Quinoloes in the treatment of respiratory tract


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Quinoloes in the treatment of respiratory tract

  4. 4. The first consideration in selecting anantimicrobial agent is whether it isindicated.6/26/2013 4amrhamdy MD FCCP
  5. 5. Antibiotics are antibacterial substancesproduced by various species ofmicroorganisms (bacterial, fungi, andactinomycetes) that suppress thegrowth of the microorganisms.6/26/2013 5amrhamdy MD FCCP
  6. 6. Common usage often exclude the termantibiotics to include syntheticantimicrobial agents, such assulphonamides and quinolones.6/26/2013 6amrhamdy MD FCCP
  7. 7. Antibiotics have three general uses:• Empirical therapy• Definitive therapy• Prophylactic or preventive therapy.6/26/2013 7amrhamdy MD FCCP
  8. 8. When used as empirical or initialtherapy, the antibiotic should cover allthe likely pathogens because theinfecting organism(s) has not yet beendefined.6/26/2013 8amrhamdy MD FCCP
  9. 9. Optimal and judicious selection ofantimicrobial agents for the therapy ofinfectious diseases requires clinicaljudgement and detailed knowledge ofpharmacological and microbiologicalfactors.6/26/2013 9amrhamdy MD FCCP
  10. 10. The quinolones are a family ofsynthetic broad –spectrum antibioticdrugs.6/26/2013 10amrhamdy MD FCCP
  11. 11. The first generation of the quinolonesbegan with the introduction ofnalidixic acid in 1962 for thetreatment of urinary tract infectionsin humans.6/26/2013 11amrhamdy MD FCCP
  12. 12. • There are simple quinolones andfluoroquinolones.• FQs are quinolone antimicrobialshaving one or more fluorinesubstituations.6/26/2013 12amrhamdy MD FCCP
  13. 13. The ‘first generation’ FQs wasintroduced in 1980’s.6/26/2013 13amrhamdy MD FCCP
  14. 14. In the 1990s, compounds with additionalfluoro and other substitutions have beendeveloped (2nd generation FQs)- furtherextending antimicrobial activity to gram+ve cocci and anaerobes, and/ conferringmetabolic stability (long t1/2), and/ orconferring metabolic stability (longer t1/2).6/26/2013 14amrhamdy MD FCCP
  15. 15. 6/26/2013 15amrhamdy MD FCCP
  16. 16. Therapeutic uses of simple quinolones:• Uncomplicated urinary tractinfection.• Urinary antiseptic.• Diarrhea casued by Proteus, E. coli.Salmonella, Shigella (ampicillinresistant).6/26/2013 16amrhamdy MD FCCP
  17. 17. Fluoroquinolones are the only class ofantimicrobial agents in clinical usethat are direct inhibitors of bacterialDNA synthesis.6/26/2013 17amrhamdy MD FCCP
  18. 18. They inhibit two bacterial enzymes,DNA gyrase and topoisomerase IV.6/26/2013 18amrhamdy MD FCCP
  19. 19. Fluoroquinolones are bactericidalagents.6/26/2013 19amrhamdy MD FCCP
  20. 20. FQ enter the host cells and aretherefore active against intracellularpathogens, e.g. Mycoplasma spp,and Chlamydia spp.6/26/2013 20amrhamdy MD FCCP
  21. 21. Spectrum of ActivityThe greatest activity of FQs is againstaerobic gm-ve bacilli, particularlyEnterobacteriaceae, and againstHaemophilus spp and gm-ve coccie.g. Neisseria spp and Moraxellacatarrhalis, and also against non-enteric gm-ve bacilli such as Psaeruginosa and againststaphylococci.6/26/2013 21amrhamdy MD FCCP
  22. 22. 6/26/2013 22amrhamdy MD FCCP
  23. 23. 6/26/2013 23amrhamdy MD FCCP
  24. 24. 6/26/2013 24amrhamdy MD FCCP
  25. 25. Use in Pregnancy• Not used during pregnancy.• Not used in lactating mothers as it issecreted in breast milk.6/26/2013 25amrhamdy MD FCCP
  26. 26. Use in ChildrenNot recommended for routine use inchildren less than 18 years of age(arthropathy with erosions of thecartilage in weight-bearing joints).6/26/2013 26amrhamdy MD FCCP
