Table of Contents
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:
- 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%
- 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.
- 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
- 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
- broad spectrum against many Gram +ves, -ves & anaerobes
- reserved for ICU use
- 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:
- 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
inhibitors of bacterial protein synthesis:
bind to 50S ribosomal subunit:
- bacteriostatic for many bacteria & rickettsiae
- 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)
- 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
- 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
- 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
- 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;
- 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:
- 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
- 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
- eg. streptomycin
- wide Gram -ve spectrum incl. Pseudomonas aeruginosa
- aminoglyc. of choice for most hosp. acquired aerobic Gram -ve sepsis
- marginally more antipseudomonal than gentamicin
- restricted use & ? if suspected pseudomonal sepsis;
- more resistant to enzymatic degradation than genta/tobramycin
- most resistant to enzymatic degradation - 20x more costly than gentamicin
- reserved for resistant cases only
- available under SAS for Rx of TB.
drugs that inhibit bacterial DNA synthesis:
- 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
- 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
- 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
- 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;
*as for metronidazole, but:
- can be given as a stat dose or short course for many indications
- longer T1/2;
- 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;
- 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.
- 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
- Useful against sensitive strains of Gram -ves but not Proteus or Neisseria;
- 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;