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Estimation and Use of Serum Levels in the Evaluation of the New Penicillins J Postgrad Med J: first published as 10.1136/pgmj.40.Suppl.17 on 1 December 1964. Downloaded from 17 demonstrate a chemotherapeutic effect of a extremely difficult to show clinically that one compound that has a reasonable degree of effective antibiotic is in fact better than another activity against a certain pathogen, particularly effective antibiotic and if comparison is to be if the dosage used in the trial is high enough made, very large numbers of patients are to provide adequate free antibiotic levels in required for it is not possible to carry out a serum and tissues. Unfortunately, with so comparitive trial at threshold dosages when many new antibiotics at our disposal, it is treating active human infections. ESTIMATION AND USE OF SERUM LEVELS IN THE EVALUATION OF THE NEW PENICILLINS J. M. BOND National Institute for Medical Research, Mill Hill, London, N.W.7. PENICILLINS are reversibly bound to serum membrane, and secondly no that there was Protected by copyright. albumin, and in their bound form are bio- differential filtration of the antibiotic itself, logically inactive, although the activity is not as occurred with certain other similar destroyed and can be recovered by dissociation techniques. of the antibiotic/protein complex. Whatever When comparing penicillins, two sources of its therapeutic significance, this binding of variation in serum binding have to be con- penicillins is important when assaying serum sidered. Firstly there is the well-known varia- levels, especially when these results are to be tion in percentage binding between different used to compare by laboratory tests the possible penicillins to the same medium. Table I efficacy of different penicillins. Assay results shows a series of results using bovine albumin. estimating the quantity of antibiotic in a serum Total antibiotic was the quantity added, and will depend on the technique used, therefore it the free level was measured by the filtration is important to know and to state exactly technique just mentioned. It seemed useful what is being estimated in an assay, whether it to have a series of penicillins all estimated by is the free (unbound) antibiotic, or the total the same technique, frequently the results from antibiotic present in both forms, or something different laboratories are compared but if they http://pmj.bmj.com/ between these two. The more precise the are using different techniques, they may not be result needed, the more necessary it is to have measuring the same fraction, therefore con- an exact measurement of the extent of the clusions may be incorrect. Bovine albumin binding. The assay of total antibiotic in a sample can be achieved by using an assay standard TABLE I. in exactly the same diluent as the sample. In on September 24, 2021 by guest. the case of serum levels, standard in homo- Percentage Binding of Penicillins to Bovine Albumin logous serum will give an exact estimate of all Antibiotic Bovine Albumin Human the antibiotic present in that particular serum. lo/ 5% Serum The assay of free, unbound antibiotic Ampicillin 14.4 21.2 depends on the use of some method of separat- Benzylpenicillin 36.2 71.5 ing the serum protein with its bound penicillin Methicillin 39.9 63.3 Phenoxymethyl from the aqueous phase, without further penicillin 49.7 84.3 80.1 dissociating the penicillin/albumin complex. We Oxacillin 55.8 82.4 have used a method of filtration under negative Phenethicillin 60.2 86.7 75.2 pressure through dialysis membrane. Controls Propicillin 82.9 94.3 89.3 showed that no protein went through the Phenbenicillin 93.0 98.1 97.2 Postgrad Med J: first published as 10.1136/pgmj.40.Suppl.17 on 1 December 1964. Downloaded from 18 TABLE II. Percentage Binding of Two Individual Human Sera Binding of Phenethicillin Binding of Penicillin G Estimated in Estimated in SERUM 1962 1963 1963 HK 82.3 (1 hr.) 83.0* 72.4 80.1 (2 hrs.) 73.7 (1 hr.) HD 75.7* 65.0 71.9 (2 hrs.) *Confidence limits (P=0.95) of potency estimates of free phenethicillin (1963). HK 0.328 -0.355 ug./ml. (2 assays combined). HD 0.438 - 0.486 jug /ml. HD 1.0.475-0.545 jug:/ml (2 assays separately). was used because it was readily available and two subjects, and examined for its binding more reproducible than serum, and also it was capacity. The same difference still existed for possible to use two concentrations of albumin. phenethicillin and was also shown with benzyl- As might be expected there was more penicillin. Confidence limits at the 5%/o binding of each penicillin with 5% albumin level calculated for the 1963 free levels of than with 1%. However, this was not a con- phenethicillin