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QUINOLONES IN CARTIs
Community Acquired Respiratory Tract
Infections
Dr. J. A. Aluoch
C.M.E – K.M.A
7th APRIL 2011
CARTIs• Community-acquired RTIs are common and
persistent causes of morbidity, disability and mortality.
• RTIs 60% of all community-acquired bacterial infections and
• Account for two-thirds of all antibiotic prescriptions.
• Effective empirical treatment is necessary.
CARTIs
The Challenges
1. Range of possible pathogens.
2. Difficulty in determining the causative pathogen.
3. Choosing appropriate antibiotic.
4. The variety of available antibiotic.
5. Increasing antibiotic resistance.
CARTIs – PATHOGENS 1970s Strep. pneumoniae Mycop – pneum Staph aureus Oral flora (aspiration pneumonia)
CARTIs PATHOGENS (cont’d) 1990s Haem. Influenza Moraxella catarhalis GNB Chlamydia Legonella
COMMON CAUSES OF CARTIs
Streptococcus pneumoniae Atypical pathogens
Mycoplasma pneumoniae Chlamydiae pneumoniae Legionella species
Respiratory viruses Aerobic gram –ve bacilli
Klebsiella pneumoniae Staphylococcus aureus
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
TECHNIQUES Microscopy
Microbial cultures
Antigen detection
Serological assays
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?
CARTIsPSI
Low risk
Moderate risk
High risk
High risk
Moderate risk
OP Treatment
IP treatment
ICU managed
Hypotension
Hypoxia
Shock
Comorbid conditions
OPTIMAL MANAGEMENT CARTIs
Diagnosis Identification of causative micro-organism Risk factors for severe illness Choice of therapy antibiotics
CHALLENGES IN MANAGEMENT
Choice of Antimicrobial Wide array of agents Local knowledge of resistance Cost New vs Old Spectrum
SELECTION OF ANTIMICROBIAL
THERAPY Potency Pharmacology Clinical Efficacy Resistance Appropriate use/guidelines – several Safety Convenience /likelihood of adherence Tolerability Cost
ECONOMICS OF CARTIs TREATMENT
Duration of antibiotics therapy Home versus hospitalization Criteria for use of antibiotics Switch therapy
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
ANTIBIOTIC TREATMENT
Outcomes
Clinical cure Microbiological cure/bacterial
eradication Prevent selection of resistant strains
GOOD ANTIBIOTICS Good in vivo / in vitro activity PK/PD Tissue penetration Clinical efficacy Slow development of resistance Well tolerated
PHARMACODYNAMICS
Pattern of Microbial Action PAE Time dependent Conc. dependent Peak conc. – time above MIC
PHARMACODYNAMICS AND PHARMACOKINETICS
Time related killing B-lactams
Erythromycin Concentration dependent killing
Quinolones
Aminoglycosides
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
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
CURRENT ANTIBACTERIAL OPTIONS FOR CARTIs
Antibacterial Advantages LimitationsMacrolides 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
QUINOLONES IN CARTIs Worldwide antimicrobials discovered in 1962
evolved in the 70s from Nalidixic Acid (Synthetic Antimicrobial).
Now four generations.
QUINOLINE EVOLUTION
Gram-positive Activity
(launch date)
None Limited Extended
(1963) (1987 – 1997) (1999)
Nalidixic acid Ciprofloxacin Gatifloxacin
Levofloxacin Moxifloxacin
Ofloxacin
Grepafloxacin
Sparfloxacin
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.
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
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
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
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
QUINOLONES IN CARTIs
THE FUTURE
Bioavailability+IV or oral O.P treatment
Excellent antimicrobial spectrum
Monotherapy (PRSP risk)
Help avoid hospitalization
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
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)
DO DIFFERENCES EXIST BETWEEN PARENTERAL ANTIBIOTICS?
Moxifloxacin IV CAP study in Europe showed quicker time to normal temperature.- IV – PO switch sooner - Shorter hospital stay - More cost-effective therapy with Avelon
MOXIFLOXACIN IV IN CAP:A NEW STANDARD EMPIRIC APPROACH?
Moxifloxacin I.V showed excellent efficacy - Superiority over the ‘gold-standard combination
therapy for CAP’ – European study - Showed quicker time to apyrexia- Eradicated bacteremic S. pneumoniae- Was equivalent to new quinolone therapy even in
an unbalanced study - Represents a new standard for empiric CAP
treatment.
SUMMARY Although infections are a growing burden
on healthcare costs, antibiotics are a small percentage of these costs.
More rapid and effective therapy can produce cost-savings.
All fluoroquinolones are not alike We need to prescribe an antibiotic with
confidence.
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.
QUINOLONES TOXICITY
1. Cardiotoxicity prolonged QTC interval (V.T)
2. Hepatoxicity
3. Phototoxicity reaction
4. CNS – Dizziness
5. GI – ANVD
6. Renal / Electrolyte imbalances
7. Caution in children and breastfeeding women.
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.