Further Observations on Penicillin

Abraham, E. P.; Chain, E. B.; Fletcher, C. M.; Gardner, A. D.; Heatley, N. G.; Jennings, M. A.; Florey, H. W.

doi:10.1016/s0140-6736(00)72122-2

Cited by 734 publications

(265 citation statements)

References 14 publications

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“…The results of our experiments in which single intramuscular injections of the antibacterial were administered to dogs are in good agreement with those of Chisholm et al (1968) and Verwey & Williams (1962a, b) and indicate that penicillins, even those which are highly bound to plasma proteins, penetrate well into extravascular spaces. This observation is supported by other workers (Abraham, Chain, Fletcher, Florey, Gardner, Heatley & Jennings, 1941;Brown, 1964;Florey, Turton & Duthie, 1946;Jawetz, 1946;McCune, 1960;Nathanson & Liebhold, 1946;Ungar, 1950;Weinstein, Daikos & Perrin, 1951;Werner, Knight, McDermott, Adams & Dubois, 1954;White, Lee & Alverson, 1946). Our experiments therefore indicate that penicillins penetrate readily from plasma to extravascular fluids as represented by peripheral lymph, thereby achieving good antibacterial concentrations of the free active penicillins in the tissues.…”

Section: Discussionsupporting

confidence: 89%

The distribution of antibacterial agents between plasma and lymph in the dog

Acred¹,

Brown²,

Clark³

et al. 1970

British J Pharmacology

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Summary1. Plasma, peripheral and thoracic lymph concentrations of penicillin V, phenethicillin, carbenicillin, ampicillin, cloxacillin, penicillin G, chloramphenicol and sulphadiazine were determined at various time intervals up to 6 h following intramuscular administration of 50 mg/kg to dogs. 2. Peak plasma concentrations of the penicillins occurred within half an hour after administration with the peak lymphatic concentrations occurring 15 to 3 h afterwards. For the remaining period of the test the concentration in the lymph exceeded the corresponding concentra-tion in the plasma. Sulphadiazine gave concentrations in thoracic lymph equal to the plasma concentration, but the peripheral lymph concentrations were lower while the concentrations of chloramphenicol in both peripheral and thoracic lymph were always lower than the plasma concentrations. 3. After the peak concentrations were reached, the concentration curves for penicillins in lymph followed the same pattern as found in plasma, the penicillin concentrations declining exponentially. Sulphadiazine produced more persistent levels both in lymph and in plasma while the concentrations of chloramphenicol were still rising 6 h after administration. 4. The free concentrations of penicillin in lymph were equal to the free concentrations in plasma, whereas the concentrations of free sulphadiazine and chloramphenicol in lymph were less than those in the plasma.

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Section: Discussionsupporting

confidence: 89%

The distribution of antibacterial agents between plasma and lymph in the dog

Acred¹,

Brown²,

Clark³

et al. 1970

British J Pharmacology

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“…faecalis ST, is comparatively resistant. Penicillin does not affect the respiration of washed suspensions of susceptible staphylococci and was consequently thought to be bacteriostatic (Abraham, Chain, Fletcher, Florey, Gardner, Heatley & Jennings, 1941) but later work demonstrated that penicillin is bactericidal when i t is allowed to act on cells which are growing or in a condition where multiplication is possible (Hobby, Meyer & Chaffee, 1942). Gardner (1940) found that bacteria will increase in size in the presence of penicillin but do not divide, with the result that enlarged and abnormal cells are produced.…”

Section: Discussionmentioning

confidence: 99%

The Assimilation of Amino-acids by Bacteria: 5. The Action of Penicillin in Preventing the Assimilation of Glutamic Acid by Staphylococcus aureus

Gale¹,

Taylor²

1947

Journal of General Microbiology

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SUMMARY:The effect on glutamic acid assimilation of the addition of penicillin to growing cultures of Stciphylococctcs uureus is described. When Stciph. ciureus is grown in media containing glut aniic acid this substance accumulates in steadily increasing concentration in the cells. The addition of penicillin to the medium is followed after an interval by rapidly decreasing concentration of glutamic acid within the cells.The assimilation of glutarnic acid by normal washed cells is not affected by penicillin in high concentration. The assimilation of glutamic acid by cells which have grown in the presence of penicillin is impaired and may be completely inhibited. Complete inhibition of assimilation is brought about by bactericidal concentrations of penicillin, low concentrations requiring a longer time to become completely effective than high ones. The loss of assimilatory power can be correlated with loss of viability.Comparison of the general properties of normal and penicillin-inactivated cells show that the respiration, glucose oxidation, glucose fermentation and lysine assimilation of the latter are normal. The internal metabolism of glutamic acid is normal in penicillin-treated cells, but, since the passage of glutamic acid across the cell wall is blocked, is limited by the existing internal concentration.Previous papers of this series (Gale, 1 9 4 7~; Taylor, 1947) have shown that Gram-positive bacteria are able to assimilate certain amino-acids from the external environment and to concentrate these aniino-acids in their internal environment so that, a t equilibrium, the internal concentration is greater than the external. Lysine passes across the cell. wall of Streptococcus faecnlis by a process of diffusion, but the migration of glutamic acid requires energy which can be supplied by metabolic processes such as glucose fermentation. The maintenance of a concentration of glutamic acid within the internal environment higher than that in the external medium is dependent upon an intact cell wall (Gale & Taylor, 1947). After glutamic acid has passed through the cell wall, a portion of it undergoes metabolic change, and the level of glutamic acid concentration measured inside the cell represents the balance between the rate of entry of that amino-acid into the cell and the rate of its metabolism within the cell (Gale & Mitchell, 1947).Since the ability to concentrate amino-acids within the internal environment is a property of Gram-positive organisms, the effect on this property of various chemotherapeutic agents has now been tested. A preliminary note on the effect of penicillin in preventing the assirnilation of glutamic acid by Staphylococcus aureus has been published (Gale & Taylor, 1946). Penicillin is highly effective as a bactericidal agent against most Gram-positive organisms, while many Gram-negative organisms are either unaffected or affected by comparatively (Fleming, 1929) ; however, the Grain-negative meningococci and gonococci are very sensitive, and the Grain-positive enterococcus, Strep. faecal...

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“…It is of interest that Abraham et al (29) concluded from their early and now classical experiments with penicillin that the presence of pus does not interfere with the antimicrobial action of the antibiotic. This conclusion was based upon experiments designed to detect the presence of possible antipenicillin factors in pus.…”

Section: (B) Effect Of Penicillin Inmentioning

confidence: 99%

An Experimental Analysis of the Curative Action of Penicillin in Acute Bacterial Infections

Wood

Smith

1956

The Journal of Experimental Medicine

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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.

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Further Observations on Penicillin

Cited by 734 publications

References 14 publications

The distribution of antibacterial agents between plasma and lymph in the dog

The distribution of antibacterial agents between plasma and lymph in the dog

The Assimilation of Amino-acids by Bacteria: 5. The Action of Penicillin in Preventing the Assimilation of Glutamic Acid by Staphylococcus aureus

An Experimental Analysis of the Curative Action of Penicillin in Acute Bacterial Infections

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