did not overlap for the two sera,Protected by copyright. stant difference for all penicillins, suggesting that there was a that the relationship between concentration of showing true, significant albumin and percentage binding could differ difference between the two, not merely for each penicillin. experimental error. The two sera have been Secondly, variations have been shown to examined by starch-gel electrophoresis which exist in the binding capacity of different human showed no marked differences between them, sera for a single penicillin. An example of only slight variations in the minor fractions. this is given in Table II. Filtration of two human The binding of phenethicillin to the sera of sera, HK and HD, both at 1 and 2 hours different species showed some variation, after injection, showed a 10% difference monkey serum 81.5%, horse 50.1%, rabbit in the binding of phenethicillin. After an interval 69.3% and rat 69.4%, compared with an of 12 months, serum was collected from these average value of 75.2% with human serum. TABLE III. http://pmj.bmj.com/ Comparison of Four Phenoxypenicillins on the Basis of the Ratio of Total or Free Blood Level to the Appropriate Minimum Inhibitory Concentration. Total Blood Level Free Blood Level Ratio M.I.C. in Serum M.I.C. in broth Organism Staph. aureus Str. pyogenes Staph. aureus Str. pyogenes on September 24, 2021 by guest. Time I hr 2 hrs. I hr. 2 hrs. I hr. 2 hrs. I hr. 2 hrs. Phenoxymethylpenicillin 9.0 3.48 137.5 1 6.0 3.7 24.0 14.7 Phenethicillin 13.4 8.0 13.4 8.0 21.3 14.6 Propicillin 4.7 2.87 14.2 8.6 2.3 1.8 9.3 7.3 Phenbenicillin 2.74 2.4 5.48 4.1 0.56 0.44 4.7 3.7 Postgrad Med J: first published as 10.1136/pgmj.40.Suppl.17 on 1 December 1964. Downloaded from 19 Estimations of the binding of ibenzyl penicillin 20 - to individual human sera, done by a slightly CLINIC A different technique, were analysed statistically 99 Blood levels and showed that variations in percentage 15 - binding between individual sera were sig- nificant and not just due to errors in the method used. The binding ranged from 3 to 2.0 - 30%. U. The extent of this variation in percentage binding between individuals is not known for 5 the various penicillins. The data is limited because it is frequently assumed to be of no importance and only mean values are quoted. 01 When attempting to predict the efficacy of 0.10 0.20 0.30 0.40 0.50 several penicillins the correct interpretation of serum levels is important. It is necessary to combine levels of free or total antibiotic with 15 the appropriate minimum inhibitory concentra- CLINIC B tion values obtained independently. Thus an 94 Blood levels estimate of total blood-level should be con- >- 10 sidered with M.I.C's. done in the presence of at least human serum, in order to com- 95%/, U. 5 pensate for the binding and temporary inactiva- Protected by copyright. tion taking place in the presence of the serum. The ratio of blood-level to M.I.C. is a useful figure to take when comparing several penicil- 0 lins, in which case a high ratio indicates a more 0.10 0.20 0.30 0.40 0.50 effective antibiotic. If the M.I.C's. have been done in broth, these values should be con- sidered with the level of free antibiotic in the 20 serum. Obviously a set of ratios for every CLINIC C penicillin can be obtained with each bacterium 173 Blood levels examined. Table III gives the ratios obtained 15 with 4 phenoxypenicillins and 2 test organisms, Staphylococcus aureus and Streptococcus pyogenes. The value for the serum U. levels, either total http://pmj.bmj.com/ or free, used in this ratio, is likely to be a mean value, averaged from a number of sera. 5 In this case, the use of pooled human serum as diluent for the assay standard, would seem to be quite satisfactory, provided that reason- ably large groups of individuals are used, groups 0.10 0.20 0.30 0.40 0.50 of at least 12, 20 or more Blood level units Penicillin/mI serum preferably subjects. FIG. Distributions of levels at 1.-Frequency blood on September 24, 2021 by guest. This use of pooled sera has been advocated 24 hours after injection of PAMI/9469 in three by many workers on the basis that variations clinics. in binding between individual sera will be can- celled out, and the mean value arrived at will be approximately correct. It does seem, how- ever, that the variation between healthy individuals, both in percentage serum binding following a given dose of a penicillin are and also in total blood levels attained for the frequently large and can be shown to be various penicillins, are factors which should considerably greater than variations due to at least be known, even if they are not always experimental error of the assays.
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