1632

by Eric Flint

  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 Clinical Pathology (1961), 14, 38-44.

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

  A Night with Venus: STIs and Their Treatment in the 1630s, Part One

  by Gus Kritikos.

  Sexually transmitted infections (formerly called venereal diseases) caused a surprising amount of discomfort, loss of fertility, madness and even death in the early modern era. There was a lack of understanding of the diseases, of the corresponding public health measures that should have been in effect, and of reliable treatments. Advances in bacteriology and serology starting in the 1890s in this time line provided the first consistent ability to diagnose the infections early in their course. Effective treatment started a decade later, with the discovery first of arsenicals for syphilis. Several decades later the sulfa class drugs and finally penicillin and chloramphenicol were developed. All of these drugs are (by canon) producible with 1630's technology and guidance from up-time sources. It is important to note that one of the most critical tenets of public health is that treatment is needed for not only the presenting patient, but also all identifiable intimate contacts of that patient.

  Please note that any prospective dates given in this article are my own personal first approximation SWAGs, and based on my estimation of the progress from 1631 to the 1660 time frame as compared to the 1900 to 1970 time frame in this time line. Iver Cooper's excellent article on Organic Chemistry (Industrial Alchemy Parts III and IV) contains references to the antibiotics in canon, and I have adapted those as the baseline.

  Syphilis

  Syphilis was named for a shepherd in the 1530 epic poem, "Syphilis, or the French disease" by Girolamo Fracastoro, an Italian physician trained at Padua. As a disease, syphilis was first characterized in 1494 with an outbreak in Naples that was linked to some of Columbus' crewmen. Other names for the disease include the Great Pox (to distinguish it from Small Pox), the French Pox (by the English, Italians and Germans), the English Disease by the French and South Sea Islanders, and the Turkish Disease by the Russians. Notice the pattern of blaming the disease on one's enemies!

  The causative agent, Treponema pallidum, is a pale, spiral shaped, mobile single celled organism that normally lives in humans. Various ideas of the source of the original infection have been proposed, with arguments about the antiquity of this disease having extended for several centuries. Currently, there are two competing ideas, first, the Old World theory, where syphilis is derived from the skin disease bejel, which has been known since antiquity, mostly in the western end of the Mediterranean. It is caused by a Treponema that is closely related to T. pallidum. It, like most of the New World forms, is a skin infection not requiring intimate sexual contact. There is some suggestion that bejel may have been confused with leprosy at times, as both produce painless ulcers, can result in scarring with loss of sensation, leading to further risk of damage from recurrent minor trauma, and both cause soft tissue and bony destruction over time. Bejel is more transmissible than leprosy, and occasionally undergoes spontaneous cure, both of which are arguments towards bejel being the Biblical Tzaraath, not what we know as leprosy today. Possible evidence of Treponema related bony changes have been noted in pre-Columbian skeletons from Pompeii, among other places.

  The New World, or Columbian, theory which theorizes that Columbus and his men brought the disease back after sexual contact with New World natives, is related to various treponemal New World tropical diseases, including yaws and pinta. As with bejel, these are skin infections not requiring intimate genital contact. Recent research tends to favor Columbian origin, as genetic testing suggests that syphilis is more closely related to yaws than bejel, and there appears to be an intermediate form (between yaws and syphilis) that occurs along the northeast coast of South America.

  Wherever syphilis originated, the epidemic form was noted with numerous cases starting in the 1493-94 timeframe, and continued unchecked through the middle 1500s, and then, in a somewhat milder form, through the late 18
00s. While the treponemal skin infections show evidence of having been long associated with humans, the epidemic suggests that during the change of the tropical form to a venereal form, suitable for transmission in the colder areas of Europe, a more aggressive subtype was selected. An interesting correlation can be noted here, as when experimental rabbits are partially shaved and then infected with T. pallidum, the shaved (cooler) areas of the rabbit's body show substantially more and worse lesions than the fully furred areas.

  Similar problems with an aggressive disease were noted in the first stages of the AIDS epidemic, but the public health authorities in the 1632 universe, lead by Dr. Balthazar Abrabanel, are determined to avoid the mistakes made in the 1980s in this time line. Like AIDS and the viral hepatitis infections, syphilis can be blood borne, and this will be a major threat to the blood supply in the early stages of blood banking.

  Several stages are associated with syphilis, which is one of the most important diseases in the 1632 time line. In the primary infection, a flat red patch (macula) is noted at the point of infection. This develops into a painless ulcer with a raw, red base, hard, smooth edges (called a chancre) and often no other symptoms. There is a latent period of 10 days to 3 months, with an average 3 weeks from the time of exposure to the appearance of the chancre. The patient is mildly infectious after the appearance of the ulcer. One to six months after the initial infection, with an average 6-8 weeks, the secondary stage starts with the appearance of a rash that occurs anywhere on the body. This is one of the very few rashes that shows up on the palms of hands and the soles of feet, and any patient in the 1632 universe with a rash on the palms and soles will be considered to have syphilis until proven otherwise.

