Widespread and often inappropriate use of antibiotics has led to increasing numbers of organisms with multiple drug resistance. Antibiotics are not required for minor infections. Although the majority of antibiotics are relatively safe drugs, important toxic effects do occur when used in the incorrect dosage and in the presence of other disease states, notably renal disease. In addition, antibacterial therapy may result in secondary yeast or fungal infection or may facilitate the growth of a second bacterial pathogen, such as Clostridium difficile, an important cause of antibiotic-associated colitis.
Choice of drug
BLIND THERAPY. Antimicrobial therapy is often begun before the organism is identified and its antibiotic sensitivities known. The choice of drug(s) is therefore dependent on a clinical diagnosis and a knowledge of the organisms likely to be involved in a given situation. Before beginning ‘blind’ therapy it is essential to obtain appropriate body fluids or other specimens for microbiological examination. Adjustments to the antibiotic regimen can then be made, if necessary, when antibiotic sensitivities are available.
SPECTRUM OF ACTIVITY. The spectrum of antibacterial activity of the drug chosen should ideally be as narrow as possible, as it will then have fewer detrimental effects on the normal bacterial flora of the host. ‘Blind’ therapy, however, by necessity generally covers a broader spectrum than required.
BACTERICIDAL vs. BACTERIOSTATIC. In the majority of infections there is no firm evidence that bactericidal drugs (penicillins, cephalosporins, aminoglycosides) are more effective than bacteriostatic drugs, but it is generally considered important to use the former in the treatment of bacterial endocarditis and in patients in whom host defence mechanisms are compromised.
PATIENT FACTORS. In addition to age and pregnancy, the following factors should be considered.
1 The site of infection. The chosen drug must be able to gain access to the part of the body involved. The brain, eye, biliary tract, prostate and loculated abscesses are inaccessible to many drugs.
2 Renal and hepatic function. Impaired renal or hepatic function necessitates a major modification of the dose regimen or even complete avoidance of certain drugs. Care should be taken when using aminoglycosides, ticarcillin, flucytosine and some antimycobacterial agents in patients with renal impairment. Other drugs, such as nalidixic acid and tetracycline, should be avoided altogether.
This is influenced by the type of infection to be treated and the age of the patient. Bacterial endocarditis and deep-seated abscesses (e.g. in brain or lung) generally require high-dose therapy for several weeks.
Route of administration
Some drugs (e.g. some of the cephalosporins) are only available as intravenous preparations, but many antibiotics are well absorbed by the oral route and in the absence of severe infection such as septicaemia there is no advantage to the patient for therapy to be adrninistered by the more expensive parenteral route. Patient compliance must, however, be taken into account.
Duration of therapy
With more potent drugs, only short courses or even single doses may be required, e.g. uncomplicated urinary tract infection, gonorrhoea.
In serious infections (e.g. infective endocarditis), monitoring of circulating drug concentrations is routinely performed for assessing efficacy of treatment. Drug concentrations can be measured directly in serum, but the efficacy of therapy is usually determined by serum bactericidal assay just before and at a standard time after admirIistration of antibiotics. The highest dilution of serum that completely kills the causative organism can then be determined. The clinical value of serum bactericidal assays is still debated.
Monitoring for toxicity is particularly important with the aminoglycoside antibiotics. Concentrations are determined immediately before (‘trough’ levels) and usually 1 hour after (‘peak’ levels) of the drug. High ‘trough’ levels of >2 mg ml-1 are considered to be the most important factor in causing the ototoxicity and nephrotoxicity commonly seen with these agents. The ‘peak’ level should be 5-10 mg ml ” to be therapeutically effective.
CombirIation antibiotic therapy
Combinations of antibiotics are commonly used in the empirical treatment of many serious infections such as septicaemia, meningitis, tuberculosis and endocarditis, but some care must be taken in the choice of drugs within such combinations. There is still some concern that a combination of a bactericidal and a bacteriostatic antibiotic may impair their therapeutic efficacy. However, this concept is by no means universally applicable, since
the bacteriostatic drug tetracycline and the bactericidal drug rifampicin are thought to be synergistic. Generally, combinations of bactericidal drugs are at least additive and in some situations are synergistic, whereas combinations of bacteriostatic drugs are generally only additive.
MECHANISMS OF RESISTANCE TO ANTIMICROBIAL AGENTS
The development or acquisition of resistance to an antibiotic by bacteria invariably involves a mutation at a single point in a gene or transfer of genetic material from another organism (Fig. 1.4). Single-point mutations occur in E. coli, for example, at the rate of approximately 1 per 105_107 cell divisions. A mutation resulting in antibiotic resistance by this mechanism would involve alteration of a single nucleotide base. Larger fragments of DNA may be introduced into a bacterium either by transfer of ‘naked’ DNA or via a bacteriophage (a virus) DNA vector. Both the former (transformation) and the latter (transduction) are dependent on integration of this new DNA into the recipient chromosomal DNA. This requires a high degree of homology between the donor and recipient chromosomal DNA.
Finally, antibiotic resistance can be transferred from one bacterium to another by conjugation, when extrachromosomal DNA (a plasmid) containing the resistance factor (R factor) is passed from one cell into another during direct contact. Transfer of such R factor plasmids can occur between unrelated bacterial strains and involve
large amounts of DNA.
Transformation is probably the least clinically important mechanism, whereas transduction and R factor transfer are probably the most important for the sudden emergence of multiple antibiotic resistance in a single bacterium. Increasing resistance to many antibiotics has developed.