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.
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penicillins:
Narrow spectrum:
mainly active against Gram +ves, Neisseria & enterococci
Beta lactamase resistant:
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:
monobactams:
carbapenems:
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:
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:
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
topical agents (these also active against Gram +ves but not Strept)
anti-tuberculous:
Examples:
Gentamicin:
Tobramycin:
Netilmicin:
Amikacin:
Streptomycin:
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
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:
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:
miscellaneous antibiotics:
Colistin:
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;