GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY Selection of a suitable drug

GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY

Selection of a suitable drug

Bacterial sensitivity Antibacterial drugs are often used unnecessarily and sometimes (as in uncomplicated diarrhoea) when they are clearly contra-indicated. However, when antibacterial therapy is essential, there is a rational basis for deciding which antibacterial drug to use in a specific case. For time-dependent bactericidal drugs and bacteriostatic drugs, the aim of therapy is to maintain an effective concentration of the drug at the site of infection to ensure eradication of the causal organisms. An effective concentration is defined as that sufficiently in excess of the minimum inhibitory concentration (MIC) of the drug to be effective for sufficient time to inactivate the causal microorganisms. Effective therapy is thus dependent on the susceptibility of the micro-organisms to the drug and the pharmacokinetics which determine its ability to attain and maintain effective concentrations at the infection site. Except in the rare cases where sensitivity data are available, assessment of the potential sensitivity of the microorganisms concerned depends firstly upon accurate clinical diagnosis and secondly upon the knowledge that these are the micro-organisms likely to be implicated and of their susceptibility to antibacterial drugs. Fortunately, detailed knowledge of MIC values is not required because microbial sensitivity to a drug can be expressed in terms of the concentrations attained in body tissues. A micro-organism will be deemed ‘sensitive’ to a drug if, following administration according to the recommended dosage regimen, tissue concentrations are likely to be in excess of the MIC for that micro-organism for a major part of the time between doses.  Having narrowed the list of possible drugs to those likely to be active against the micro-organism or micro-organisms concerned, the final choice is based on the following criteria.

Species, breed, and age differences affect an animal’s ability to eliminate antibacterial drugs; the following of which are examples. Cats are less able than other species to metabolise chloramphenicol, which may accumulate following prolonged administration in this species. The young of all species are similarly deficient in their ability to metabolise drugs. Antibacterial action can disrupt bacterial fermentation and therefore animals with a functional rumen should not be given broad-spectrum antibacterials by mouth. Many antibacterials and particularly tetracyclines by any route may be associated with a fatal enterocolitis in horses subjected to stress. Penicillins, macrolides, and lincosamides should not be administered to gerbils, guinea pigs, hamsters, or rabbits in which they are likely to cause a fatal enterotoxaemia.

Predisposition to toxicity Certain conditions may exacerbate the toxicity of antibacterial drugs; the following are examples. Renal disease may predispose animals, especially cats, to the toxic effects of aminoglycosides because they are eliminated solely by renal excretion and so will accumulate in renal failure. Tetracyclines are contraindicated in bitches and queens in late pregnancy when they may cause enamel defects and discoloration in the offsprings’ milk teeth. In growing dogs and cats, fluoroquinolones may cause an arthropathy.

Site of infection Special considerations apply to the treatment of infections at particular sites. For example, antibacterials such as chloramphenicol and the macrolides are extensively metabolised and so are not used to treat urinary tract infections. For these infections, drugs that are excreted unchanged in the urine are preferred. In addition, in the treatment of urinary-tract infections it is important to choose a drug with actions that are favoured by the prevailing urinary pH to maximise efficacy. In particular, aminoglycosides are much more active in alkaline urine. Some body compartments, notably the brain and the internal structures of the eye, are penetrated only by lipophilic drugs that are able to cross intact cell membranes. Permeability is increased by inflammation. Although chloramphenicol and sulphonamides normally enter the brain, ampicillin and doxycycline do so only in the presence of inflammation. Similarly, milk is separated from the general circulation by an intact membrane through which only the nonionised lipophilic form of a drug may pass. When the nonionised form of a basic drug such as a macrolide enters the relatively acidic milk it dissociates and so becomes trapped resulting in high concentrations in milk – the so called ‘iontrap’. Conversely, acidic drugs such as benzylpenicillin are largely excluded from the healthy udder. Both factors cease to operate in the presence of inflammation so that drugs penetrate the acutely inflamed mammary gland to the same extent as any other inflamed tissue.

Mode of antibacterial action As noted with individual groups of drugs, some are bactericidal, that is they are able to kill bacteria, whereas others are bacteriostatic, only inhibiting multiplication and hence relying upon host defences to clear the infection. Although the advantages of bactericidal drugs have probably been exaggerated in the past, there are certain situations in which their use is essential. These include the treatment of endocarditis, and in cases of immunosuppression occurring either naturally or due to administration of corticosteroids.

Antibacterial policy It is essential that antibacterials are given according to a predetermined policy in order that efficacy may be monitored. Changes in resistance patterns in a particular area should be noted and therapy altered accordingly.

Before commencing therapy

The dose of an antibacterial drug expressed as weight of drug per kg body-weight will vary with a number of factors including intercurrent disease, severity of the infection, and size of the animal. In serious infections high doses are administered more frequently. Depot preparations are long-acting but attain relatively low plasma-drug concentrations; they are not suitable for the treatment of severe acute infections. In general, the larger the animal the smaller the dosage per unit body-weight.

The dosing regimen used should also reflect the mode of action of the antibacterial drug. For bactericidal drugs, such as beta-lactams, which operate time-dependent killing mechanisms, and bacteriostatic drugs, it is important to maintain tissue concentration of the drug above the MIC for as long as possible during the inter-dosing interval. For bactericidal drugs, such as aminoglycosides and fluoroquinolones, which operate concentration-dependent killing mechanisms, the most successful dosing regimen is one which produces a peak tissue concentration of the drug which greatly exceeds the MIC value for the bacterium and the time the concentration of the drug is above the MIC is much less significant.

The duration of therapy depends upon the nature of the infection and the response to treatment. In general, therapy should continue for 2 to 3 days beyond the clinical cure for acute infections and for 1 to 2 weeks beyond the clinical cure for chronic infections. However, this guidance does not apply in all instances. For example, acute cystitis in the bitch often responds very quickly to antibacterial drugs (24 to 48 hours) but if treatment is not continued for 7 to 10 days, relapses may well occur. This more extended period of treatment allows the important mucosal defence mechanisms within the bladder to heal fully and therefore be effective in preventing re-infection when the treatment stops. Clinical experience has shown that some chronic infections may require more prolonged duration of therapy (for example, deep pyodermas, chronic prostatitis and osteomyelitis in dogs). Empirically, therapy for 4 to 6 weeks may be required in these cases.

The route of administration depends upon the severity of the disease and ease of administration. In the treatment of severe infections it is advantageous to give the initial dose by the intravenous route in appropriate cases. In companion animals subcutaneous injection may be preferred to the more painful intramuscular route. In order to attain effective concentrations in the cerebrospinal fluid, an initial intrathecal injection may be administered. However, penicillins should not be administered by the intrathecal route because seizures may result.  Although oral medication given with food is often convenient, it may considerably reduce the amount of drug absorbed. For example, ampicillin (unlike amoxicillin) is poorly absorbed in dogs if administered following a meal. Milk, iron salts, and antacids all interfere with the absorption of tetracyclines from the gastro-intestinal tract. However, in some cases, for example ketoconazole, administration with food will reduce side-effects such as nausea. In other cases, giving the drug with food is important to aid in its absorption, for example griseofulvin is highly lipid soluble and requires biliary secretion to allow optimal absorption from the gastro-intestinal tract.