《药理学》课程PPT教学课件（Antimicrobial Drugs）43a Quinolones and Urinary Tract Antiseptics

Quinolones 喹诺酮类 andUrinary Tract Antiseptics

Quinolones 喹诺酮类 and Urinary Tract Antiseptics

OverviewA new synthetic antibacterial drug was patented in 1962:nalidixicacid,ineffective against systemic infections,but useful againsturinary infectionsItsoverusehasnowledOHtomanyresistances,butithasbeenthebasisformoredrugdevelopmentHnalidixic acid2

2 Overview A new synthetic antibacterial drug was patented in 1962: nalidixic acid, ineffective against systemic infections, but useful against urinary infections Its overuse has now led to many resistances, but it has been the basis for more drug development

氟喹诺酮类1. FluoroguinolonesantibacterialOHactivitymembrane-fixationsitespenetrationnalidixicH3C&gyraseacidRSinhibitionFOHROHglobalRspectrumantibacterialactivityanaerobesRpyrridone β carboxylic acidFluorination enhanced cell penetration and activity3

3 1. Fluoroquinolones 氟喹诺酮类 Fluorination enhanced cell penetration and activity

Mechanism of ActionchromosomesupercoiledRNA coreRNAcoreDNAgyrasechromosomefoldedearoundRNAcore个quinolonesQuinolonesinhibitthereplicationofbacterial DNAbyinterfering withthe indispensableactionoftheDNAgyrase(topoisomeraseIl)

4 Mechanism of Action Quinolones inhibit the replication of bacterial DNA by interfering with the indispensable action of the DNA gyrase (topoisomerase II)

Entry into BacteriumFluoroguinolones are water-soluble drugs. They enter thebacteriumthroughporins,orwater-filled channelsintheoutermembraneofGram-negativebacteriaThis acounts fortheir higherefficiencyagainst Gram-negativemicro-organisms5

5 Entry into Bacterium Fluoroquinolones are water-soluble drugs. They enter the bacterium through porins, or water-filled channels in the outer membrane of Gram-negative bacteria This acounts for their higher efficiency against Gram￾negative micro￾organisms

Antimicrobial SpectrumAll quinolonesare bacteri-cidalciprofloxacinagainstgonorrhoeaeIn general theygram-Neisseria gonorrhoeaecocciare activeMoxarellaagainst Gram(-)gram-enteficorganismsEscherichiaotherrodsEnterobactelgram-gastrointestinalbacilliProteusSalmonellainfectionsShigellaHaemophilusKlebsiellaLegionellaPseudomonasciprofloxacinand norfloxacinagainsturinarytractinfectionsciprofloxacinagainstresistantrespiratoryinfections(butweakagainststreptococcuspneumoniae)6

6 Antimicrobial Spectrum All quinolones are bacteri-cidal. In general they are active against Gram(-) organisms

PharmacokineticsBioavailability of norfloxacin is only 35-70%,but 70-90% oftheotherfluoroguinolonesareabsorbed.Bioavailabilityisthe greatest for ofloxacin. Ciprofloxacin and ofloxacin areadministered IVaswell asorallyAbsorptionisreducedbyantiacidscontainingAl orMg,ordietaryAIZntMgFesupplements of Fe orZnDistribution is largeCiprofloxacineaccumulatesintheOHkidneys,prostate and lungsRThedrugsandtheirmetabolitesare found in the urine7

7 Pharmacokinetics Bioavailability of norfloxacin is only 35-70%, but 70-90% of the other fluoroquinolones are absorbed. Bioavailability is the greatest for ofloxacin. Ciprofloxacin and ofloxacin are administered IV as well as orally Absorption is reduced by antiacids containing Al or Mg, or dietary supplements of Fe or Zn Distribution is large. Ciprofloxacine accumulates in the kidneys, prostate and lungs The drugs and their metabolites are found in the urine

Clinical UsesFallopiantubeGonorrhea 淋病 is causedby Neisseria gonorrheae.It ismainly transmittedthroughsexual contact or during childdelivery. If untreated, suchOvarychildren may develop aUterusseriousinflammation oftheeyes. Symptoms are soresaround genital parts, and adischarge. In women, apossiblelong-termconseguence is closureof theEscherichia coli, Proteus mirabilis andFallopian tubes.In very rareKlebsiella pneumoniae are the mostcases,it can turn intocommon causes of infections of thesepticemia (infectiousurinarytract (Nitrofurantoin,ororganisms in theblood)sulfomethoxazole + trimethoprim maybe used first)8

8 Clinical Uses Gonorrhea 淋病 is caused by Neisseria gonorrheae. It is mainly transmitted through sexual contact or during child delivery. If untreated, such children may develop a serious inflammation of the eyes. Symptoms are sores around genital parts, and a discharge. In women, a possible long-term consequence is closure of the Fallopian tubes. In very rare cases, it can turn into septicemia (infectious organisms in the blood) Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae are the most common causes of infections of the urinary tract (Nitrofurantoin, or sulfomethoxazole + trimethoprim may be used first)

Main DrugsCiprofloxacin环丙沙星is themost potent drug.ItCOOHis active against gram(+) in addition to gram(-) e.g.itisapprovedagainstBacillusanthracis炭疽热Itisafirst-choice against systemic infections caused byenterobacteriaesuchasSalmonellatyphi*伤寒沙门菌,and a second-line drug against Pseudomonas单胞菌andtuberculosis（TB）肺结核ciprofloxacinNorfloxacin诺氟沙星hasthesamespectrum,butOHis not usedfor systemicinfections because itcannotreach sufficient plasmalevels.It treats infections ofHIthe urinarytractand prostatitis前列腺炎OCOOHnorfloxacinOfloxacin氧氟沙星isprimarilyusedinthe treatment of prostatitis duetoEscherichia coli大肠埃希菌，andsexuallyHtransmitted deseases with the exception ofsyphilis 梅毒9ofloxacin*Chloramphenicol is still a first-choice in parts of the world

9 Main Drugs Norfloxacin 诺氟沙星 has the same spectrum, but is not used for systemic infections because it cannot reach sufficient plasma levels. It treats infections of the urinary tract and prostatitis 前列腺炎 Ciprofloxacin 环丙沙星 is the most potent drug. It is active against gram(+) in addition to gram(-) e.g. it is approved against Bacillus anthracis 炭疽热 It is a first-choice against systemic infections caused by enterobacteriae such as Salmonella typhi* 伤寒沙 门菌, and a second-line drug against Pseudomonas 单胞菌 and tuberculosis (TB) 肺结核. Ofloxacin 氧氟沙星 is primarily used in the treatment of prostatitis due to Escherichia coli 大肠埃希菌, and sexually￾transmitted deseases with the exception of syphilis 梅毒 *Chloramphenicol is still a first-choice in parts of the world

ResistanceResistance has developedamongStaphylococcus aureus(G+), Pseudomonas (G-) and Enterococci (G+)Mechanismsinclude:.Modification ofthe DNAgyrase.Reduced entrance of the quinolones into the bacterial cellthrough a reduction in number of the porin proteins that letthe drug throughthe outermembrane.An energy-dependent efflux of the drug10

10 Resistance Mechanisms include: • Modification of the DNA gyrase • Reduced entrance of the quinolones into the bacterial cell through a reduction in number of the porin proteins that let the drug through the outer membrane • An energy-dependent efflux of the drug Resistance has developed among Staphylococcus aureus (G+), Pseudomonas (G-) and Enterococci (G+)