  27. 27. Use in Children cont’d• Used in cystic fibrosis?• Complicated urinary tract infectionsand pyelonephritis?6/26/2013 27amrhamdy MD FCCP
  28. 28. AbsorptionThe quinolones are well absorbedfrom the upper gastrointestinal tract.6/26/2013 28amrhamdy MD FCCP
  29. 29. Concentration in prostate tissue, stool,bile, lung, and neutrophlis as well asmacrophages usually exceed serumconcentrations.6/26/2013 29amrhamdy MD FCCP
  30. 30. Resistance• Resistance to FQs has been slow todevelop.• Increasing resistance has beenreported amongSalmonella, Pseudomonas, Staphylococci, Gonococci and Pneumococci.6/26/2013 30amrhamdy MD FCCP
  31. 31. Resistance cont’d• The likelihood of developingquinolone resistance is thought to berelated to the intensity and durationof therapy.• Resistance may occur via mutationsin chromosomal genes via mutationsin plasmids6/26/2013 31amrhamdy MD FCCP
  32. 32. Resistance cont’d• The use of the most potent FQ is alogical choice if resistance has to beavoided/ delayed.• Previous exposure to an FQ in therecent past precludes the use of amember of this class for theempirical treatment of CAP.6/26/2013 amrhamdy MD FCCP 32
  33. 33. Among “atypicals’, antibiotic resistanceis rare and very seldom responsiblefor clinical failure.6/26/2013 amrhamdy MD FCCP 33
  34. 34. Side Effects6/26/2013 34amrhamdy MD FCCP
  35. 35. Gastrointestinal• Occurs in 3-17% of patients.• Anorexia, nausea, vomiting, anddiarrhea.• Abdominal discomfort.6/26/2013 35amrhamdy MD FCCP
  36. 36. Nervous System• In 0.9 -11%.• Mild headache and dizziness.• Insomnia.• Alteration of mood.• Hallucinations, delirium, seizures.6/26/2013 36amrhamdy MD FCCP
  37. 37. Rash and other AllergicManifestations• In 0.4-2.2 %.• Photo toxicity.6/26/2013 37amrhamdy MD FCCP
  38. 38. Arthropathy• Arhtropathy with cartilage erosionsand non inflammatory effusionsoccurs in the weight-bearing joints(in animals).• Tendinopathy and tendon ruptureshave been reported, mainly theAchilles tendon, also rotator cuff,hand, biceps, and thumb.6/26/2013 38amrhamdy MD FCCP
  39. 39. Arrhythmia and QT IntervalProlongationMoxifloxacin, levofloxacin andgemifloxacin should be avoided inpatients with known QT intervalprolongation and withhypokalemia, hypomagnesemia anduse of anti arrhythmic drugs.6/26/2013 39amrhamdy MD FCCP
  40. 40. Contraindications6/26/2013 amrhamdy MD FCCP 40
  41. 41. • Known allergy to the drug.• Epilepsy.• QT prolongation.• Pre-existing CNS lesions orinflammation or stroke.• With benzodiazepines6/26/2013 amrhamdy MD FCCP 41
  42. 42. In the USA, a “Black Box” warning ofincreased risk of developingtendonitis and tendon rupture inpatients of all ages. This risk isfurther increased in individuals over60 yrs, taking CS drugs, and havereceived kidney, heart or lungtransplantations.6/26/2013 amrhamdy MD FCCP 42
  43. 43. May exacerbate weakness in patientswith myasthenia gravis due to theirneuromuscular blocking activity.6/26/2013 amrhamdy MD FCCP 43
  44. 44. Combination Therapy6/26/2013 44amrhamdy MD FCCP
  45. 45. 1. For empirical therapy of an infection inwhich the cause is unknown.2. For treatment of polymicrobialinfections.3. To enhance antimicrobial activity( i.e.synergism) for a specific infection.4. To prevent the emergence of resistance.6/26/2013 45amrhamdy MD FCCP
  46. 46. Uses of FQs• Upper respiratory tract infections.• Lower respiratory tract infections.• MD resistant TB.6/26/2013 amrhamdy MD FCCP 46
  47. 47. Upper Respiratory Tract Infections6/26/2013 47amrhamdy MD FCCP
