Grantville Gazette, Volume X Page 39

  It seems clear given the historical evidence, that an adequate medium for relatively large-scale (beyond small laboratory batches) production of crude penicillin will be found and utilized.

  But obtaining the media for crude penicillin production is just one factor. Another will be obtaining the appropriate containers and manpower to produce the crude penicillin on a regular schedule. Another factor that will be important is some substance or substances that can act as an effective "biocide."

  In terms of an effective biocide, the most useful for penicillin production is borax. In a 1945 study done in Wisconsin, "37 different chemicals were tested for their ability to prevent the growth of contaminants and still allow penicillin production in contaminated shake flask fermentations. Of the chemicals tested, only borax and boric acid could be used at a level high enough to delay the growth of contaminants and still not interfere with penicillin production." [8, 515]. The importance of this to 1632 is that borax was one of some twenty-seven common mineral substances used in medicinal or cosmetic recipes [11, 125]. While the most expensive mineral ingredient (2–3 guilders per pound), borax nevertheless was available throughout much of Europe. The amount necessary to prevent contamination of penicillin cultures is quite small, two-tenths of one percent. Since borax has other important uses however, as in the making of borosilicate glass, it is likely that resources in Tuscany will be developed fairly quickly, helping to drive down the price.

  Uses and Limitations

  From the literature on the use of crude penicillin, it is apparent that it will be most useful for infections in open wounds, and infections involving staph, strep, and gonorrheal bacteria. Syphilitic sores might also respond to treatment, although a complete cure would likely have to wait until large doses of a partially pure product could be injected. Diphtheria is also penicillin sensitive, so application as throat and nasal drops might drastically lower mortality rates. Unfortunately, penicillin will not work with cases of typhoid, cholera, plague and typhus, nor will it be effective against viral diseases. Crude penicillin will also have other limitations. Batches will tend to be highly variable in all but the best laboratories or hospitals. There will have to be a continuous production line because without refrigeration, penicillin loses its potency fairly rapidly over a span of about two weeks. Even with refrigeration the maximum lifespan will be measured in weeks, not months. There will be a constant need to maintain sterile conditions to prevent contamination. Hence either autoclaves or dry heat ovens will be required.

  Crude penicillin production, however, will be much more likely to be attempted and utilized than sulfanilamide and chloramphenicol production outside the USE. Technologically speaking, it is much closer to the typical activities attempted by down-time medical practitioners of all kinds. Crude penicillin production will foster the development of sterile procedures, instrumentation, glassware and microscopes. As technology improves, the work on crude penicillin will set the stage for purification of a pure product that can be used internally through the use of injections or IVs. It will also foster investigation of the soil for the complete cornucopia of organisms that are part of the modern arsenal of antibiotics.

  Now the crucial question, of course, is can a hospital or laboratory produce enough crude penicillin to serve a population of thousands? Evidence from Hawaii in 1945 seems to indicate that this is indeed possible [4, 47]. In Hawaii approximately forty liters of crude penicillin filtrate were being prepared every week. This was enough for 16,000 dressings and this amount in turn was enough to serve 100 physicians around Hawaii as well as any ship or naval depot that required the product. Given the likely per capita ratio of doctors in 1945, this was sufficient to serve at least 100,000 people. Given the necessary incubation period for maximum yield, maintaining this level of production on a weekly basis probably requires somewhere in the vicinity of 500 to 600 liter bottles or containers. This certainly seems doable within the context of 1632, especially given the resources that were expended on hospitals by many urban centers.

  Bibliography

  [1] Behind the Sulfa Drugs: A short History of Chemotherapy. Iago Galdston. 1943.

  [2] New Light on the History of Penicillin. Ronald Hare. Medical History, 1982, 26: 1-24.

  [3] C.G. Paine and the earliest surviving clinical records of penicillin therapy. Milton Wainwright and Harold T. Swan. Medical History, 1986, 30: 42-56.

  [4] The History of the Therapeutic Use of Crude Penicillin. Milton Wainwright. Medical History, 1987, 31: 41-50.

  [5} Robert Pulvertaft's Use of Crude Penicillin in Cairo. H.V. Wyatt. Medical History, 1990, 34:320-326.

