Specialty: Other
Compare the mechanisms of action and side effects of aminoglycosides and beta-lactam antibiotics. Discuss how these antibiotics should be administered so as to achieve maximal anti-bacterial activity and list side-effects
Rationale: .Aminoglycoside antibiotics
Aminoglycosides kill bacteria by interfering with ribosomal function and thus disrupting the production of proteins in the cell.  The killing power of the aminiglycoside is directly related to the peak level of antibiotic that is achieved.  The higher the peak achieved, the more effectively the antibiotic kills sensitive bacteria.  This has major implications in patients with a a high volume of distribution (premature infants, critically ill patients, oedematous patients) where is it difficult to achieve a high peak level without the drug then being present in the system for a long time with subsequent nephro and ototoxicity.

Aminoglycosides do not penetrate well into areas such as the Central nervous system.  They do not work well within the acid environment of abscess cavities.  They are concentrated in the kidneys and excreted through this route.  Consequently they easily achieve very high levels in the urine and this makes them ideal for the therapy of renal tract infections.

Aminoglycosides demonstrate the “post-antibiotic effect” whereby the killing or inhibition of growth of bacteria persists even after the antibiotic has been removed from the system.  Thus even if the antibiotic levels drop to virtually non-existent levels, bacterial regrowth will not start to take place for a reasonable period of time.

Aminoglycosides have a relatively short half life in the context of normal renal function.  However they may remain in the circulation for long periods of time in patients with renal failure.

The toxicity of the aminoglycosides relates to their uptake into the renal and hearing systems.  With increasing level of antibiotic the rate of uptake increases until a threshold level.  Thereafter there is no increase in the rate of antibiotic uptake.  Thus thus the toxicity of the aminoglycosides to the inner ear and the kidney depends on the duration of time that the antibiotic is in the circulation and particularly when levels are at or above the threshold level.

The optimal use of aminoglycosides  requires the achievement of very high peak serum levels together with rapid clearance of the antibiotic and relatively long periods when virtually no antibiotic is present in the circulation.  This would achieve optimal bacterial killing with minimal toxicity. This means that optimal dosing for maximal antibacterial activity may be infrequent, with once daily administration of the agents shown in almost all cases to be equivalent to or superior to twice daily administration for bacterial killing.  

The antibiotic needs to be given quickly (most commonly 30  minutes to 1 hour is the recommended rate of administration).  Given more rapidly the aminoglycosides may interfere with neuromuscular transmission with consequent weakness.  Levels should be taken within 30 minutes of the end of the infusion to check that optimal peak levels have been obtained.

Trough levels should be taken just before administration of the next dose.  The higher the trough level, the higher the chances of toxicity.  If trough levels are high it may be more appopriate to use other agents, rather than to reduce the dose or increase the dose interval.

Clearly it is not optimal to use these agents in patients with renal failure as:
Poor peak levels are likely in the face of high body water (with poor bacterial killing)
Poor renal clearance will mean that the drug remains in the circulation for long periods with maximum chances of toxicity.

Prolonged use of the aminoglycosides is likely to be associated with increased toxicity

Use of the aminoglycosides together with other nephrotoxic agents may potentiate any problems of toxicity.

Beta-lactam antibiotics
Beta-lactam antibiotics have their effect on the cell wall of bacteria.  The agents interfere with synthesis of the cell wall causing bacterial lysis.  The effects are dose dependent until they are at a threshold level.  Once above the level at which killing of bacteria takes place increases in the level do not increase the killing of bacteria.  If the antibiotic is removed from the system bacterial killing ceases and regrowth may occur.  

Beta lactams are generally excreted via the renal system with ceftriaxzone an exception that is excreted into the biliary system.  Drug half-life is short although longer in neonates, and prolonged in renal failure.  Many of these agents are metabolised in the liver.

Thus from a bacterial killing point of view the agents should be kept above the bactericidal level at all times.  This is best achieved by regular small doses (i.e giving the agents 4-6 hourly), with the possible adjunct of agents such as probenecid that may decrease the renal elimination of the antibiotic.

Toxicity of the beta-lactams is either related to hypersensitivity reactions (anaphylaxis, Stevens Johnson syndrome, dermatitis) or to high serum levels (CNS irritation with convulsions and depressed level of consciousness).  There is thus no benefit in trying to achieve very high serum levels, as these increase the risks of toxicity and carry no increased bacterial killing.  Higher serum levels may be required to ensure that the drug crosses the blood brain barrier or gets into inflamed tissue at the required levels for bacterial killing.

Agents such as ceftriaxzone are highly protein bound with the result that the free drug is very slowly released into the system.  It is thus possible to achieve excellent bacterial killing despite infrequent dosage of the antibiotic.

Combination therapy
As the two agents work via different pathways they may be used synergistically in patients with severe infection or compromised immunity.  This may also help to reduce the incidence of resistant organisms.