  48. 48. Guidelines from the IDSA ( InfectionDisease Society of America)recommend the following options forempiric-second line treatment forABRS:6/26/2013 48amrhamdy MD FCCP
  49. 49. • Amoxicillin-clavulanate 2000mg/125mg b.i.d.• Levofloxacin 500mg/ day.• Moxifloxacin 400mg/ day.6/26/2013 49amrhamdy MD FCCP
  50. 50. If improvement is seen within 3-5 daysof initiation of therapy, a total courseduration of 7-10 days isrecommended.6/26/2013 50amrhamdy MD FCCP
  51. 51. Lower Respiratory TractInfections6/26/2013 51amrhamdy MD FCCP
  52. 52. Community-aquired LRTI is a verycommon cause of acute illness andprobably the most common reasonfor lost working time in adults.6/26/2013 amrhamdy MD FCCP 52
  53. 53. The spectrum of disease ranges from amild mucosal colonization orinfection, an acute bronchitis orAE/COPD to an overwhelmingparenchyma infection with thepatient presenting with a severe CAP.6/26/2013 amrhamdy MD FCCP 53
  54. 54. It is an acute illness (present for 21days or less), usually with cough asthe main symptom, with at least oneother LRT symptom (sputum,dyspnea, wheeze or chestdiscomfort/pain) and no alternativeexplanation (e.g. sinusitis or asthma).6/26/2013 54amrhamdy MD FCCP
  55. 55. Definitive CAP• Is an acute illness with cough and atleast one of new focal chestsigns, fever more than 4 days ordyspnea/ tachypnea, and without anobvious cause.• Supported by chest radiographfindings of lung shadowing that islikely to be new.6/26/2013 55amrhamdy MD FCCP
  56. 56. • CAP is a common and potentiallyserious illness.• It is associated with considerablemorbidity and mortality, particularlyin elderly patients and those withsignificant co-morbidities.6/26/2013 amrhamdy MD FCCP 56
  57. 57. • Pneumonia, which is most often abacterial disease, should, in general,be treated with antibiotics.• A delay of more than 8 hours intreatment is associated withincreased mortality.6/26/2013 amrhamdy MD FCCP 57
  58. 58. Older quinolones, such as ciprofloxacinand ofloxacin have rather poor anti-pneumococcal efficacy and are notrecommended for the empiricaltreatment of CAP.6/26/2013 amrhamdy MD FCCP 58
  59. 59. Advantages of Respiratory FQ• They exhibit broad spectrum coverageincluding all common LRTI pathogens.• They have a high bioavailability.• They have good penetration resulting inhigh intra-celullar concentrations.• A long half-life permitting once or twicedaily dosing.• Are rapidly bactericidal.6/26/2013 amrhamdy MD FCCP 59
  60. 60. Respiratory quinolones are more likelyto result in treatment success thanthe combination of a beta-lactamplus a microlide for treatment of CAP.6/26/2013 amrhamdy MD FCCP 60
  61. 61. AE/COPDAn event in the natural course of thedisease characterized by a worseningof the patient’s baseline dyspnea,cough and/or sputum beyond day-to-day variability sufficient towarrant a change in management(chest radiograph shadowingconsistent with infection confirmsCAP)6/26/2013 61amrhamdy MD FCCP
  62. 62. The newer FQs have excellent intrinsicactivity against Str. Pneumonia, H.influenzae, Moraxella catarrhalisand the atypical respiratorypathogens.6/26/2013 amrhamdy MD FCCP 62
  63. 63. • FQs may be used as mono-therapy totreat high risk patients withAE/COPD, for patients with CAPrequiring hospitalization, but notadmission to ICU.• The newer FQs often achieve clinicalcure rates in more than 90 % of thesepatients.6/26/2013 amrhamdy MD FCCP 63
  64. 64. Key factors to consider when selectingAntibacterial Therapy for LRTIs6/26/2013 64amrhamdy MD FCCP
