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antibiotics

antibiotics

beta lactam ring antibiotics:

  • These drugs attack the bacterial cell wall with bactericidal effect.
  • All beta-lactams act by binding to penicillin-binding proteins (PBPs) which are under chromosomal control & mutations may alter their affinity for specific beta lactams.
  • After binding, the transpeptidation reaction is inhibited which blocks synthesis of peptidoglycan - a main constituent of the cell wall. In addition, inhibition of autolytic enzymes in the cell wall is inactivated.
  • Bacteria may be resistant to beta lactams via:
    • impermeable outer cell membrane (but only Gram -ves have this membrane)
    • alteration in numbers or affinity of PBP's - eg. MRSA
    • production of beta lactamase enzymes via plasmids (eg. Staph, Gram -ves)
    • temporary conversion to L-forms without cell walls
    • quiescence - bacteria not actively multiplying are not effected
    • failure to activate autolytic enzymes
  • Most beta-lactams are safe except in those pts hypersensitive to them.
    • penicillins and cephalosporins exhibit partial and incomplete cross-reactivity of up to 7%
    • Reactions to beta-lactam antibiotics can be classified into:
      • immediate
        • IgE mediated and classically manifest as anaphylaxis, urticaria, angioedema, bronchospasm and allergic rhinoconjunctivitis.
        • while penicillin-induced anaphylaxis is rare (0.01-0.05% of courses), it may be fatal in 10% of cases
        • it is difficult to obtain reliable data about the frequency of cephalosporin anaphylaxis, but published figures are 0.0001-0.1%
      • non-immediate
        • such as maculopapular or morbilliform rashes are probably T-cell mediated.
        • less common but serious adverse reactions to cephalosporins include serum sickness-like reactions, acute interstitial nephritis and cytopenias.
    • Patients with a history of penicillin allergy are four times more likely to have a reaction to cephalosporins than patients without a penicillin allergy.
    • A history of mild reactions to penicillin, such as rashes, does not imply that a reaction to cephalosporins will not be life-threatening - if a cephalosporin is prescribed to a patient with penicillin allergy, the first dose should be taken in a monitored setting.

penicillins:

  • Narrow spectrum:
  • mainly active against Gram +ves, Neisseria & enterococci
    • eg. benzyl penicillin, Pen V, procaine penicillin
  • Beta lactamase resistant:
    • active against Staph. aureus but NOT MRSA
    • eg. flucloxacillin, methicillin
  • Broad spectrum aminopenicillins:
    • active against many Gram -ves but NOT Enterobacter, indole+ve Proteus
    • eg. amoxicillin, ampicillin
  • Anti-Pseudomonal:
    • active against Pseudomonas but used with aminoglycosides to prevent resistance developing.
    • eg. carbenicillin, ticarcillin, piperacillin

cephalosporins:

  • NOT active against enterococci;
  • Poorly cross BBB and not used in Rx of meningitis except 3rd gens.
  • 1st generation:
    • mainly for Gram +ves & some Gram -ves
    • eg. cephalexin
  • 2nd generation:
    • less Gram +ve cover, more Gram -ve cover
    • some active against B. fragilis & thus used in mixed anaerobe infections such as peritonitis, diverticulitis:
      • eg. cefotetan, cefoxitin
    • others active against H. influenzae:
      • eg. cefaclor, cefamandole
  • 3rd generation:
    • expanded Gram -ve cover, even less Gram +ve cover
    • cross BBB adequately for Rx of meningitis
    • used in H.influenzae septicaemia
    • eg. cefotaxime, ceftriaxone

monobactams:

  • monocyclic beta lactams active against Gram -ve rods incl. Pseudomonas but not active against Gram +ves or anaerobes.
  • eg. aztreonam

carbapenems:

  • broad spectrum against many Gram +ves, -ves & anaerobes
  • reserved for ICU use
  • Imipenem:
    • a derivative of thienamycin;
    • It is a potent broad spectrum antibiotic used for severe intra-abdominal sepsis or serious infections with Enterobacteriaceae which produce inducible b-lactamase;
    • Suitable for most penicilin-sensitive pts;
    • It has a high degree of stability in presence of b-lactamases;
    • It is inactivated by dihydropeptidases in the renal tubules → low urinary concentrations → hence combined with cilastatin (a renal dipeptidase inhib.) for Rx of UTI
    • It has activity against enteric Gram -ve rods & Pseud.aer. comparable to aminoglycosides, & also has excellent activity against anaerobes incl. B.fragilis & many Gram +ves.
    • It is given with aminoglycosides to reduce risk of Pseudomonas resistance emerging.
    • It does not reliably cover MRSA nor is it active against some strains of Pseudomonas.
    • Expensive, restricted use.

beta lactamase inhibitors:

  • substances that resemble beta lactams & competitively inhibit beta lactamases
  • used to extend the activity of penicillins
  • eg. clavulanic acid, sulbactam, tazobactam

other cell wall inhibitors:

