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  1. 1. QUINOLONES IN CARTIs<br />Community Acquired Respiratory Tract<br />Infections<br />Dr. J. A. Aluoch<br />C.M.E – K.M.A <br />7th APRIL 2011 <br />
  2. 2. CARTIs<br /><ul><li> Community-acquired RTIs are common and persistent causes of morbidity, disability and mortality.
  3. 3. RTIs 60% of all community-acquired bacterial infections and
  4. 4. Account for two-thirds of all antibiotic prescriptions.
  5. 5. Effective empirical treatment is necessary. </li></li></ul><li>CARTIs The Challenges <br />Range of possible pathogens.<br />Difficulty in determining the causative pathogen. <br />Choosing appropriate antibiotic.<br />The variety of available antibiotic. <br />Increasing antibiotic resistance.<br />
  6. 6. CARTIs – PATHOGENS<br />1970s<br />Strep. pneumoniae <br />Mycop – pneum<br />Staph aureus <br />Oral flora (aspiration pneumonia)<br />
  7. 7. CARTIs PATHOGENS (cont’d)<br />1990s<br />Haem. Influenza <br />Moraxella catarhalis <br />GNB<br />Chlamydia<br />Legonella <br />
  8. 8. COMMON CAUSES OF CARTIs<br />Streptococcus pneumoniae <br />Atypical pathogens <br />Mycoplasma pneumoniae<br />Chlamydiae pneumoniae <br />Legionella species<br />Respiratory viruses <br />Aerobic gram –ve bacilli<br />Klebsiella pneumoniae<br />Staphylococcus aureus <br />
  9. 9. CHALLENGES IN IDENTIFYING CAUSATIVE AGENT<br />Laboratory tests often insensitive <br />Slow in identifying causative pathogen <br />Pathogen isolated in few cases only <br />Therapy therefore presumptive <br />Choice of appropriate antibiotics “with full cover” <br />Increasing resistance <br />
  10. 10. TECHNIQUES<br />Microscopy <br />Microbial cultures <br />Antigen detection <br />Serological assays <br />
  11. 11. DEFINITION AND DIAGNOSIS OF CARTIs<br />Signs and symptoms <br />Duration not defined in most studies<br />Fever and leucocytosis <br />New infiltrate on chest radiograph <br />Aim to establish aetiology <br />Only successful in 50%?<br />Quality of sputum?<br />Role of blood culture?<br />
  12. 12. CARTIs<br />PSI<br />Low risk <br />Moderate risk <br />High risk <br />High risk <br />Moderate risk <br />OP Treatment <br />IP treatment <br />ICU managed <br />Hypotension <br />Hypoxia <br />Shock<br />Comorbid conditions <br />
  13. 13. OPTIMAL MANAGEMENT CARTIs<br />Diagnosis <br />Identification of causative micro-organism<br />Risk factors for severe illness <br />Choice of therapy antibiotics <br />
  14. 14. CHALLENGES IN MANAGEMENTChoice of Antimicrobial <br />Wide array of agents <br />Local knowledge of resistance <br />Cost <br />New vs Old <br />Spectrum <br />
  15. 15. SELECTION OF ANTIMICROBIAL THERAPY<br />Potency <br />Pharmacology <br />Clinical Efficacy <br />Resistance <br />Appropriate use/guidelines – several <br />Safety <br />Convenience /likelihood of adherence <br />Tolerability <br />Cost <br />
  16. 16. ECONOMICS OF CARTIs TREATMENT<br />Duration of antibiotics therapy <br />Home versus hospitalization <br />Criteria for use of antibiotics <br />Switch therapy <br />
  17. 17. SELECTION OF EMPIRICAL ANTIBIOTIC IN OUT-PATIENT THERAPY<br />Community-acquired RTIs often treated empirically <br />Therapy choice depends on : <br />Clinical presentation <br />Severity of infection <br />Affordability of drug <br />Local resistance patterns are rarely known to the doctor<br />
  18. 18. ANTIBIOTIC TREATMENT Outcomes <br />Clinical cure <br />Microbiological cure/bacterial eradication <br />Prevent selection of resistant strains <br />
  19. 19. GOOD ANTIBIOTICS <br />Good in vivo / in vitro activity<br />PK/PD<br />Tissue penetration <br />Clinical efficacy <br />Slow development of resistance <br />Well tolerated <br />