  [6] The Use of Gauze Inoculated with Penicillium Notatum or Impregnated with Crude Penicillin In The Treatment of Surface Infections. R.S. Myers, R.H. Aldrich, R.W. Howard, and R.A. Walsh. New England Journal of Medicine. Volume 231 No. 23. December 7, 1944.

  [7] Crude Penicillin: Its Preparation and Clinical Use Externally. Charlotte Dunayer, Lillian Buxbaum, and Hilda Knobloch. Annals of Surgery. Volume 119 No. 5. May 1944.

  [8] The Effect of Medium Constituents on Penicillin Production from Natural Materials. Bhuyan BK, Johnson MJ.Appl Microbiol. 1957 Jul; 5(4): 262-267.

  [9] The Control of Contaminants in Penicillin Fermentations by Antiseptic Chemicals. Knight SG, Frazier WC.J Bacteriol. 1945 Nov; 50(5): 505-516.

  [10] Microbiological Aspects of Penicillin: IX. Cottonseed Meal as a Substitute for Corn Steep Liquor in Penicillin Production. Foster JW, Woodruff HB, Perlman D, McDaniel LE, Wilker BL, Hendlin D.J Bacteriol. 1946 Jun; 51(6): 695-698.

  [11] Midwifery and Medicine in Early Modern France: Louise Bourgeous. Wendy Perkins. 1996. ISBN 0859894711.

  Penicillin: Its Practical Application. Alexander Fleming, editor. 1946.

  Launching The Antibiotic Era: Personal Accounts of the Discovery and Use of the First Antibiotics. Carol L. Moberg and Zanvil A. Cohn, editors. 1990. ISBN 0-874770-047-7.

  The Effect of Certain Mineral Elements on the Production of Penicillin in Shake Flasks. Koffler H, Knight SG, Frazier WC.J Bacteriol. 1947 Jan; 53(1): 115-123.

  Comparative Study of Penicillin Production with Vegetative and Spore Inoculum of Penicillium chrysogenum. Bhuyan BK, Ganguli BN, Ghosh D.Appl Microbiol. 1961 Jan; 9(1): 85-90.

  Chemical Changes in Submerged Penicillin Fermentations. Koffler H, Emerson RL, Perlman D, Burris RH.J Bacteriol. 1945 Nov; 50(5): 517-548.

  Microbiological Aspects of Penicillin: III. Production of Penicillin in Surface Cultures of Penicillium notatum. Foster JW, Woodruff HB, McDaniel LE.J Bacteriol. 1943 Nov; 46(5): 421-433.

  Microbiological Aspects of Penicillin: II. Turbidimetric Studies on Penicillin Inhibition. Foster JW, Wilker BL.J Bacteriol. 1943 Oct; 46(4): 377-389.

  Microbiological Aspects of Penicillin: IV. Production of Penicillin in Submerged Cultures of Penicillium Notatum. Foster JW, Woodruff HB, McDaniel LE.J Bacteriol. 1946 Apr; 51(4): 465-478.

  Mode of Action of Penicillin: I. Bacterial Growth and Penicillin Activity—Staphylococcus aureus FDA. Lee SW, Foley EJ, Epstein JA.J Bacteriol. 1944 Oct; 48(4): 393-399.

  Penicillin. III. The Stability of Penicillin in Aqueous Solution. Benedict RG, Schmidt WH, Coghill RD, Oleson AP.J Bacteriol. 1945 Jan; 49(1): 85-95.

  Evaluation of Precursors for Penicillin G. Singh K, Johnson MJ.J Bacteriol. 1948 Sep; 56(3): 339-355.

  Microbiological Aspects of Penicillin: VIII. Penicillin from Different Fungi. Foster JW, Karow EO.J Bacteriol. 1945 Jan; 49(1): 19-29.

  The Relation of Natural Variation in Penicillium notatum to the Yield of Penicillin in Surface Culture. Whiffen AJ, Savage GM.J Bacteriol. 1947 Feb; 53(2): 231-240.

  Antibacterial Substances from Plants Collected in Indiana. Sanders DW, Weatherwax P, McClung LS.J Bacteriol. 1945 Jun; 49(6): 611-615.