Vancomycin:
  • A tricyclic glycopeptide antibiotic derived from Nocardia orientalis (f. Streptomyces orientalis)
  • inhibits peptidoglycan synthesis at a different site to the beta lactams
  • Inhibits cell wall synthesis & also alters bacterial cell wall permeability & RNA synthesis;
  • active against MRSA
  • No cross-resistance with other antibiotics;
  • Does not cross blood-brain barrier well;
  • Bactericidal against many Gram +ves & used to Rx pseudomembranous colitis

  *Poorly absorbed from GIT;

Bacitracin:
  • inhibits peptidoglycan synthesis at a different site to the beta lactams
  • too nephrotoxic for systemic use thus used topically as it is active against beta lactamase producing Staph.
Cycloserine:
  • inhibits incorporation of D-alanine into peptidoglycan
  • used in UTI's & occasionally for relapsed resistant TB
  • high doses cause serious CNS toxicity incl. psychoses & convulsions

inhibitors of bacterial protein synthesis:

bind to 50S ribosomal subunit:

  • Chloramphenicol:
    • bacteriostatic for many bacteria & rickettsiae
    • uses:
      • Salmonella (eg. typhoid/paratyphoid)
      • meningitis (not 1st choice now though)
    • Use limited by:
      • risk of delayed onset aplastic anaemia (1:25,000 - 1:100,000)
      • resistant organisms (eg. Hib)
  • Macrolides:
    • bactericidal, binds to 23S rRNA on the 50S subunit, activity enhanced at high pH
    • active against most Gram +ves, Mycoplasma, Legionella, Chlamydia, Helicobacter
    • uses for the usual macrolides (eg. erythromycin, roxithromycin):
      • atypical pneumonia, corynebacterial infections,
      • chlamydial infections esp. where tetracyclines C/I
      • Streptococcal infections where HS to penicillins
      • MAIS in AIDS pts
    • eg. clarithromycin, azithromycin
  • Lincosamines:
    • bind as for macrolides with similar activities BUT:
    • NOT for enterococci, H.influenzae, Neisseriae, Mycoplasma
    • activity against Bacteroides & other anaerobes
    • NOT effective in meningitis
    • eg. clindamycin, lincomycin
    • uses:
      • anaerobic infections (often with metronidazole or aminoglycoside) such as penetrating wounds to gut, septic aborts, pelvic abscesses
      • aspiration pneumonia
      • topically for acne & vaginally after cervical diathermy
    • Lincomycin:
      • Produced by the growth of a member of the lincolnensis gp of Streptomyces lincolnensis;
      • Inhibit bacterial cell protein synthesis;
      • Similar antibacterial activity as the macrolides;
      • Some cross-resistance with macrolides - “macrolide effect”
      • Good for Strep (not faecalis) & Staph. but not Haemophilus or other Gram -ves;
      • Risk of pseudomembranous colitis limits use;
    • Clindamycin:
      • A semi-synthetic derived from lincomycin;
      • Active against Gram +ve aerobes & most anaerobes but causes diarrhoea
      • Role in Mx of Toxoplasma gondii infection;

  *Can also be used topically in Rx of acne;

bind to 30S ribosomal subunit:

  • Tetracyclines:
    • bacteriostatic, broad spectrum for many Gram +ves, -ves, some anaerobes, rickettsiae, chlamydiae, mycoplasmas, L-forms, some protozoa (eg. amoebae).
    • uses: atypical pneumonia, PID, acne, malaria
    • clarithromycin & other macrolides inhibit the p-glycoprotein pump resulting in decreased amount of digoxin pumped back into gut & thus risk of acute digoxin toxicity
  • Aminoglycosides:
    • bactericidal group originally obtained from Streptomyces species
    • ototoxic & nephrotoxic if high dose or prolonged use
    • active mainly against enteric Gram -ve bacteria
    • uses: septicaemia, endocarditis
      • eg. gentamicin, tobramycin, netilmicin
    • topical agents (these also active against Gram +ves but not Strept)
      • eg. neomycin, framycetin, kanamycin
    • anti-tuberculous:
      • eg. streptomycin
    • Examples:
      • Gentamicin:
        • wide Gram -ve spectrum incl. Pseudomonas aeruginosa
        • aminoglyc. of choice for most hosp. acquired aerobic Gram -ve sepsis
      • Tobramycin:
        • marginally more antipseudomonal than gentamicin
        • restricted use & ? if suspected pseudomonal sepsis;
      • Netilmicin:
        • more resistant to enzymatic degradation than genta/tobramycin
      • Amikacin:
        • most resistant to enzymatic degradation - 20x more costly than gentamicin
        • reserved for resistant cases only
      • Streptomycin:
        • available under SAS for Rx of TB.

drugs that inhibit bacterial DNA synthesis:

Quinolones:
  • synthetic fluotinated analogues of nalidixic acid (see under urinary antiseptics)
  • active against a variety of Gram -ves & +ves by inhib. of DNA gyrase
  • activity includes Enterobacteriacaea, Pseudomonas, Neisseria, and at higher levels, Staph, Legionella, Chlamydia & some mycobacteria with anaerobes being less susceptible.
  • uses: UTI, infectious diarrhoea (Shigella, Salmonella, toxigenic E.coli) Helicobacter, PID, & have also been used in soft tissue, bone & joint infections
  • eg. norfloxacin, ciprofloxacin, ofloxacin
  • may cause tendinitis & tendon rupture, especially in older patients on corticosteroids, or in your patients with prolonged Rx (> 1 month)
Folate antagonists
  • inhibit folate formation & thus purine synthesis
  • Sulphonamides:
    • competitive with PABA for dihydropteroate synthase which converts PABA to dihydrofolic acid
    • broad spectrum but resistance is now common
    • rickettsiae are STIMULATED by sulphonamides!!
    • excreted renally, may ppt in acid urine
    • cause haemolysis in pts with G6PD defic.
    • increase risk of kernicterus in neonates
    • inhibits metabolism of sulphonylureas by CYP2C9 & thus may cause hypoglycaemia in diabetics on these medications
    • uses: 
      • UTI, otitis media, chlamydia (not 1st choice)
        • eg. sulphamethoxazole + trimethoprim
      • nocardiosis (1st line)
        • eg. sulfisoxazole, sulphadiazine
      • dermatitis herpetiformis
        • eg. sulphapyridine
  • Dihydrofolate reductase inhibitors:
    • inhibits dihydrofolate reductase which converts dihydrofolic acid to tetrahydrofolic acid
    • often used with a sulphonamide (eg. sulphamethoxazole)
    • bacterial: trimethoprim
      • uses: UTI's
    • protozoal: pyrimethamine
      • uses: falciparum malaria, toxoplasmosis, leishmaniasis

Nitroimidazoles:

  • Metronidazole:
    • unknown mechanism of action
    • A deriv. of the substituted imidazole compounds;
    • Good oral/rectal absorption means that oral/supp. preps can often be used instead of IV.
    • Specific bactericidal activity against important obligate anaerobes:
      • Gram +ve anaerobes eg. Clostridium
      • anaerobic protozoa eg. Trich. vag., Giargia lamblia, Entamoeba histolytica;
  • Tinidazole:

  *as for metronidazole, but:

  • can be given as a stat dose or short course for many indications
  • longer T1/2;

urinary antiseptics:

Nitrofurantoin:

  • not active against Pseudomonas or many strains of Proteus
  • activity greatly enhanced at low pH → often given with acidifying agents
  • clinical drug resistance emerges slowly
  • A synthetic antibacterial nitrofuran derivative mainly used to Rx UTIs;
  • As does not reach effective plasma levels, it is not indicated for cortical or perinephric abscesses, or prostatitis.
  • Bacteriostatic at low concentrations & bactericidal at high concentrations;
  • ? interferes with several bacterial enzyme systems.
  • Active against Gram +ve & Gram -ve UTI pathogens except Pseudomonas, & some Klebsiella, Aerobacter & Proteus species.

  *C/I in infants < 1mth old as may cause haem. anaemia;

Nalidixic acid:

  • the 1st antibacterial quinolone.
  • excreted too rapidly for systemic effects
  • similar activity against Gram -ves as for nitrofurantoin but resistance emerges rapidly during treatment
  • may cause false +ve tests for glycosuria but also may cause hyperglycaemia
  • Antibacterial via inhib. bacterial DNA synthesis.
  • Active esp. against Gram -ves except Pseudomonas, hence mainly used for UTI's;
  • C/I - PH convulsive disorders; prepubertal children (causes arthropathy);

  *Avoid sunlight as photosensitisation may occur. Methenamine mandelate & methenamine hippurate:

  • bactericidal if urine pH kept < 5.5 as methenamine releases formaldehyde
  • sulphonamides must not be given as insoluble compound may form.

miscellaneous antibiotics:

Colistin:

  • Useful against sensitive strains of Gram -ves but not Proteus or Neisseria;

Fusidic acid:

  • A potent antibiotic derived from the fungus Fusidium coccineum.
  • Inhib. bacterial protein synthesis by preventing translocation on the ribosome.
  • Effective mainly against Gram +ves, esp. Staph, incl. penicillinase-producing strains;

  *Resistance may develop.   *Monitor LFT's if high doses or prolonged course;

Spectinomycin:   *An aminocyclitol antibiotic produced by Streptomyces spectabilis;   *Unrelated to other antibiotics;   *Used as a single dose Rx of N. gonorrhoeae with ~95% success rate;

antibiotics.txt · Last modified: 2013/12/27 22:57 by gary1