Rational Antimicrobial Therapy--How to Choose the Best Drug for Your Patient
The goal of antibacterial therapy is to help the body eliminate infectious organisms without toxicity to the host. It is important to recognise that the natural defense mechanisms of a patient are of primary importance in preventing and/or controlling infection. The difficulty of controlling infections in the immunocompromised patients emphasizes that antibacterial therapy is supplementary rather than a magic "cure all".
Factors Influencing the Clinician's Choice of Antibacterial Drug
Antibacterial agents should only be used if bacterial/fungal infection has been definitively diagnosed or is a likely diagnosis. Do not prescribe antibacterials for every clinical problem and in lieu of a diagnosis.
Although ideally culture and sensitivity should be performed before initiating antibacterial therapy, this may not be practical, often for economic reasons. In these situations the clinician should prescribe based on the most likely organisms to be pathogens in that site. However if therapy fails or immediately recurs once therapy has ceased, culture and sensitivity is strongly recommended.
The clinician should also consider the possibility that other factors are impairing therapy e.g., the presence of urinary calculi, foreign body, the need for surgical drainage. The clinician should also ensure that the client understands dosing instructions and is able to administer medication--demonstrate tablet administration if necessary.
Is a bacterial infection confirmed or probable?
Can you predict the type of infection and sensitivity pattern?
Are there any special considerations re tissue penetration?
Are there any potential side effects of concern?
Is a culture and sensitivity indicated?
Classification of Antibacterial Drugs
Antimicrobial drugs can be classified in various ways--by their mechanism action, by the method by which they suppress bacterial growth and by the spectrum of activity.
Mechanism of Action
The four major categories of antibacterial agents exert their antibacterial action through:
Inhibition of cell wall synthesis--penicillins, cephalosporins, bacitracin
Inhibition of cell membrane function--polymyxins, amphotericin B, imidazoles, nystatin
Inhibition of protein synthesis--chloramphenicol, erythromycin, lincomycin, tetracyclines, aminoglycosides
Inhibition of nucleic acid synthesis--sulphonamides, trimethoprim, quinolones
Methods of Bacterial Suppression/Killing
Antibacterial agents are often described as bacteriostatic or bactericidal.
Bacteriostatic drugs e.g., tetracyclines, chloramphenicol, sulphonamides temporarily inhibit the growth of an organism but the effect is reversible once the drug is removed. For these drugs to be clinical effective the drug concentration at the site of the infection should be maintained above the minimal inhibitory concentration (MIC) throughout the dosing interval.
Under ideal conditions, bactericidal drugs (aminoglycosides, cephalosporins, fluoroquinolones, metronidazole, penicillins, potentiated sulphonamides) cause the death of the microbe. These are preferred in infections that cannot be controlled or eradicated by host mechanisms, because of the nature or site of the infection (e.g., bacterial endocarditis) or because of reduced immunocompetence of the host (e.g., patient with immunosuppressive illness or receiving immunosuppressive therapy). However, successful clinical outcomes are reported in humans with gram-positive meningitis, endocarditis and osteomyelitis treated with bacteriostatic drugs such as clindamycin. For gram-positive infections, the susceptibility of the organism and the ability of the drug to penetrate and concentrate in infected tissue are often more important predictors of a successful clinical outcome than whether the drug is bactericidal or bacteriostatic.
Bactericidal drugs are further classified as time-dependent or concentration-dependent drugs. Time-dependent drugs (penicillins and cephalosporins) are slowly bactericidal. Plasma levels should be above MIC for as long as possible during each 24 hour period although no strict guidelines on the exact percentage of time required have been established. For these drugs there is little or no advantage (regarding proportion of pathogens killed or duration of post-antibacterial effect) in achieving a peak plasma concentration (Cmax) greater than 2-4 times MIC.
For concentration-dependent drugs (aminoglycosides and fluoroquinolones) the peak concentration achieved (aminoglycosides, fluoroquinolones) and/or the area under the plasma concentration versus time curve (fluoroquinolones) predicts antibacterial success. For these drugs the higher the peak plasma concentration, the greater the proportion of target bacteria killed, the longer the post-antibiotic effect. The Cmax/MIC ratio is predictive of success of treatment--optimal regimens achieve a ratio greater than 8:1.
Predicting the Bacteria Present
When the clinician has answered the first key question--"Is a bacterial infection confirmed or probable?" in the affirmative, the next key question is--"Can you predict the type of infection and sensitivity pattern?" Predicting the type of infection involves consideration primarily of the presumed site of infection. It may be possible to predict the most common bacterial species that infect this site (e.g., E. coli for urinary tract infections, Staphylococcus sp. for skin infections). In other cases it can be possible to predict the most common group of bacteria (e.g., obligate and facultative anaerobes in pyothorax and abscesses, gram-negative plus anaerobes for suppurative cholangiohepatitis). And in other cases it is not possible to predict the likely bacteria or one wishes to cover as many bacterial groups as possible while awaiting culture and susceptibility data.
