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PubMed1956

An experimental analysis of the curative action of penicillin in acute bacterial infections. I. The relationship of bacterial growth rates to the antimicrobial effect of penicillin.

Three strains of pneumococcus (types I and III), equally sensitive to penicillin, have been shown to be killed by the antibiotic in vitro when grown either in enriched beef infusion broth or in a thin serous exudate. Killing of the bacteria resulted promptly when the penicillin was added during the logarithmic phase of growth but failed to occur if addition of the antibiotic was delayed until the later "stationary" growth phase. In analogous experiments with thick purulent exudates from established subcutaneous abscesses, the pneumococci failed to grow rapidly, and added penicillin exerted only a relatively slow bactericidal effect. The relevance of these in vitro observations to the curative action of penicillin was demonstrated in a systematic histologic study of the antimicrobial effect of the drug in experimental (type I) pneumococcal pneumonia. Evidence was obtained that at least two distinct processes are involved. The first, the direct bactericidal effect of the penicillin itself, was shown to operate in the outer edema zone of the spreading pneumonic lesion where the micro-organisms multiply rapidly in the thin serous exudate. The second, which predominates in the older more central portions of the lesion, was demonstrated to depend upon destruction of the pneumococci by phagocytosis. Here the bacteria, having presumably reached a relatively stationary phase of growth in the alveolar exudate, are resistant to the bactericidal action of the penicillin but are readily destroyed by the phagocytes.

Anti-Bacterial Agents↗
PubMed1956

An experimental analysis of the curative action of penicillin in acute bacterial infections. II. The role of phagocytic cells in the process of recovery.

Type I pneumococci injected into the leg muscles of otherwise normal mice reached a maximum total population of approximately 10(6) organisms. In mice rendered severely leucopenic by previous irradiation the maximum bacterial counts recorded were of the order of 10(9). Since the lesions in the latter animals were relatively acellular, the thousandfold difference in the two experiments represented a rough measure of the antibacterial action of the leucocytic exudate. The suppressive effect of the leucocytic exudate was shown by histologie studies to involve phagocytosis. The ingestion of pneumococci was clearly demonstrable within the first 12 to 18 hours. Accordingly, it was attributed to surface phagocytosis. In support of this conclusion was the finding that type III pneumococci reached a significantly higher total population in the myositis lesions than did type I. The type III strain used had been previously shown to be resistant to surface phagocytosis during active growth, whereas the type I strain was known to be susceptible throughout its growth phase. Evidence was also presented that the dense leucocytic exudate probably caused in addition a significant degree of bacteriostasis. When penicillin therapy was begun 9 hours after inoculation, the pneumococci were cleared from the lesions with equal rapidity regardless of the presence or absence of leucocytic exudate. At this early stage the pneumococci were multiplying rapidly in the lesions of both the irradiated and unirradiated mice and therefore were promptly killed by the direct action of the penicillin. When the start of treatment was delayed, however, until 24 hours after inoculation, the bacteria in both sets of lesions had already reached their maximum counts and therefore were presumably resistant to the bactericidal effect of the antibiotic. Under such circumstances the destruction of the bacteria was found to be significantly less prompt in the acellular lesions than in those with a normal cellular exudate. It is concluded from these findings that, in established pneumococcal myositis in mice, the curative effect of penicillin is due, not to the bactericidal action of the antibiotic alone, but rather to the combined effect of the drug and the cellular defenses of the host. The same conclusion also appears to be applicable to analogous acute infections in man, particularly when they are sufficiently advanced to be definitively diagnosed.

Animals↗
PubMed1956

An experimental analysis of the curative action of penicillin in acute bacterial infections. III. The effect of suppuration upon the antibacterial action of the drug.

