8. COMMON CAUSES OF CARTIs Streptococcus pneumoniae Atypical pathogens Mycoplasma pneumoniae Chlamydiae pneumoniae Legionella species Respiratory viruses Aerobic gram –ve bacilli Klebsiella pneumoniae Staphylococcus aureus
9. CHALLENGES IN IDENTIFYING CAUSATIVE AGENT Laboratory tests often insensitive Slow in identifying causative pathogen Pathogen isolated in few cases only Therapy therefore presumptive Choice of appropriate antibiotics “with full cover” Increasing resistance
11. DEFINITION AND DIAGNOSIS OF CARTIs Signs and symptoms Duration not defined in most studies Fever and leucocytosis New infiltrate on chest radiograph Aim to establish aetiology Only successful in 50%? Quality of sputum? Role of blood culture?
12. CARTIs PSI Low risk Moderate risk High risk High risk Moderate risk OP Treatment IP treatment ICU managed Hypotension Hypoxia Shock Comorbid conditions
13. OPTIMAL MANAGEMENT CARTIs Diagnosis Identification of causative micro-organism Risk factors for severe illness Choice of therapy antibiotics
14. CHALLENGES IN MANAGEMENTChoice of Antimicrobial Wide array of agents Local knowledge of resistance Cost New vs Old Spectrum
15. SELECTION OF ANTIMICROBIAL THERAPY Potency Pharmacology Clinical Efficacy Resistance Appropriate use/guidelines – several Safety Convenience /likelihood of adherence Tolerability Cost
16. ECONOMICS OF CARTIs TREATMENT Duration of antibiotics therapy Home versus hospitalization Criteria for use of antibiotics Switch therapy
17. SELECTION OF EMPIRICAL ANTIBIOTIC IN OUT-PATIENT THERAPY Community-acquired RTIs often treated empirically Therapy choice depends on : Clinical presentation Severity of infection Affordability of drug Local resistance patterns are rarely known to the doctor
22. THE IDEAL ANTIBIOTIC FOR USE IN CARTIs Kills all known micro-organisms Distributed throughout the body Acceptable tolerability profile Cost effective in terms of money, time and safety
23. THE IDEAL RESPIRATORY ANTIBIOTIC Appropriate spectrum of microbiological activity Superior efficacy to that of current standard therapies Once-daily dosing Rapid penetration into target tissue High bioavailability on oral dosing High and sustained tissue levels Levels above MIC values for all susceptible pathogens Low propensity for developing resistance No serious adverse events No drug-drug interactions No phototoxicity No dose alterations necessary for elderly or renally impaired patients
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
25. QUINOLONES IN CARTIs Worldwide antimicrobials discovered in 1962 evolved in the 70s from Nalidixic Acid (Synthetic Antimicrobial). Now four generations.
27. EVOLUTION OF QUINOLONES IN THE TREATMENT OF BACTERIAL INFECTIONS Early quinolones used traditionally for Gram-negative infections Limited coverage of Gram-positive bacteria, particularly streptococci and staphylococci Structural changes made to increase Gram-positive activity 8-Methoxyfluoroquinolones provide broad Gram-positive coverage while retaining Gram-negative activity of earlier quinolones.
28. CLASSIFICATION OF QUINOLONE ANTIMICROBIALS First Generation Nalidixic acid Cinoxacin Second generation Norfloxaxin Ciprofloxacin Lomefloxacin Ofloxacin Levofloxacin Third generation Sparfloxacin Gatofloxacin Grepafloxacin Fourth generation Trovafloxacin Moxifloxacin Gemifloxacin
29. QUINOLONES IN CARTIs Back to basics eliminating infection - The drug - The infecting pathogen - The host Pharmacokinetics - (Disposition) Absorption Protein binding Distribution Elimination Pharmacodynamics - Interaction Drug concentration
30. MECHANISM OF ACTION OF QUINOLONES Inhibit two enzymes essential in bacteria DNA replication: DNA gyrase and topoisomerase IV Bind to enzyme-DNA complex after cleavage of double-stranded DNA has occurred, thus preventing further DNA replication. Introduction of double-stranded DNA breaks leads to lethal damage
31. PHARMACOKINETICS AND PHARMACODYNAMICS OF QUINOLONES Pharmacokinetics Excellent oral bioavailability Extensive penetration into tissues and body fluids Long elimination half-life permitting once-daily dosing of newer fluoroquinolones Oral and intravenous formulations Pharmacodynamics Concentration-dependent bacterial activity In vivo activity predicted by AUC:MIC
32. QUINOLONES IN CARTIs THE FUTURE Bioavailability+IV or oral O.P treatment Excellent antimicrobial spectrum Monotherapy (PRSP risk) Help avoid hospitalization
33. SUMMARY: IN VITRO ACTIVITY Fluoroquinolones offer excellent activity against Gram-negative pathogens; 8-methoxyfluoroquinolones exhibit enhanced Gram-positive activity. Resistance among isolates of S. pneumoniae to Penicillin and macrolides increasing Fluoroquinolones inhibit DNA gyrase and topoisomerase IV, thereby preventing DNA replication. 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
34. PHASE IV SURVEILLANCE OF ORAL MOXIFLOXACIN IN CAP PATIENTS Resolution of clinical symptoms with MXF therapy evaluated in 2 Phase IV studies in Germany. - one in primary care – 4401 patients - one hospital-based study – 2288 patients from 410 hospitals Consecutive patients of all ages with CAP were included and treated with oral MXF - majority of patients received MXF 400 mg od for < 10 days. Resolution of symptoms received and severity of disease were rated by the treating physician. Landen & Bauer. Clin drug invest (2001) Landen eta al. J Intern Med Res (2001)
42. WHAT IS CLINICAL CONFIDENCE? Ability to treat infections empirically and safely with one agent. The option to treat patients in the community rather than hospital. To enable patients to return to normal activities sooner and not worry about callbacks or return visits to the office. Maintain antimicrobial activity for future empiric use.
43. QUINOLONES TOXICITY Cardiotoxicity prolonged QTC interval (V.T) Hepatoxicity Phototoxicity reaction CNS – Dizziness GI – ANVD Renal / Electrolyte imbalances Caution in children and breastfeeding women.
44. OVERVIEW OF QUINOLONE SAFETY As a class considered safe and well tolerated. Reactions normally mild and reversible. Hypersensitivity rare – 0.4-2% of patients. Most are common to the class, but their frequency and severity can vary from agent to agent. Sparfloxacin and clinafloxacin – phototoxicity. Trova – hepatotoxicity Grepa – cardiotoxicity All only noted post marketing and large numbers of patients tested. Now very strict controls and checks.
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