Antimicrobial 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:

1.Natural penicillins:benzylpenicillin,phenoxymethylpenicillin.

2.Penicillinase- resistant penicillins: meticillin, flucloxacillin.

3.Aminopenicillins :ampicillin,amoxicillin.

4.Carboxy-and ureidopenicillins:ticarcillin ,piperacillin.

5.Cephalosporins :1st-4th generation compounds.

6.Monobactams:aztreonam.

7.Carbapenems: imipenem ,meropenem.

8.B-lactamase inhibitors ,e.g. clavulanic acid.

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 :0.004-0.015%*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.

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 antibioticsErythromycin:remains the ‘reference’ macrolide antibioticPharmacokinetics:

-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 10-100 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 1:25 000-40 000 treatment regimens ( unrelated to dose , duration of therapy or route of administration)