An antibacterial drug kills or inhibits a bacterium by interfering with some vital process. Any one drug is effective against only some bacterial groups and species, and usually against only some strains of any given species. The remaining bacteria owe their resistance to:
(1) Impenetrability of their outer layers to the drug.
(2) Lack of any important metabolic process to which the drug has any relevance for example sulphonamide resistance due to possession of a dihydrofolic acid reductase which does not 'confuse' sulphonamides with PABA .
(3) Ability to destroy the drug or convert it into an inactive form for example penicillinases (β-lactamases), which open up the β-lactam rings of penicillins and to variable extents also of cephalosporins; or the acetyltransferases by means of which some bacteria can acetylate chloramphenicol. Since the bacteria that produce such enzymes are as a rule intrinsically sensitive to the drug, their resistance may not be manifested when small numbers of them are exposed to an adequate concentration of the drug without being given time to produce enzyme; this is particularly the case when the enzyme is inducible rather than constitutive.
Even when an antibacterial drug is first introduced, the existence of naturally resistant bacterial species and strains places limits on its usefulness. However, there can have been few pathogenic bacteria in circulation 30 years ago which could have survived the onslaught of our present-day armoury of drugs if these had all become available at once. Many of our modern therapeutic problems are due to the fact that in most cases the introduction of a new drug has been followed by proliferation of bacterial strains resistant to it. Staphylococcus aureus has been notably successful in keeping pace with new discoveries. In relation to penicillin it is thought that evolution of new strains has played a relatively small part, the increase in frequency of penicillin-resistant Staphylococcus aureus and other species is largely due to existing resistant strains as their more sensitive colleagues were eliminated. But with most other drugs sensitive strains give rise to rare resistant mutants; these normally have no particular survival value, but in the presence of an appropriate concentration of the drug in question they alone are able to multiply, giving rise to a new strain with increased drug resistance.
For a superficial infection of the skin or an accessible mucous surface it may be possible to apply the drug in high concentration directly to the lesion; but unfortunately such topical application, notably of the penicillins, is particularly liable to provoke a hypersensitivity reaction and so to deprive the patient of subsequent systemic use of the group of antibiotics in question. A different form of local application that gives less trouble and is sometimes indicated is direct injection into a body cavity:
Oral administration is possible only if the drug can be produced in a palatable form; if it survives the action of the gastric secretions or it can be protected from it in capsules that dissolve in the small intestine; if it does not provoke significant gastro-intestinal upset; and above all if it is reliably absorbed into the blood (unless its site of action is to be the bowel lumen) and passes through the liver without being inactivated. Sometimes an ester or other derivative, itself not an effective antibacterial drug, meets all of these requirements and is converted into the active form after absorption. Oral preparations have, in addition to their unsuitability for patients who are vomiting or cannot swallow, the disadvantage that their absorption may be unreliable in very ill patients, in whom it is particularly important to achieve good levels rapidly and consistently.
Some antibacterials, notably metronidazole, are well absorbed when given as rectal suppositories, provided that the patient does not have diarrhoea.
Parenteral that is non-alimentary administration is usually intramuscular or intravenous. For intramuscular injection it is necessary to produce a strong solution (so that the volume is tolerable) which is of physiological pH and which does not cause excessive pain, or damage the injected muscle; this is not possible for some antibiotics. Also, having been injected, the drug must be rapidly and reliably absorbed into the blood (unless it is deliberately given as a slow-release depot preparation, as is sometimes done with penicillin). Intravenous injection or infusion is in some ways the ideal way of getting a drug into the blood, but it is seldom the most practicable or convenient. Furthermore, some drugs are difficult to give repeatedly by this route because they cause local phlebitis and thrombosis and a consequent shortage of accessible veins.
Once in the blood-stream, drugs vary in their distribution to tissues and body fluids and in their renal handling, and therefore a high blood level is no guarantee of good tissue levels. Indeed, a high and sustained blood level could well be due to the drug's inability to get out of the blood! Part of this variability in tissue penetration is related to differences in binding to plasma proteins. Virtually all antibacterials are bound to some degree, but some very much more than others— even others in the same group. Bound drug is in general no longer active against bacteria, so two drugs may give comparable total blood levels but with one mostly bound and inactive and the other mostly free and active. There is a reversible equilibrium between bound and unbound drug, but it may be only the unbound portion that is free to diffuse out of the circulation—and even then its troubles are by no means over, as it may bind to tissue proteins.
Rapid excretion of an antibacterial drug by the kidneys may make it highly suitable for dealing with urinary tract infections, provided that it is not, like chloramphenicol, excreted mainly in an inactive form. Such rapid excretion also necessarily means that blood and tissue levels are not well sustained—which may be an advantage, as we shall see below, under. Conversely, persistent high levels will be achieved if a drug that is not excreted in bile or metabolized in the liver or elsewhere is only slowly excreted by the kidneys— either because of its nature or because of renal failure.
Antibacterial drugs also vary widely in their ability to pass into body fluids other than urine. For example, sulphadiazine or chloramphenicol levels in cerebrospinal fluid are usually 40-80% of the prevailing blood levels. On the other hand, only traces of the penicillins or of streptomycin reach the cerebrospinal fluid from the blood if the meninges are healthy, though much larger amounts go through and much higher cerebrospinal fluid levels are achieved when the meninges are inflamed. Similarly, when ampicillin is used in treatment of suppurative chronic bronchitis it may pass fairly readily into the sputum at first, but as the infection is brought under control and the sputum ceases to be purulent its ampicillin content falls sharply. However, penetration of the closely related drug amoxycillin into sputum is far less dependent upon local inflammation. Penicillin given to pregnant women may reach much higher concentrations in the liquor amnii than in the maternal blood; yet streptomycin, the tetracyclines and chloramphenicol hardly penetrate to the liquor at all. These examples indicate something of the complexity of a subject which is of great clinical importance but is far from being thoroughly understood.
Has a vast experience in medical bacteriology