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • MECHANISM OF ACTION*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • PHARMACOKINETICSWell absorbed orallyTmaxis 1- 2 h, and Cmaxis 25 mg/mL. Oral bioavailability is not affected by food, but peak serum levels will be delayed to 2 h. Metronidazole appears in CSF, saliva, and breast milk in concentrations similar to those found in plasma. Less than 20% is protein bound.Elimination is via urine (60% to 80%) & feces (6%-5%)half-life is 8 h and the hydroxy-metabolite half-life is 15 hDecreased renal function does not alter single-dose pharmacokinetics of metronidazoleHepatic Function Impairment: PO/IV Use lower doses cautiously and close monitoring of plasma metronidazole levels and toxicity is recommended*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • DOSAGE AND ADMINISTRATIONAnaerobic Bacterial InfectionsGive IV initially when treating most serious anaerobic infections.IV infusion: 15 mg/kg over 1 h (1 g for 70 kg adult); then a maintenance dose of 7.5 mg/kg over 1 h every 6 h (500 mg for 70 kg adult). Do not exceed 4 g in 24 h.For prophylaxis, loading dose is to be completed 1 h before surgery, followed by maintenance dose 6 & 12 h later.Flagyl 750 ER, 500, 375 , 250 mg tablets; Injection, solution 5 mg/mL7.5 mg/kg (500 mg for 70 kg adult) every 6 h (max, 4 g/24 h) for 7-10 days.Children dose: PO 5 mg/kg/dose 3 times daily for 7 days

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • SIDE EFFECTSNausea, Vomiting, epigastric distress, abdominal crampsoral thrushMetallic taste*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • B. Nitroimidazoles and nitrofuransNITROFURANTOIN is used in the treatment of UTI.Antibacterial levels are not reached in the blood and the drug is concentrated in the urine. NITROFURAZONE is used mainly as a topical agent in the treatment of burns and wounds and also in certain types of ear infections.

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • RIFAMYCINSNatural and semi-derived from filamentous soil bacteriaComplex macrocyclic antibioticsMembers of the classRifabutin RifapentineRifampin = rifampicin (The most common used)

    *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • C. RIFAMPIN (RIFAMYCIN)Bactericidal broad spectrum antibiotic.Bactericidal (aerobic & anaerobic Gram+ve cocci)Bacteriostatic (enterococci)Very effective in treatment of tuberculosis.Penetrates well into CSF Treatment of tuberculous meningitisActive against N. gonnorhea, N. meningitis, H. Influenzae.It is frequently used in prophylaxis of meningitisActive against Enterobacteriaceae.Inhibits Brucella sp. and Coxeilla burnetti intracellularly. *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • MECHANISM OF ACTIONInhibits DNA-dependant RNA polymerase.Forms a stable complex with DNA dependant RNA polymerase.Binds to -subunit of the core enzyme of RNA polymerase & blocks the action of the enzyme at initiation stage of transcription.Prevents the initiation stage of transcription. Doesnt inhibit transcription once it has been initiated.Does not affect mammalian RNA synthesis.*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • MECHANISM OF RESISTANCEResistance to rifampicin develops quickly.Rifampin-Resistant isolates posses an altered DNA-dependant RNA polymerase, which arises easily by single step mutations during therapy. missense mutations in therpoBgene*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • PHARMACOKINETICRapid & complete absorption after oral administration. Absorption is improved when taken on an empty stomach Wide distributed into most body tissues & fluids including CSFIt concentrates intracellularly up to five times that of extracellular concentrations, primarily in PMN. The protein binding of rifampin is approximately 80 %.Rifampinundergoes extensive hepatic metabolism to less active metabolites, with a half-life of 3 hours. Renal elimination of unchanged drug is minimal (
  • DOSING AND ADMINISTRATIONFor treatment of TB is 10mg/kg(maximum 600 mg daily) given daily or either twice or three times weekly by DOT. IV doses are similar to those administered orally. Oral doses should be administered 1 h before or 2h after meals.The therapeutic range for rifampin againstM. tuberculosisis a two-hour post-dose concentration of 8 to 24microgram/mLNo dose adjustments are needed for renal dysfunction or dialysis*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • ADVERSE EFFECTSGastrointestinal effects (nausea, vomiting, diarrhea),CNS effects (headache, fever)Dermatologic effects (rash, itching, flushing)Hematologic effects (thrombocytopenia, neutropenia, and acute hemolytic anemia)Hepatitis is infrequently associated withrifampinPatients should be advised that rifampintypically causes an orange or red-orange discoloration of body fluids (including urine, sweat, saliva, and tears)*PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

  • DRUG INTERACTIONSDecreases half life of many drugs by inducing CYPs cytochrome P450 isoenzyme CYP3A4 Potentially decreasing serum concentrations of co-administered drugs. oralcontraceptives,corticosteroids,cyclosporine,warfarin,phenytoin,theophylline, azole antifungals, oral hypoglycemics,verapamil, beta-blockers & HIV protease inhibitors as well as the nonnucleoside reverse-transcriptase inhibitors is not recommended. *PHL424 DNA inhibitors*

    PHL424 DNA inhibitors

    **Qnr determinants (qnrA, qnrB, qnrS, qnrD, qnrC)= q**Approved clinical uses for selected fluoroquinolones.international normalized ratio(INR).*