antibiotics

see also:

• clinically important bacteria
• penicillins
• cephalosporins
• tetracycline antibiotics
• macrolide antibiotics
• aminoglycoside antibiotics
• flouroquinolone antibiotics
• antibiotics used to treat TB
• antibiotics for Rx of Staph. aureus
• Urinary Antiseptics
• antibiotic doses for peritoneal dialysis patients
• antibiotic resistance
• RCH guidelines - 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.
  • Aust Presc 2007 - Cross-reactivity of penicillins and cephalosporins

• 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

• 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

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

• see carbapenem antibiotics
• 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.
• meropenem

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

• 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;

• 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.

• 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

• 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;

• 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.

• 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)

• 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

• 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;

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.

fosfomycin

• a novel class of antibacterial drugs with a chemical structure unrelated to other known antibiotics
• a bactericidal drug that disrupts cell wall synthesis by inhibiting phosphoenolpyruvate synthetase and thus interferes with the production of peptidoglycan
• broad spectrum of activity against both gram-positive and gram-negative organisms, including many antibiotic-resistant organisms such as MRSA, VRE, ESBL and fluoroquinolone-resistant E. coli
• low oral bioavailability results in serum levels which are low relative to the minimum inhibitory concentrations (MICs) hence suitable for Rx of UTIs but not as good for pyelonephritis.
• dose in adults for uncomplicated UTI in women:
  • single dose of 3g orally dissolved in water
  • longer Rx needed for prostatitis

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;