  20. 20. PHARMACODYNAMICS<br />Pattern of Microbial Action<br />PAE <br />Time dependent <br />Conc. dependent <br />Peak conc. – time above MIC <br />
  21. 21. PHARMACODYNAMICS AND PHARMACOKINETICS<br />Time related killing <br />B-lactams <br /> Erythromycin <br />Concentration dependent killing <br />Quinolones <br />Aminoglycosides <br />
  22. 22. THE IDEAL ANTIBIOTIC FOR USE IN CARTIs<br />Kills all known micro-organisms <br />Distributed throughout the body <br />Acceptable tolerability profile <br />Cost effective in terms of money, time and safety <br />
  23. 23. THE IDEAL RESPIRATORY ANTIBIOTIC<br />Appropriate spectrum of microbiological activity <br />Superior efficacy to that of current standard therapies <br />Once-daily dosing <br />Rapid penetration into target tissue <br />High bioavailability on oral dosing <br />High and sustained tissue levels <br />Levels above MIC values for all susceptible pathogens <br />Low propensity for developing resistance <br />No serious adverse events <br />No drug-drug interactions <br />No phototoxicity <br />No dose alterations necessary for elderly or renally impaired patients <br />
  24. 24. CURRENT ANTIBACTERIAL OPTIONS FOR CARTIsAntibacterial AdvantagesLimitationsMacrolides Goods activity No in vitro activity against typical against erythromycin (except)Haemophilus A- resistance S Influenza A) and Pneumonia atypical/intracellular pathogens Can be used in Cross-resistance to Penicillin –allergic Macrolides among patients Penicillin- resistant <br />
  25. 25. QUINOLONES IN CARTIs<br />Worldwide antimicrobials discovered in 1962 evolved in the 70s from Nalidixic Acid (Synthetic Antimicrobial).<br />Now four generations.<br />
  26. 26. QUINOLINE EVOLUTION<br />Gram-positive Activity <br /> (launch date) <br />None Limited Extended <br />(1963) (1987 – 1997) (1999) <br />Nalidixic acid Ciprofloxacin Gatifloxacin <br /> Levofloxacin Moxifloxacin <br /> Ofloxacin <br /> Grepafloxacin <br /> Sparfloxacin <br />
  27. 27. EVOLUTION OF QUINOLONES IN THE TREATMENT OF BACTERIAL INFECTIONS<br />Early quinolones used traditionally for Gram-negative infections<br />Limited coverage of Gram-positive bacteria, particularly streptococci and staphylococci <br />Structural changes made to increase Gram-positive activity<br />8-Methoxyfluoroquinolones provide broad Gram-positive coverage while retaining Gram-negative activity of earlier quinolones.<br />
  28. 28. CLASSIFICATION OF QUINOLONE ANTIMICROBIALS <br />First Generation <br /> Nalidixic acid <br /> Cinoxacin <br />Second generation <br /> Norfloxaxin <br /> Ciprofloxacin <br /> Lomefloxacin <br /> Ofloxacin <br /> Levofloxacin <br />Third generation<br /> Sparfloxacin <br /> Gatofloxacin <br /> Grepafloxacin <br />Fourth generation<br /> Trovafloxacin <br /> Moxifloxacin <br /> Gemifloxacin <br />
  29. 29. QUINOLONES IN CARTIs<br />Back to basics eliminating infection <br /> - The drug <br /> - The infecting pathogen <br /> - The host <br />Pharmacokinetics - (Disposition) <br /> Absorption <br /> Protein binding <br /> Distribution <br /> Elimination <br />Pharmacodynamics - Interaction <br /> Drug concentration <br />
  30. 30. MECHANISM OF ACTION OF QUINOLONES<br />Inhibit two enzymes essential in bacteria DNA replication: DNA gyrase and topoisomerase IV<br />Bind to enzyme-DNA complex after cleavage of double-stranded DNA has occurred, thus preventing further DNA replication.<br />Introduction of double-stranded DNA breaks leads to lethal damage<br />
  31. 31. PHARMACOKINETICS AND PHARMACODYNAMICS OF QUINOLONES<br />Pharmacokinetics <br />Excellent oral bioavailability <br />Extensive penetration into tissues and body fluids <br />Long elimination half-life permitting once-daily dosing of newer fluoroquinolones <br />Oral and intravenous formulations<br />Pharmacodynamics <br />Concentration-dependent bacterial activity <br />In vivo activity predicted by AUC:MIC<br />
