Presentation on theme: "Antimicrobial therapy"— Presentation transcript:
1Antimicrobial therapy Beta-Lactam AntibioticsThese antibiotics have a B-lactam ring structure and exert a bactericidal action by distrupting cell wall synthesis in rapidly dividing organisms.Generally , they achieve good levels in the lung, kidney , bone , muscle and liver ,and in pleural , synovial , pericardial and peritoneal fluids.They are classified into 8 groups :
4Pharmacokinetics *Not inhibited by abscess environment ( low PH ,low O2 , high protein and polymorphonuclear cells). *Poor penetration to monocytes , low CSF levels except in the presence of inflammation. *Generally safe in pregnancy ( except imipenem/cislastatin).
5Adverse reactions*Generalized allergy :0.7-10%.*Anaphylaxis : %*Infectious mononucleosis :>90% develop a rash if given aminopenicillins.N.B….established penicillin allergy does not imply allergy to other classes,particularly the cephalosporins.*The 2nd and 3 rd generations cephalosporins have a low incidence of allergy and an almost negligible rate of anaphylaxis.
6Adverse effects*GI upset ,diarrhea ,and a mild irreversible hepatitis.*Leucopenia , thrombocytopenia and coagulation deficiencies.*Interstitial nephritis and increased renal damage in combination with aminoglycosides.*Seizures and encephalopathy particularly with high doses in the presence of renal insufficiency.N.B…..direct intrathecal injection of a B- lactam is contraindicated.
7Macrolide and lincosamide antibiotics Erythromycin:remains the ‘reference’ macrolide antibioticPharmacokinetics:-Poorly absorbed orally.-Short half –life(except azithromycin)-High protein binding.-Excellent intracellular accumulation, good CSF penetration.
8Pharmacokinetics of lincosamide: -Good bioavailability.-Food has no effect on absorption.-Limited CSF penetration.Adverse effects(both macrolides and lincosamides)*Generally very safe.*GI upset , especially in young adults.*Cholestatic jaundice with erythromycin estolate.*Prolongation of QT interval on ECG ,potential for torsades de pointes.*Clindamycin-diarrhea in 2-30% linked to Cl.difficile.
9Aminoglycosides:*Are very effective anti-Gram negative antibiotics.*Are particularly useful where B-lactam or quinolones resistance occurs in health care –acquired infections.Pharmacokinetics:-Negligible oral absorption.-Hydrophilic so excellent penetration to body cavities and serosal fluids.
10-Very poor intracellular penetration( except hair cells in cochlea and renal cortical cells ). -Negligible CSF and corneal penetration.-Peak plasma levels 30 minutes after infusion.-Post-antibiotic effect allows once-daily administration ( except in endocarditis , pregnancy , chronic renal disease and ascites ).-Monitoring of therapeutic levels required.
11Adverse reactions*Renal toxicity ( usually reversible) , worse with concomitant vancomycin , cisplatin , amphotericin B,contrast media.*Cochlear toxicity( permanent) more likely in order people.*Neuromuscular blockade after rapid intravenous infusion( increased with calcium channel blockers , myasthenia gravis and hypomagnesaemia).N.B…..Aminoglycosides are very effective in Gram-negative sepsis and body fluid infection.
12Quinolones*Of these synthetic agents, the early quinolones had purely anti-Gram negative activity, fluoroquinolones ( e.g. ciprofloxacin) have times greater activity against Gram-negative organisms , and newer drugs , levo-,moxi-, spar-,gemi- and gatefloxacin, have improved anti –Gram-positive and anti-anaerobic capability.N.B…..These antibiotics may now be used against respiratory pathogens in an empirical manner.
13Pharmacokinetics:*Well absorbed after oral administration but delayed by food , antacids,ferrous sulphate and multivitamins.*Wide volume of distribution.*Good intracellular penetration concentrating in phagocytes with high bioavailability.*Tissue concentration twice that of serum.
