Presentation on theme: "Antimicrobial therapy Beta-Lactam Antibiotics These antibiotics have a B-lactam ring structure and exert a bactericidal action by distrupting cell wall."— Presentation transcript:
Antimicrobial therapy Beta-Lactam Antibiotics These 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 :
Pharmacokinetics *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).
Adverse 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 2 nd and 3 rd generations cephalosporins have a low incidence of allergy and an almost negligible rate of anaphylaxis.
Adverse 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.
Macrolide and lincosamide antibiotics Erythromycin:remains the reference macrolide antibiotic Pharmacokinetics: -Poorly absorbed orally. -Short half –life(except azithromycin) -High protein binding. -Excellent intracellular accumulation, good CSF penetration.
Pharmacokinetics 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.
Aminoglycosides: *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.
-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.
Adverse 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.
Quinolones *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.
Pharmacokinetics: *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.
Adverse 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.
Glycopeptides(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.
Pharmacokinetics 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.
Averse 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.
Folate 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.
Pharmacokinetics: *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.
Adverse 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.
Tetracyclines *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.
Pharmacokinetics: *Best oral absorption in the fasting state( doxycycline 100% absorbed unless gastric PH rises). *CSF levels increased in chronic inflammation( useful in Lyme disease).
Adverse 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)
Chloramphenicol *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.
Pharmacokinetics: *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.
Adverse 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)