Relevance of animal models for clinical treatmentCraig, W.
doi: 10.1007/BF02389879pmid: 8477764
The use of animal models has become an integral part of the evaluation of drugs for antimicrobial chemotherapy. Animal models can be used to define the penetration of antimicrobial agents at foci of infections, the time course of in vivo antimicrobial therapy, dose-response relationships, and the influence of therapy on the pathophysiologic consequences of infection. Animal models have been useful in the delineation of many of the basic principles currently used in clinical practice and in the selection of new agents and new therapeutic approaches for clinical trials in humans. In spite of the many positive aspects of animal models, several problems, such as altered pharmacokinetics in animals, can preclude direct application of results to clinical practice. Studies in animal models cannot replace the need for human clinical trials.
The value of new antimicrobial agentsWagenvoort, J.
doi: 10.1007/BF02389878pmid: 8477763
New antimicrobial agents require careful assessment to determine whether they possess the appropriate properties for clinical use. Many new compounds of value in the prophylaxis and therapy of infections have been included in the current armamentarium. Close monitoring to identify possible adverse effects of new agents is essential. Alternative uses of older agents also expands therapeutic opportunities in the combat against infectious diseases. Inappropriate use of antimicrobial agents contributes to the worldwide problem of increasing bacterial resistance. The dramatic spread of such bacterial strains is partially responsible for the rising costs of infectious diseases. A rational and strict antibiotic policy is thus of great importance for the optimal use of these agents.
Basic mechanisms of bacterial tolerance of antimicrobial agentsGoessens, W.
doi: 10.1007/BF02389871pmid: 7682950
Although it has been known for many years that beta-lactam antibiotics inhibit the synthesis of peptidoglycan, it was the phenomenon of tolerance which allowed elucidation of the mode of action of beta-lactam antibiotics particularly with respect to the lysis of the bacteria. By studying tolerant pneumococci it was shown that penicillin triggers the production of autolytic enzymes which degrade the peptidoglycan to such an extent that lysis and killing of cells occurs. Since this discovery many studies have shown that various microorganisms are capable of preventing the lysis and/or killing action of beta-lactams. InStaphylococcus aureus strains, for instance, tolerance appears to be due to the lower specific activity of autolytic enzymes, extracted after exposure to a high concentration of methicillin (64 μg/ml). At these high concentrations of beta-lactams the same strains also show inhibition of RNA and protein synthesis. This inhibition of macromolecular synthesis is probably due to a feed-back mechanism which synchronizes synthesis rates of protein, RNA, peptidoglycan and the activity of autolytic enzymes.
Diseases and drug-related interventions affecting host defenceMarie, S.
doi: 10.1007/BF02389876pmid: 8477761
Recognition of an impaired immune system has implications for the diagnosis, treatment and outcome of infections. Not only the type of immunological dysfunction but also the degree of the dysfunction is important. A review is presented of the systemic diseases and immunosuppressive agents which may result in defects in host defence and associated infections. Especially in transplant patients and patients with HIV infection, knowledge of the stage of the host defence defect is important for the success of prophylactic regimens and for the clinical approach in the event of infection.
Anatomical barriers for antimicrobial agentsBarza, M.
doi: 10.1007/BF02389875pmid: 8477760
It is often suggested that there are substantial anatomic barriers to the passage of antibiotics from the circulation into tissues and fluids of the body. In fact, most capillary beds are fenestrated and allow the passage of antimicrobial agents into tissue fluids fairly readily. At equilibrium, the mean concentrations of free (unbound) antibiotic in plasma and tissue fluids over the dosing interval are equal. However, the time to achieve equilibrium may range from minutes to days, depending on the ratio of surface area to volume of the tissue fluid compartment. There are several sites in the body in which nonfenestrated capillary beds pose appreciable barriers to the diffusion of antibiotics, namely the central nervous system, the eye and the prostate gland. Only lipid-soluble drugs traverse these capillaries readily. If the nonporosity of the capillaries were the only barrier to drug diffusion in these sites, the mean concentrations would eventually be equal to those in the plasma. However, in the central nervous system and the retina of the eye, transport pumps for organic anions combine with the effect of nonporous capillaries to produce concentrations which, even at equilibrium, are lower than those in the plasma. Bulk flow may also play a role in lowering drug concentrations in the cerebrospinal fluid. In the prostate gland, pH partition may cause mean concentrations in the prostatic secretions to differ from those in the plasma at equilibrium.
The threat of multiresistant microorganismsVandenbroucke-Grauls, C.
doi: 10.1007/BF02389874pmid: 8386639
Enthusiasm about newly developed antimicrobial agents and disappointment because of the development of resistance have been alternating in the decades since the introduction of antibacterial chemotherapy around 1940. During the last few years several mechanisms of bacterial resistance have been elucidated, and new insights into the genetic basis of multiresistance have been gained. The clinical implications of multiresistance depend on timely recognition of the problem, i.e. knowledge of the epidemiology of multiresistant microorganisms and the availability of alternative drugs. A particular problem arises from the fact that infections with multiresistant microorganisms often occur in the most critically ill patients.
Interleukin-1 as a possible agent for treatment of infectionMeer, J.; Vogels, M.; Curfs, J.; Eling, W.
doi: 10.1007/BF02389883pmid: 8477769
Treatment of experimental animals with bacterial products, such as cell wall components of gram-negative bacteria, leads to enhanced resistance to a variety of microorganisms. Since interleukin-1 and other pro-inflammatory cytokines are induced by such bacterial products, it has been investigated whether these cytokines are induced by such bacterial products, it has been investigated whether these cytokines are also capable of enforcing host resistance. It has been possible to demonstrate that a low dose of interleukin-1 protects mice against death from either gram-negative or gram-positive bacteria,Candida albicans andPlasmodium berghei. The protection against lethal bacterial and fungal infection can be produced in both normal and neutropenic animals. Despite extensive investigations, the mechanism of protection is not understood. A possible mechanism, which is currently being investigated, is that interleukin-1 interferes with the deleterious action of the pro-inflammatory cytokines during the lethal phase of the infection.
Role of glucocorticosteroids in the treatment of infectious diseasesThompson, J.
doi: 10.1007/BF02389882pmid: 8477768
The role of glucocorticosteroids in the management of infectious diseases in man remains controversial, although experimental data obtained both in in vitro systems and in experimental infections in animals provide evidence of a beneficial effect of such treatment. Their use in the treatment ofPneumocystic carinii pneumoniae and severe typhoid fever seems indicated. A beneficial effect on the treatment of bacterial meningitis needs to be confirmed. Sufficient data are now available that argue against steroid treatment in septic shock. However, new treatment modalities such as monoclonal antibodies against endotoxin and inflammatory mediators are currently being developed to modulate infectious inflammation. This could also bring a renaissance of the role of glucocorticosteroids in the treatment of infectious diseases.