The results of the experimental analysis reported in this and the two preceding papers (10, 11) indicate that in murine pneumococcal infections penicillin per se destroys the invading organisms only in those parts of the lesions where the bacteria are multiplying rapidly and are thus maximally susceptible to the bactericidal action of the drug. In areas where the bacterial growth rate is slowed, either because the pneumococci have reached a maximum population density, or because the accumulated exudate affords a relatively poor medium for rapid growth, the destructive effect of the antibiotic is greatly diminished. In such portions of the lessions the cellular defenses of the host are observed to play a major role in eliminating the bacteria. In sites where frank suppuration has developed, however, even the combined actions of the penicillin and the cellular defenses of the host are relatively ineffective in ridding the tissues of bacteria. Here, because of the poor medium provided by the pus, the pneumococci remain metabolically sluggish and therefore are not killed rapidly by the penicillin. At the same time the leucocytes in the necrotic exudate have deteriorated to the point where they cannot effectively perform their phagocytic functions. As a result, bacteria persist in such lesions for many days in spite of the most intensive penicillin treatment administered both locally and systemically. A strict analogy cannot be drawn between the action of penicillin upon specific pneumococcal lesions produced in the laboratory and its effect upon acute bacterial infections in man. Host-parasite relationships in acute bacterial infections are determined not only by the strain of parasite and the specific host involved, but also by the site in the body at which the infection occurs (16). Nevertheless, in spite of the number of variables involved, it may be possible, by means of selected laboratory models, to illustrate general principles of infection which in all probability apply to human disease. Bearing in mind the limitations of the methods employed in the present experiments, it would appear justifiable to draw the following conclusions concerning the clinical use of penicillin in acute infections caused by penicillin-sensitive bacteria. The earlier that treatment is begun the more likely is penicillin to effectuate a rapid cure. When therapy is started before the bacteria have reached a maximum population density in any part of the lesion, and before a cellular exudate is formed, the great majority of the infecting organisms will be in a state of active multiplication and thus will be killed promptiy by the bactericidal action of the drug. If, on the other hand, treatment is delayed until the bacterial growth has attained its maximum in older parts of the lesion, and the inflammatory reaction has become well advanced, the resultant slowing of bacterial metabolism will so interfere with the bactericidal action of the penicillin that ultimate destruction of many of the bacteria will have to depend upon the slower clearing effect of the phagocytic cells. In such instances of delayed therapy specific antibody, which is formed relatively slowly, may play an important role in recovery (6). If relapse is to be avoided, however, penicillin therapy must often be continued longer in well established infections than in those treated at a very early stage. Still further delay in treating infections which are prone to cause tissue destruction and suppuration, may lead to the establishment of abscesses. Fully developed abscesses often will not respond to chemotherapy alone; they will ultimately require drainage. As shown by the present murine experiments, the relative ineffectiveness of penicillin under these circumstances is due not only to the failure of the drug to kill the metabolically sluggish bacteria surviving in the pus, but also to the ineffectiveness of the phagocytic cells, most of which are non-motile or dead. Even if specific antibody gains access to such purulent foci, many of the bacteria will continue to survive because of the degenerated state of the leucocytes. It is evident, therefore, that the stage of the infection at which penicillin treatment is begun is often crucial. Equally critical may be the location of the infection. Bacterial lesions in different sites of the body vary greatly in their responses to penicillin therapy. This inconstancy of therapeutic effectiveness is due primarily to the participation of host factors of defense which differ widely in various tissues and at the same time play a major role in the curative action of the antibiotic. In cases of pneumococcal pneumonia, for example, in which each milliliter of the patient's blood contains more than 1000 pneumococci, blood cultures may become negative in a matter of minutes after the start of intensive treatment (17). The remarkable promptness with which penicillin therapy controls such acute bacteriemia is due, first, to its suppressive effect upon the primary infection in the lungs and regional lymph nodes from which the bacteria are being poured into the blood stream (16) and, secondly, to its synergistic action with the cellular defenses of the circulation. The latter are known to be extraordinarily efficient, perhaps more so than in any other tissue of the body (18). Assisting them in destroying the circulating bacteria is the penicillin's own bactericidal effect, which operates rapidly upon the metabolically active organisms in the plasma. Rarely, if ever, as they often do in other tissues of the body (10), do bacteria in the bloodstream reach such numbers, or do inflammatory cells accumulate intravascularly to such an extent, as to create metabolic conditions which depress the bactericidal actions of the antibiotic. In contrast, more prolonged and extensive penicillin therapy is needed to cure pneumococcal endocarditis (19), meningitis (19, 20), or infections of the serous cavities (3, 4). The cellular defenses of the heart valves and of the "open" fluid-containing cavities of the body are relatively inefficient as compared to those that operate in the bloodstream and in tissues with tightiy knit architectures such as the lungs and lymph nodes (16). In endocarditis relatively few phagocytic cells ever reach the site of the offending bacteria (21), and in infections of fluid-containing cavities, the phagocytic efficiency of the mobilized leucocytes is seriously interfered with by the "dilution effect" of the fluid (22, 23). Accordingly, final destruction of the bacteria must depend primarily upon the bactericidal effect of the antibiotic itself, since little assistance is provided by phagocytosis. It is no wonder, therefore, that such infections, as compared to bacteriemia, are relatively refractory to penicillin therapy. Certainly penicillin, in spite of its remarkable therapeutic properties, falls far short of being a therapia sterilans magna (24). Its effectiveness does not depend solely upon the inherent susceptibility of the infecting agent to its antimicrobial action. How readily it will cure a given infection is determined also by the state of growth of the bacteria in the various zones of the lesions, the influence of the purulent exudate upon the bactericidal action of the drug, and the destructive effect of the inflammatory phagocytes upon the invading bacteria. Optimal use of penicillin as a therapeutic agent requires due consideration of all of these factors. Finally, it should be emphasized that the conclusions drawn from this experimental analysis cannot be applied to antibiotic therapy in general. They pertain only to the action of penicillin in acute infections caused by penicillin-sensitive bacteria which act in the host as extracellular parasites (16). The most common human infections included in this category are those caused by pneumococci and Group A beta hemolytic streptococci.(7) Whether they apply also to infections due to penicillin-sensitive staphylococci may be questioned because of recent evidence that certain pathogenic strains will survive phagocytosis (27). In diseases such as tuberculosis, brucellosis, and typhoid fever, which are treated with antibiotics having properties different from those of penicillin (28) and which are caused by bacteria capable of intracellular parasitism (28), factors other than those considered in the present analysis must certainly be involved in the curative effect of antimicrobial therapy.

