CLINIC-PHARMACOLOGIC APPROACHES TO ANTIMICROBIAL THERAPY IN

RESPIRATORY INFECTIONS

Djakubekova A.U.

MAIN QUESTIONS FOR ANTIMICROBIAL THERAPY IN

RESPIRATORY INFECTIONS• Can antibiotics be administered?• Which drugs should be selected?• Which route of drug administration

and dosage regimen should be used?• What is the aim of treatment

Empirical Antimicrobial Therapy

• Antimicrobial agents are frequently used before the pathogen responsible for a particular illness or the susceptibility to a particular antimicrobial agent is known. This use of antimicrobial agents is called empirical (or presumptive) therapy and is based upon experience with a particular clinical entity.

Empirical antimicrobial therapy

• Causative agents• Location of infection (Upper and

lower respiratory tract)

TWO TYPES OF RESPIRATORY INFECTIONS

• NON-HOSPITAL• HOSPITAL (NOSOCOMIAL)

COMMON CAUSATIVE AGENTS OF NON-HOSPITAL RESPIRATORY INFECTIONS

RATE (%)

Streptococcus pneumoniae 40-60Haemophilus influenzae 25-40Moraxella catarrhalis 2-10Staphylococcus aureus 0-5

S. pneumoniae

STREPTOCOCCI

Staphylococcus aureus GramGram+ +

Located in the skin anLocated in the skin anrespiratory tractrespiratory tract

HOSPITAL OR NOSOCOMIAL INFECTIONS

• clinically and laboratorial estimated infection that is not situated in incubation period at patient’s admission and developed 48 hours after patient’s hospitalization.

COMMON CAUSATIVE AGENTS OF NOSOCOMIAL RESPIRATORY INFECTIONS

P. aeruginosaE.coliK.pneumoniaeAcinetobacter spp.

Antimicrobial therapy

The aim and main tasks:•to minimize the influence of AMD on normal microorganisms of RT;• to minimize the risk of adverse effects;•to decrease the cost of treatment.

Antimicrobial therapy• β-lactam antibiotics• Macrolides• Fluoroquinolones (III-IV- generation)

β-lactam antibiotics

+ Bactericidal action+ Low toxicity+ Dose-dependent

distribution in the body

+ Wide therapeutic diapason

- Cross-hypersensitivity- Low activity against

intracelular bacteria- High level of resistance

SEMISYNTHETIC PENICILLINSCombined with β-lactamase inhibitors• Amoxicillin+clavulanic acid• Ampicillin +sulbactam• Ticarcillin+sulbactam• Piperacillin+clavulanic acid

Comparative characteristics of Aminopenicillines

AEROBS Ampic. Amoxic. Amox/clav.acid

Streptococcus pneumoniae

++ ++ +++

H. influenzae β-lactamaza(-)β-lactamaza(+)

++0

+++0

++++++

β-hemolytic streptococcus A +++ +++ +++

Comparative characteristics of Aminopenicillines

Ampic. Amoxic. Amox/clav.acid

Route Oral, I/v, I/m

Oral Oral, I/v

Bioavailability 40 70-93 70

Drug-food interaction In 2 folder

- -

Concentration in mucus low high high

Adverse effects Diarrhea, rash

Diarrhea (rarely)

Diarrhea(rarely)

Aminopenicillines: resume for practice

• Use orally only amoxicilline• Usual dose for amoxicilline – 0,5x3 times

a day. Maximal dose 1 gx3 times a day• Parenterally – ampicilline• In cases of previous use of ampicilline

and amoxicilline and natural penicillines – use only amoxicilline/clavulanic acid

• In case of chronic RT infections – use only amoxicilline/clavulanic acid

CLASSIFICATION OF CEFALOSPORINS

Generation Parenterally used Orally used

I Cefasolin Cefalexin, Cefadroxyl

II Cefuroxim Cefuroxim acethyl, Cefaclor

III Cefotaxim, Ceftriaxon, Ceftazidim, Cefoperazon, Cefaperaz./sulbactam

Cefixim, Ceftibuten

VI Cefepim

Spectrum of action for Ist generation of сefalosporines

Gram (+)• Staphylococcus spp. (except MRSA)• Streptococcus spp.• S. pyogenes

Comparative characteristics of Ist generation сefalosporines

Cefalexine Сefadroxyl Сefalexine

S. pneumoniae + + +

Staphylococcus spp. ++ ++ +++

Streptococcus spp. ++ ++ +++

H. Influenzae and - - -M. catarrhalis

Spectrum of action for II generation of сefalosporines

Gram (+)• Staphylococcus spp.

(except MRSA)• Streptococcus spp.• S. pyogenes• S. pneumoniae

Gram (-)• H. influenzae• M. catarrhalis• Enterobacteriaceae– E. coli– Proteus spp.– Klebsiella spp– Enterobacter spp

Comparative activity of II generation сefalosporines

S. pneumoniae1 Staphylococcus2

Сefaclor ++ ++Сefuroxim +++ ++

Spectrum of action for III generation of сefalosporines

Gram (+)• Streptococcus spp.• S. pyogenes• S. pneumoniae

Anaerobs• only

сefoperazone/sulbactam

Gram (-)• Neisseria spp.• H. influenzae• Enterobacteriaceae

(E. coli, Proteus spp., Klebsiella spp, Enterobacter spp, Citrobacter spp., Serratia spp and others)

• P. aeruginosa (not all)• Acinetobacter spp.