  CORN STEEP LIQUOR IN MICROBIOLOGY. Liggett RW, Koffler H.Bacteriol Rev. 1948 Dec; 12(4): 297-311.

  Sterilization by dry heat. E. M. Darmady, K.E.A. Hughes, J.D. Jones, D. Prince, and Winifred Tuke. Journal of Cl
inical Pathology (1961), 14, 38-44.

  The Sterilization of Dressings. V.G. Alder and W. A. Gillespie. Journal of Clinical Pathology (1957), 10, 299-306.

  Herd Immunity

  By Vincent W. Coljee

  Life, disease and death in the 1630s

  Imagining life in a small town in Germany in the 1630s is difficult for the average twenty-first century dweller. Picture awaking from an interrupted night's sleep, courtesy of the local swine brawling in the alley below your bedroom window. Extracting yourself carefully from between the siblings sharing the bed with you, you arise and count your bedbug bites.

  This may sound crude and uncivilized, but they were the plain facts of awakening in that day and age. Bedbugs, communal sleeping, bedpans, contaminated drinking water and lack of personal hygiene were commonplace, depending on where you lived. This also meant that disease was rife, childhood mortality was through the roof, and overall life expectancy in Germany during the Thirty Years' war was less than that of the Roman era.

  In the cities, the death rate usually exceeded the birth rate. It was in the cities that epidemics of plague, typhoid, smallpox and many other diseases ran rampant. For example, the plague hit the city of Amsterdam multiple times in the 1600s. This caused a loss of about twenty percent of the population each time the plague hit in 1624-25, 1635-36, 1655 and 1664.

  Nonetheless, the population of Amsterdam had grown from 60,000 in 1600 to double that by 1632 and to 200,000 by 1670. This was in spite of the loss to disease. That many cities grew in this period of history was due to immigration from other cities or from the rural population. Rural communities, while by no means healthy by twenty-first century standards, suffered less from the continued onslaught of disease than the cities did.

  Medical treatment

  On top of having a far greater chance of coming down with a disease, there were few remedies that were known to be effective for many of the diseases. Many people used folk remedies which were passed down along the generations or adopted from friends or neighbors. Some of these folk remedies survive to this day, such as chamomile tea for soothing the stomach and nerves, or willow bark tea as a pain reliever and to reduce inflammation.

  Often, ingredients were picked because of the physical appearance of the source of the ingredient For example, walnuts were thought to have the "signature of the head." Some of these remedies were effective because at least one ingredient contained a suitable active agent (e.g., salicylates in willow bark). The problem then was with dosage control (a particular problem with the digoxin content of digitalis).

  If Grandma's home remedy didn't work, you had to consult a medical professional. Regular doctors, trained at university, were often unavailable to most of the population. Cambridge and Oxford universities, for example, graduated on average just one MD per year.

  The MDs mostly learned "classical" medicine, based upon the Greek physicians Galen and Hippocrates. These ancient physicians emphasized knowledge of the "humors," which constituted the fluid contents of the body, such as bile, blood and phlegm. Disease was thought to be the result of an imbalance in the humors, which could be detected by studying the patient's bodily functions. Their prescriptions often consisted of purgatories, enemas and/or bleeding their patients, to "purge" the patient of the bad unbalanced humors. It must be admitted that their teachings went beyond this, and many aspects still make sense now, such as advocating a balanced diet.

  Unfortunately, even Galen made mistakes. For example, in his time, vivisection or dissection of human bodies was forbidden and he studied his anatomy on pigs. This meant that the Renaissance anatomists ran into a few differences when they started their dissections of real human bodies. Nonetheless Galen's teachings were still adhered to, in spite of being wrong.

  Worse, the MDs "cures" were often life-threatening in their own right. Consequently, the general population, even if able to afford access to MDs, might avoid them like the plague.

  Consider Dr. Symcott's treatment of the younger son of the Earl of Bridgewater, who suffered an apparent stroke. Symcott describes blowing tobacco and sneezing powder up the patient's nostrils, putting mustard and vinegar in his mouth, administering enemas and suppositories, applying dead pigeons to his feet, holding a hot frying pan close to his head and finally leeches to his rectum. It is no surprise that the patient died.

