QUINOLONES IN CARTIs

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QUINOLONES IN CARTIs Community Acquired Respiratory Tract Infections Dr. J. A. Aluoch C.M.E – K.M.A 7 th APRIL 2011

Transcript of QUINOLONES IN CARTIs

Page 1: QUINOLONES IN CARTIs

QUINOLONES IN CARTIs

Community Acquired Respiratory Tract

Infections

Dr. J. A. Aluoch

C.M.E – K.M.A

7th APRIL 2011

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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.

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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.

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CARTIs – PATHOGENS 1970s Strep. pneumoniae Mycop – pneum Staph aureus Oral flora (aspiration pneumonia)

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CARTIs PATHOGENS (cont’d) 1990s Haem. Influenza Moraxella catarhalis GNB Chlamydia Legonella

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COMMON CAUSES OF CARTIs

Streptococcus pneumoniae Atypical pathogens

Mycoplasma pneumoniae Chlamydiae pneumoniae Legionella species

Respiratory viruses Aerobic gram –ve bacilli

Klebsiella pneumoniae Staphylococcus aureus

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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

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TECHNIQUES Microscopy

Microbial cultures

Antigen detection

Serological assays

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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?

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CARTIsPSI

Low risk

Moderate risk

High risk

High risk

Moderate risk

OP Treatment

IP treatment

ICU managed

Hypotension

Hypoxia

Shock

Comorbid conditions

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OPTIMAL MANAGEMENT CARTIs

Diagnosis Identification of causative micro-organism Risk factors for severe illness Choice of therapy antibiotics

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CHALLENGES IN MANAGEMENT

Choice of Antimicrobial Wide array of agents Local knowledge of resistance Cost New vs Old Spectrum

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SELECTION OF ANTIMICROBIAL

THERAPY Potency Pharmacology Clinical Efficacy Resistance Appropriate use/guidelines – several Safety Convenience /likelihood of adherence Tolerability Cost

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ECONOMICS OF CARTIs TREATMENT

Duration of antibiotics therapy Home versus hospitalization Criteria for use of antibiotics Switch therapy

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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

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ANTIBIOTIC TREATMENT

Outcomes

Clinical cure Microbiological cure/bacterial

eradication Prevent selection of resistant strains

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GOOD ANTIBIOTICS Good in vivo / in vitro activity PK/PD Tissue penetration Clinical efficacy Slow development of resistance Well tolerated

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PHARMACODYNAMICS

Pattern of Microbial Action PAE Time dependent Conc. dependent Peak conc. – time above MIC

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PHARMACODYNAMICS AND PHARMACOKINETICS

Time related killing B-lactams

Erythromycin Concentration dependent killing

Quinolones

Aminoglycosides

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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

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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

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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

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QUINOLONES IN CARTIs Worldwide antimicrobials discovered in 1962

evolved in the 70s from Nalidixic Acid (Synthetic Antimicrobial).

Now four generations.

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QUINOLINE EVOLUTION

Gram-positive Activity

(launch date)

None Limited Extended

(1963) (1987 – 1997) (1999)

Nalidixic acid Ciprofloxacin Gatifloxacin

Levofloxacin Moxifloxacin

Ofloxacin

Grepafloxacin

Sparfloxacin

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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.

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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

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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

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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

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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

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QUINOLONES IN CARTIs

THE FUTURE

Bioavailability+IV or oral O.P treatment

Excellent antimicrobial spectrum

Monotherapy (PRSP risk)

Help avoid hospitalization

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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

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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)

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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

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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.

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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.

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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.

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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.

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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.