Many texts list (appropriately) the bacterial species that are sensitive to various antibacterials--these lists are usually organized by class of antibacterial and are useful if one has identified the species of bacteria or can be reasonably confident of the species most likely to be causing an infection in a patient.
However, often we do not know the bacterial species we wish to treat. It is for this reason that it is often useful to consider the spectrum of antimicrobial action related to broad categories of bacteria. Bacteria can be classed based on their staining properties (gram-negative or gram-positive or other) and on the environment in which they grow--i.e., aerobic, anaerobic and facultative anaerobic. Combining these factors can give a useful classification which helps select the most appropriate antimicrobial drug when culture and sensitivity information is not available.
The most practical classification in small animal practice is as follows:
Gram-positive aerobic bacteria (and facultative anaerobes)
Gram-negative aerobic bacteria (and facultative anaerobes)
Obligate anaerobes--both gram-negative and positive
The reason for this grouping is that there are some predictable differences between the sensitivity of gram-negative and gram-positive aerobic bacteria but there are no predictable difference between gram-negative and gram-positive anaerobic bacteria. In addition, due to its ability to produce penicillinase, Staphylococcus can have a very different sensitivity compared with other gram-positive aerobic bacteria.
Factors Affecting the Success of Antibacterial Therapy
In general if bacteria are resistant to a drug in vitro it will be resistant in vivo. (An exception is drugs that achieve extremely high concentrations in urine such as penicillins, which may overcome bacterial resistance.) If bacteria are sensitive to a drug in vitro the drug may be effective in vivo depending on other factors.
Distribution to the Site of Infection (Pharmacokinetic Phase)
To be effective an antibacterial agent must be distributed to the site of infection in adequate concentration and come into intimate contact with the infecting organism.
For most, but not all, tissues antibacterial drug diffusion is perfusion limited, i.e., provided the tissue has an adequate blood supply, antibacterial concentrations achieved in serum or plasma are equal to the drug concentration in the extracellular (interstitial) space unless the drug is highly protein bound (uncommon). However, drug diffusion to the central nervous system, eye, epithelial lining of the lung (bronchial secretions), the prostate and mammary gland, is permeability limited, i.e., the lipid membrane provides a barrier to drug diffusion.
An infectious process usually affects the distribution of a drug in vivo adversely. An exception to this is inflammation of the meninges (meningitis) which reduces the normal barrier that exists between the blood and CSF and allows antibacterial agents that normally cannot cross the blood-CSF barrier to gain access to the CSF. This breakdown of membrane barriers as a result of inflammation does not occur to an appreciable extent with the blood-prostatic barrier or the blood-bronchus barrier.
Effective antibacterial concentrations may not be achieved in poorly vascularized tissues for example extremities during shock, sequestered bone fragments and endocardial valves.
Favourable Environmental Conditions (Pharmacodynamic Phase)
Local factors that restrict access of antibacterial agents to the site of infection include abscess formation, pus and necrotic debris (inactivates aminoglycosides) and oedema fluid. The presence of a foreign material in an infected site markedly reduces the likelihood of effective antibacterial therapy--in an attempt to phagocytize and destroy the foreign body, the phagocytes degranulate resulting in depletion of intracellular bactericidal substances. Thus these phagocytes are relatively inefficient in killing bacterial pathogens. In addition, foreign material in a wound can protect bacteria from antibacterial drugs and phagocytosis by forming a biofilm (glycocalix) at the site of infection.
These factors highlight the importance of creating an environment conducive to wound healing and antibacterial action, e.g., appropriate surgical drainage and wound cleansing.
Prophylactic Antibacterials in Surgery
Prophylactic antibacterials in surgery are not indicated for routine, clean surgery where no inflammation is present, the gastrointestinal or respiratory systems have not been invaded, and aseptic technique has not been broken.
Prophylactic antibacterial therapy is indicated after dental procedures in which there has been bleeding (almost all), patients with leucopoenia (viral, drug induced), contaminated surgery and surgery where either the consequences of infection would be disastrous (orthopaedic) or there is major tissue trauma (major thoracic and abdominal surgery).
If prophylactic antibacterial agents are used, they should be administered before the procedure so that adequate levels are present in blood and tissue at the time of surgery--to achieve maximum effect the drug must be present in the wound at the time of bacterial contamination.
The prophylactic advantages of antibacterial therapy are minimal if therapy is commenced any later then 3-5 hours after contamination. Intravenous administration 20-30 minutes prior to surgery is currently recommended.
Therapy is not usually continued for longer than 24 hours postoperatively and in some institutions, a post-operative dose of antibacterial is only administered if the surgery time is greater than 90 minutes.