  When Symcott himself came down with gout, his brother, a London merchant, felt free to give him advice on how to treat it, thus exemplifying how much lay people held university trained doctors in contempt.

  There were some notable exceptions, however. Graduates of Padua, Leiden and Edinburgh received more practical anatomy lessons than those who attended Paris, Cambridge or Oxford. Also, doctors trained in Arabic medicine tended to have a more rounded and generally more scientific underlying education which included, for example, keeping instruments clean for surgery. Many of these doctors were either Jewish or recent Iberian Jewish "converts" to Christianity. Their superior track record led to them being retained as court physicians, even for the pope.

  Aside from regular university trained doctors, MDs, there were numerous lay physicians. This is a catch-all term which includes barber-surgeons, midwives, herbalists (who include "white witches"), and even bath attendants and executioners. The lay physicians by far outnumbered MDs, and were more deeply rooted in the community. Many of these had practical experience which made them more effective than the MDs. Hence, they had plenty of patients.

  Since the MDs didn't appreciate this competition, they did everything in their power to exclude the opposition. For example, a century before the Ring of Fire, in the aftermath of Columbus' travel to the New World, there was a syphilis outbreak that hit—among other places—the papal court. Two court physicians, Torrella and Pintor, managed, with a varied degree of success, to treat this disease with metallic mercury, as well as other corrosive and abrasive substances, such as calcium oxide (similar to drain cleaner), ammonia and vitriol (acid).

  One of the difficulties with using mercury was that it was a substance known to be used by many lay physicians in treating skin conditions. The MDs didn't want the lay physicians to be able to treat the skin lesions of syphilis. They pointed out to the powers-that-be that mercury has rather severe side effects which could impair the mental health of the patient or even kill him/her. Hence, they contrived that the "professional and safe" use of mercury would be the sole realm of the trained MD.

  There were many women among the lay physicians. Treating the sick was one of the few niches a woman could work in, especially when left destitute by widowhood. This, combined with their common practical education in midwifery or in herbology, and the fact that they would charge far less, frequently made these women more successful in treating the sick than the MDs. Consequently, they were denounced by the MDs. In the 1630s, James Primrose, an English MD, published a pamphlet, "Popular Errours," which was very critical of female practitioners.

  The tale of Madame Louise Bourgeois shows how much power the MDs had and how willing they were to use it against women practitioners, even when the MDs were in the wrong. Madame Bourgeois had been the royal midwife since 1601 when she attended the delivery of a French princess, the sister-in-law of the king, in 1627. There were six doctors present. When the princess died a week later, the "learned" doctors did an autopsy and laid the blame at the feet of the midwife, so as to exonerate themselves. The midwife, with all her practical experience, wrote a very extensive reply in defense of her reputation. She brought forth an overwhelming amount of evidence showing that the princess was suffering from a massive abdominal infection in her last trimester, but had no sign of that infection in her uterus. She completely refuted the doctor's claims that the princess died from having incompletely passed the placenta at birth. Scientifically and medically she was correct as far as we can evaluate the evidence through the eyes of history. The doctor's responses to her refutation of the autopsy report was little more than "Woman, you don't know your place, shut
up or we shall try and get you killed." Such was the influence of the court physicians that the increasing attacks forced her to end her career at the French court.

  This battle would continue until the MDs finally managed to achieve a virtual monopoly on "healing" during the Victorian era. Whether or not they were more successful at curing people by that time is debatable, but they certainly won the propaganda war.

  How would the Ring of Fire change medicine?

  One seemingly small, but in fact huge, contribution Grantville would bring is a concept in modern science that is called the "Scientific Method." Originally, Descartes outlined the main tenets of this method in his 1637 book, Discourse on Method. One basic principle that is requested of anyone asking a question scientifically is to be objective. This is very difficult because virtually everyone makes assumptions of some kind and some of these assumptions inevitably end up being wrong. The scientific method further declares that any theory or hypothesis, a suggested explanation of a phenomenon, should be testable. The method involves a number of other principles, such as: "cause and effect" have to follow one another and plausible alternatives have to be eliminated.