Spectrum of action for IV generation of сefalosporines

(cefepim)Cefalosporines III +• P. aeruginosa• Acinetobacter spp.• B. fragilis• Gram (+) cocci (except MRSA)• More tolerant to β-lactamaze

CLASSIFICATION OF MACROLIDES Natural macrolides Semisynthetic

macrolides14-atom lacton macrolide

ErythromromycinRoxythromycinClarithromycinOleandomycin

15-atom lacton macrolide (azalides)

Azithromycin

16-atom lacton macrolide

SpiramycinMidecamycinJosamycin

Midecamycin acetate

SPECTRUM OF ACTION OF MACROLIDES

Gram (+) cocci• S. aureus (кроме MRSA)• Coagulaze-negative staphyllococci• S. pneumoniae• S. pyogenes (type А)Gram (-) cocci• Neisseria gonorrhoeae Moraxella catarrhalisGram (-) bacteria• Hemophilus influenzae Helicobacter pyloriIntracellular microorganisms• Chlamidia trachomatis Chlamidia pneumoniae• Mycoplasma pneumoniae Ureaplasma

urealiticum• Legionella pneumophila

FACTORS DEFINING THE USE OF MACROLYDES IN RTI

• High activity against Gram(+) cocci (S.pneumoniae, S.pyogenes), atypical bacteria (C.pneumoniae, M.pneumoniae), Gram(-) bacteria (H.influenzae, M.catarrhalis)

• High concentration in bronchial secret and lung tissue• No cross-hypersensitivity• Low toxicity• Additional antiinflammatory and immunostimulating

effects

Advantages of modern macrolides

• Wider spectrum of action• High concentration in body fluids and

tissues• Prolonged duration of action• Improved tolerance or lower toxicity• Minimal risk of adverse effects

FLUOROQUINOLONESSubgroup DrugI generation- non-fluorated quinolones

Nalidixic acid

II generation – Gram(-) FQ NorfloxacineCiprofloxacineOfloxacine

III generation – respiratory FG

LevofloxacineSparfloxacine

IV generation - respiratory and antaerobic FG

MoxifloxacineHemifloxacine

DISADVANTAGE OF OLDER FLUOROQUINOLONES

MINIMAL ACTIVITY AGAINST:•S.pneumoniae•Mycoplasma pneumonia•Chlamydia pneumonia•Anaerobs

3rd way of antimicrobial therapy of respiratory infections

Why cotrimoxasole should be limited in Respiratory Infections?

(1) High level of resistance: S.pneumoniae – 35-52% H.influenzae – until 20%

(2) No activity to S.pyogenes(3) High risk of toxic-allergic reactions

Why DOXYCYCLINE is ineffective in respiratory infections?

High level of resistance: S.pneumoniae – about 40%

Drug selection in exacerbation of COPD

Nosologic form Causative agents 1st choice drug Alternative drugsSimple (uncomplicated)

H. influenzaeS. pneumoniaeM. catarrhalis

AmoxicillineClarithromycinAzithromycin

Amoxicillin/clav.ac.LevofloxacineMoxifloxacineHemifloxacine

Complicated H. influenzaeS. pneumoniaeM. catarrhalisEnterobacteriaceae

Amoxicillin/clav.ac.LevofloxacineMoxifloxacineHemifloxacine

Complicated with risk of P.aeruginosa

H. influenzaeS. pneumoniaeM. catarrhalisEnterobacteriaceaeP. aeruginosa

CiprofloxacineLevofloxacineSparfloxacineHemifloxacine

Drug selection in non-hospital pneumonia

Nosologic form Causative agents 1st choice drug Alternative drugsNon-severe pneumonia in patients under 60 years of age

S. pneumoniaeH. influenzaeM. PneuminiaeC.pneumoniae

AmoxicillineClarithromycinAzithromycin

LevofloxacineMoxifloxacineHemifloxacineDoxycyckine

Non-severe pneumonia in patients older than 60 years

S. pneumoniaeH. influenzaeS.aureusC.PneumoniaeEnterobacteriaceae

Amoxicillin/Clav.ac.

LevofloxacineMoxifloxacineHemifloxacine

Severe pneumonia

S. pneumoniaeLegionella spp.S.aureusEnterobacteriaceae

Amoxic./Clav.ac.Сefotaxim orСeftriaxone+

macrolide

LevofloxacineMoxifloxacineHemifloxacine

EMPIRIC ANTIMICROBIAL THERAPY OF NOSOCOMIAL PNEUMONIA

• Сefotaxim• Сeftriaxone• Amoxicilline/Clavulanic acid• Ampicilline/Sulbactam• Ertapenem• Levofloxacin, Ciprofloxacin, Moxifloxacine