Abscess↗
PubMed1956

Reversible changes in the susceptibility of mice to bacterial infections. I. Changes brought about by injection of pertussis vaccine or of bacterial endotoxins.

MICE WERE INJECTED INTRAPERITONEALLY WITH ONE OF THE FOLLOWING BACTERIAL PRODUCTS HAVING ENDOTOXIN ACTIVITY: pertussis vaccine, a suspension of heat-killed cells of Klebsiella pneumoniae (type C), or a purified lipopolysaccharide prepared from cultures of Salmonella typhosa. Following treatment with either one of these materials, the animals were infected intravenously with virulent cultures of coagulase-positive staphylococci, with bovine tubercle bacilli, or Friedländer bacilli. The effect of treatment with endotoxin materials on resistance to Friedländer bacilli, staphylococci, or tubercle bacilli was estimated by observing the mortality rates in infected animals, and by determining quantitatively the numbers of living bacteria in the organs at different periods of time after infection. It was found that mice receiving the infective dose of virulent culture a few hours after treatment with the endotoxin material, were usually more susceptible to infection than were untreated animals. In contrast, mice infected at a later period proved far more resistant to infection than did untreated animals. The duration of the negative and of the positive phase of resistance was affected by the amount of endotoxin injected. Marked increase in resistance of mice to infection with staphylococci or tubercle bacilli was still evident several weeks after treatment with pertussis vaccine or with purified lipopolysaccharide extracted from typhoid bacilli.

Animals↗
PubMed1956

Reversible changes in the susceptibility of mice to bacterial infections. II. Changes brought about by nutritional disturbances.

A study has been made of the time variations in the susceptibility of albino mice to experimental infections with Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium tuberculosis. Susceptibility to infection was determined by two criteria: (a) mortality rates following intravenous injection of a known infective dose; (b) numbers of bacterial colonies that could be recovered from the tissues of the infected animals at various times after infection. When measured in terms of either one of these two criteria, susceptibility was consistently modified by temporary deprivation of food, and by various changes in the composition of the diet. Increase in susceptibility to infection could be detected within a few hours to a few days depending upon the nature and intensity of the nutritional disturbance imposed upon the animal. Under the proper conditions, return to a normal state of resistance could also occur within a very short time. There was commonly observed an explosive bacterial multiplication in mice receiving the infective dose shortly after being subjected to nutritional disturbances. In the case of infection with Klebsiella pneumoniae, however, this phase of increased susceptibility was often followed a few hours later by one during which the numbers of living bacteria that could be recovered from the various organs fell to a very low level. Many of the animals which had exhibited severe but transient bacteriemia recovered rapidly and survived the infection. Mice rendered more susceptible to infection by being fed deficient diets progressively recovered their normal resistance while being kept on the same inadequate regimens. This adaptation occurred even though the weight of the animals on these regimens remained much lower than the weight of the animals fed a complete diet ad lib. The weight of the animal at the time of infection appeared to have little bearing on susceptibility. However, susceptibility consistently increased during the periods while the animals were losing weight-whatever the cause of the weight loss. The facts disclosed in the present study, as well as findings reported by other investigators, make clear that profound changes in susceptibility to infection can be brought about by varied non-specific procedures. These changes can occur within very short periods of time and are often rapidly reversible.

Animals↗
PubMed1956

Increased resistance to infection and accompanying alteration in properidin levels following administration of bacterial lipopolysaccharides.

It has been shown that injection of lipopolysaccharides, derived from a variety of Gram-negative bacterial species, evokes in mice a rapidly developing rise in resistance to infection with Gram-negative pathogens. This is accompanied by an elevation in properdin titer, at times to levels 2 to 3 times the normal. The rate, magnitude, and duration of these responses are dependent on many factors, the most important of which are the quantity and timing of the lipopolysaccharide administered. The increased resistance to infection evoked in mice by lipopolysaccharides was effective against infections produced by endotoxin-bearing organisms-bacterial species highly susceptible in vitro to the bactericidal action of the properdin system. Properdin titers of mice prior to infection provide an incomplete picture of the subsequent reaction of the host to the infective agent. Following infection with Gram-negative organisms, properdin levels accurately reflect the bacteriologic course and outcome of the infection. Thus, in control animals, properdin titers progressively declined and the animals died, while in mice appropriately treated with lipopolysaccharide, properdin levels were either maintained in the normal range or increased, depending on the dose and time of administration of lipopolysaccharide; this was always accompanied by successful management of the infection. The complex nature of the alterations produced in the host by lipopolysaccharides is stressed. It is pointed out that the increase in the ability of the host to cope with Gram-negative infections may be the result of stimulation of other defense mechanisms, in addition to the properdin system.

Animals↗