  65. 65. 6/26/2013 65amrhamdy MD FCCP
  66. 66. 6/26/2013 66amrhamdy MD FCCP
  67. 67. 6/26/2013 67amrhamdy MD FCCP
  68. 68. 6/26/2013 68amrhamdy MD FCCP
  69. 69. Modifying factors that Increase theRisk of Infection with SpecificPathogens6/26/2013 69amrhamdy MD FCCP
  70. 70. 6/26/2013 70amrhamdy MD FCCP
  71. 71. 6/26/2013 71amrhamdy MD FCCP
  72. 72. 6/26/2013 72amrhamdy MD FCCP
  73. 73. 6/26/2013 73amrhamdy MD FCCP
  74. 74. 6/26/2013 74amrhamdy MD FCCP
  75. 75. Risk Factors for MDR Pathogens CausingHAP, HCAP, and VAP6/26/2013 75amrhamdy MD FCCP
  76. 76. Treatment of MDR TB6/26/2013 amrhamdy MD FCCP 76
  77. 77. • There appears to be an increase inmultidrug- resistant TB.• It was estimated that in 2004 half amillion new cases of MDR-TB caseswere diagnosed world wide.6/26/2013 amrhamdy MD FCCP 77
  78. 78. Of the new compounds being testedfor their efficacy in TB treatment, theFQ are the first novel drugs since thedevelopment of rifamycins to havebeen shown to have significantactivity against M. tuberculosis.6/26/2013 amrhamdy MD FCCP 78
  79. 79. • Multidrug-resistant TB (MDR-TB) isdefined as TB resistant to at leastisoniazid and rifampin.• Extensively drug-resistant TB (XDR-TB) is caused by MDR strains that arealso resistant to at least one FQ andone or more injectable agents.6/26/2013 amrhamdy MD FCCP 79
  80. 80. • The anti-TB activity of FQs has beenunder investigation since the 1980s.• FQs are novel anti-TB drugs to beused when a patient is infected witha MDR-TB strain.6/26/2013 amrhamdy MD FCCP 80
  81. 81. Many are active in vitro but only afew, includingoflaxicin, ciprofloxacin, levofloxacin,sparfloxacin, levofloxacin andlemofloxaxin, have been clinicallyassessed.6/26/2013 amrhamdy MD FCCP 81
  82. 82. • The choice of FQ should be basednot only on the in vitro activity, butalso on the long-term tolerance.• The in vivo activity of FQs isconcentration dependent.6/26/2013 amrhamdy MD FCCP 82
  83. 83. • The administration of FQ for CAPpatients with TB has been associatedwith delay in diagnosis and increasedresistance and poor outcomes.• Multiple FQs prescriptions forundiagnosed TB were more likely tohave FQ resistant M. TB.6/26/2013 amrhamdy MD FCCP 83
  84. 84. According to a recent meta analysis of 11randomized controlled trials comprising atotal of 1,514 patients, no statisticallysignificant difference was observed inrelation to cure, treatment failure andclinical and radiological improvementwhen first-line drugs were replaced by aFQ (ciprofloxacin, oflaxacin ormoxifloxacin).6/26/2013 amrhamdy MD FCCP 84
  85. 85. Thus, there is currently no justificationfor the substitution of a FQ for firstline drugs or the addition of a FQ tothe standard regime.6/26/2013 amrhamdy MD FCCP 85
  86. 86. Moxifloxacin at the recommendeddaily dose of 400mg is the mostactive FQ against TB, whileciprofloxacin is the least effective.6/26/2013 amrhamdy MD FCCP 86
  87. 87. WarningThe broad spectrum activity andcommon use against many otherinfections is also concern, sincewidespread use of this class ofantibiotics may lead to a rapidincrease in already emergingresistance problems.6/26/2013 amrhamdy MD FCCP 87
  88. 88. It is wise not to use respiratory FQs asa first-line therapy for LRTI, but toreserve these drugs for selectedpatients with CAP.6/26/2013 amrhamdy MD FCCP 88
  89. 89. 6/26/2013 amrhamdy MD FCCP 89
  90. 90. References6/26/2013 amrhamdy MD FCCP 90
  91. 91. • Andriole VT: The Quinolones. Acadamic Press(1989).6/26/2013 amrhamdy MD FCCP 91
  92. 92. THANK YOU6/26/2013 amrhamdy MD FCCP 92