14Adverse reactions*Very rare side-effects.*Rare skin reactions ( phototoxicity).*GI side effects in 1-5% , tremor , dizziness and occasional seizures in 5-12%.*Coadministration with xanthines and theophylines reduces clearance of these drugs so may produce insomnia and increases seizure potential.*CNS effects such as confusion and seizures occur potentially in elderly.
15Glycopeptides(vancomycin and teicoplanin) *Vancomycin is effective against Gram-positive organisms and, with teicoplanin, remains useful against MRSA and enterococci.*The inappropriate use of vancomycin should be limited , particularly in the management of Cl. Difficle infections , to prevent further resistance development.
16Pharmacokinetics of vancomycin: -Must be given by slow intravenous infusion with good tissue distribution and has a short half-life.-Only enters CSF in the presence of inflammation.Pharmacokinetics of teicoplanin:-Longer half-life allows once-daily dosing.-More lipophilic than vancomycin, with good tissue penetration.
18Averse effects of vancomycin: *Histamine release due to rapid infusion produces the ‘ red- man’ anaphylactoid reaction.*Nephrotoxicity enhanced by concomitant aminoglycosides.*Requires therapeutic monitoring.Adverse effects of teicoplanin:*Rash , bronchospasm , eosinophilia and anaphylaxis.*Markedly less toxic than vancomycin ; only requires monitoring in renal impairment.
19Folate antagonists-Interfere with the prokaryotic cell metabolism of para-aminobenzoic acid to folic acid.-A combination of two antibiotics ( a sulphonamide and either trimethoprim or pyrimethamine) is most commonly used.N.B…..Co-trimoxazole in high doses ( 120 mg/kg) is the first- line drug for Pneumocystis pneumoniae infection in HIV disease.
20Pharmacokinetics:*Well absorbed orally with good bioavailability.*Displace bilirubin from albumin so predispose to kernicterus in infants.*Sulphonamides are hydrophilic , distributing well to the extracellular fluid.*Trimethoprim is lipophilic with high tissue concentrations.
21Adverse reactions:*Most are dose- and time- related( therapy for UTI should be no more than 3 days),*Fatal marrow dysplasia and hemolysis in G6PD more common in the elderly.*Skin and mucocutaneous reactions especially common and related to sulphonamide component.*All reactions more common in high- dose therapy in HIV disease.
22Tetracyclines*Of this mainly bacteriostatic class , the newer drugs doxycycline and minocycline show better absorption and disribution than older ones.*Are mostly used against Mycoplasma ,Chlamydia and Rickettsia , plus Borrelia and other spirochaetes.
23Pharmacokinetics:*Best oral absorption in the fasting state( doxycycline 100% absorbed unless gastric PH rises).*CSF levels increased in chronic inflammation( useful in Lyme disease).
24Adverse reactions:*All tetracyclines except doxycycline are contraindicated in renal failure.*Marked effect on bowel flora , causing side-effects of nausea and diarrhoea.*Bind to metallic ions in bones and teeth , causing discoloration(avoid in children and pregnancy).*Phototoxic skin reactions.*Hypernatraemia ( used therapeutically in hyponatraemia)
25Chloramphenicol*This potentially toxic antibiotic is bacteriostatic to most organisms but apparentlly bactericidal to H.influenzae ,Strep. Peumoniae ,and Neisseria meningitidis.*It has a very broad spectrum of activity against aerobic and anaerobic organisms, spirochaetes,Rickettsia , Chlamydia and Mycoplasma.*It has quite useful clinical activity against anaerobes such as Bacteroides fragilis.
26Pharmacokinetics:*Well absorbed after i.v. or oral dose ( not i.m.).Good tissue distribution and levels.*Good CSF levels.*Crosses placenta and reaches breast milk.*Competes for binding site with macrolides and lincosamides.
27Adverse reactions:*Dose- dependent ‘ grey-baby’ syndrome in infants( cyanosis and circulatory collapse due to inability to conjucate drug and excrete active form in urine).*Reversible dose- dependent bone marrow depression( adults) if >4 g per day administered or cuulative dose>25 g.*Severe idiopathic aplastic anaemia in 1: treatment regimens ( unrelated to dose , duration of therapy or route of administration)