  32. 32. QUINOLONES IN CARTIs<br />THE FUTURE <br />Bioavailability+IV or oral O.P treatment <br />Excellent antimicrobial spectrum <br />Monotherapy (PRSP risk) <br />Help avoid hospitalization<br />
  33. 33. SUMMARY: IN VITRO ACTIVITY<br />Fluoroquinolones offer excellent activity against Gram-negative pathogens; 8-methoxyfluoroquinolones exhibit enhanced Gram-positive activity.<br />Resistance among isolates of S. pneumoniae to Penicillin and macrolides increasing <br />Fluoroquinolones inhibit DNA gyrase and topoisomerase IV, thereby preventing DNA replication. <br />Resistance selected in stepwise manner due to mutations in subunits of target enzymes and/or expression of efflux pumps; lower selection of resistant Gram-positive strains with 8-methoxyfluoroquinolones <br />
  34. 34. PHASE IV SURVEILLANCE OF ORAL MOXIFLOXACIN IN CAP PATIENTS<br />Resolution of clinical symptoms with MXF therapy evaluated in 2 Phase IV studies in Germany. <br /> - one in primary care – 4401 patients <br /> - one hospital-based study – 2288 patients from 410 hospitals <br />Consecutive patients of all ages with CAP were included and treated with oral MXF <br /> - majority of patients received MXF 400 mg od for < 10 days.<br />Resolution of symptoms received and severity of disease were rated by the treating physician. <br />Landen & Bauer. Clin drug invest (2001)<br />Landen eta al. J Intern Med Res (2001) <br />
  35. 35. DO DIFFERENCES EXIST BETWEEN PARENTERAL ANTIBIOTICS?<br />Moxifloxacin IV CAP study in Europe showed quicker time to normal temperature.<br /><ul><li>IV – PO switch sooner
  36. 36. Shorter hospital stay
  37. 37. More cost-effective therapy with Avelon </li></li></ul><li>MOXIFLOXACIN IV IN CAP:A NEW STANDARD EMPIRIC APPROACH?<br />Moxifloxacin I.V showed excellent efficacy <br /><ul><li>Superiority over the ‘gold-standard combination therapy for CAP’ – European study
  38. 38. Showed quicker time to apyrexia
  39. 39. Eradicated bacteremic S. pneumoniae
  40. 40. Was equivalent to new quinolone therapy even in an unbalanced study
  41. 41. Represents a new standard for empiric CAP treatment.</li></li></ul><li>SUMMARY <br />Although infections are a growing burden on healthcare costs, antibiotics are a small percentage of these costs.<br />More rapid and effective therapy can produce cost-savings.<br />All fluoroquinolones are not alike<br />We need to prescribe an antibiotic with confidence. <br />
  42. 42. WHAT IS CLINICAL CONFIDENCE?<br />Ability to treat infections empirically and safely with one agent.<br />The option to treat patients in the community rather than hospital.<br />To enable patients to return to normal activities sooner and not worry about callbacks or return visits to the office. <br />Maintain antimicrobial activity for future empiric use. <br />
  43. 43. QUINOLONES <br />TOXICITY<br />Cardiotoxicity prolonged QTC interval (V.T) <br />Hepatoxicity <br />Phototoxicity reaction <br />CNS – Dizziness <br />GI – ANVD<br />Renal / Electrolyte imbalances <br />Caution in children and breastfeeding women.<br />
  44. 44. OVERVIEW OF QUINOLONE SAFETY<br />As a class considered safe and well tolerated.<br />Reactions normally mild and reversible.<br />Hypersensitivity rare – 0.4-2% of patients. <br />Most are common to the class, but their frequency and severity can vary from agent to agent.<br />Sparfloxacin and clinafloxacin – phototoxicity.<br />Trova – hepatotoxicity <br />Grepa – cardiotoxicity <br />All only noted post marketing and large numbers of patients tested. <br />Now very strict controls and checks.<br />