  In this time line, the rash is reddish pink and appears evenly on both sides of the body, extending to the extremities. In the 1630s, the rash was more pronounced, often with open sores that gave rise to the name "Great Pox" to differentiate it from smallpox. Flat, pale, fleshy masses, called condyloma lata, occur in skin folds and other moist areas of the body and, like the palmar rash, are considered diagnostic for the disease. Other signs of generalized inflammation including swollen lymph nodes, fever, sore throat, malaise and headache also occur. In about 2% of the cases in any stage of the disease, a form of meningitis may occur, which is a dire sign. Because infective treponema can be found in the rashes, condylomata and ulcers, the secondary stage is the most infective stage of the disease. An interesting sign is a patchy loss of hair on the head, where the rash interferes with hair growth, that occurs in about 5% of the patients. The outer edges of the eyebrows can also be affected.

  The latent stage starts with resolution of rash and healing of any active ulcers and disappearance of any condylomata, which may occur two weeks after the rash starts, but is most often a month or more later. At this point, there is little physical evidence of the disease, however the patient remains infective, but much less so than secondary stage. The progression of the infection from here shows that roughly one quarter of the cases result in spontaneous resolution, another quarter remain in the latent state for long periods of time (possibly the rest of their life), and ultimately one half progress to the tertiary stage, from one year to a decade or more later.

  It is at this stage that syphilis becomes known as "The Great Imitator," because the presentation of the disease is so variable. Rashes may occur across any area of the body, and again occur on the palms and the soles. In the 1630s, these rashes also included open sores. Gummas, formed of reactive granuloma tissue, occur in many areas of the body, most typically in the liver and on the face. These non-cancerous tumors (swellings) are firm, rounded, and not tender. They may resolve spontaneously, leaving either a scar or a lump, or may persist for years. Some of them will cause bone or cartilage damage, leading to such problems as collapsing of the nose or ears. Heart failure due to muscle damage, aortic arch aneurysms (which were noted in Sherlockian canon), stomach ulcers, nose bleeds and kidney damage were also common.

  Neurosyphilis was one of the most feared complications of long-term syphilis, and was ultimately a terminal condition prior to the advent of antibiotics. While most common in the tertiary stage, neurosyphilis could actually occur in any stage. Common findings included tabes dorsalis (a wide based gait with "slapping" steps due to the loss of sensory feedback from the legs and feet), and Argyll Robertson pupils (or "whore's eyes," described as "accommodating, but not reactive" because the pupils of the eyes will narrow as the patient tries to track a finger moving closer to the patient's face (accommodation), but will not narrow when a light is flashed into the eyes (reactivity)). Ultimately, psychosis, insanity and a particular form of flaccid (limp) paralysis called general paresis of the insane will occur, leading to death. In this time line, the connection between general paresis and syphilis was not made until the late 1850s and finally confirmed by the finding of active spirochetes in damaged brains in 1913.

  Diagnosis

  A history of sexual contact with known infected persons or of birth to an infected mother (perinatal transmission) is the most important single factor in the diagnosis of syphilis until the development of serological tests for syphilis (STS), which will probably be sometime after 1636. Secondary history findings of the patient having any other sexually transmitted disease, or having what I will politely call a "rakehell" history, will be as highly suspicious for syphilis exposure in the 1630s as it is today. Additionally, a history of receiving a blood transfusion, followed by typical physical findings, will be highly suspicious for syphilis.

  I have already discussed the physical findings above, starting with the chancre, the rash (especially on the palms and soles), the "Great Pox" and progressing to the findings of neurosyphilis.

  Lab findings

  Serologic tests for syphilis (STS) have been the mainstay of screening for syphilis in this time line since the development of the Wasserman test prior to WWI. All of the screening tests are based on the cross reaction of beef cardiolipin antigen (diphosphatidyl glycerol, an alcoholic extract of beef heart that has the same structure as part of the treponema cell membrane), and are thus referred to as non-treponemal antigen tests.

  It must be noted that these tests are not specific for syphilis, but can also cross react to other antibodies produced by the body in response to autoimmune conditions such as rheumatoid arthritis, and a number of other infections, including non-syphilis treponemal infections, tuberculosis and viral diseases. Additionally, because of the peculiarities of serologic testing and the relationship between the antibodies and antigens as they are tested, high levels of antibodies can result in a false negative test, even in a highly infectious patient. If there is a high degree of suspicion, the patient's serum will be diluted (several times if needed) and retested.

  The non-treponemal serologic tests for syphilis (STS) fall into two broad categories, hemolysis and flocculation.

  Hemolysis testing, most notably the Wasserman test, is where sheep red blood cells (sRBCs) are mixed with the cardiolipin solution, which results in the blood cells being "tagged" with the cardiolipin. Antibodies in the serum being tested cause the sRBCs to break down or "hemolyse" in a process known as complement fixation. This hemolysis is measured on a scale from zero to four depending on the measurement of free hemoglobin in the solution after all of the sRBCs have settled out. Syphilis patients can expect to remain at least weakly positive for the rest of their lives. Several modifications of Wasserman's original test were developed before hemolysis testing was superseded in the 1940s by the development of flocculation testing.

  Flocculation tests, developed initially by Hinton, and further developed to the Venereal Disease Research Laboratory (VDRL) test, and then the Rapid Protein Reagin (RPR) test, are easier to perform, as well as both more sensitive and more specific than the hemolysis tests. These tests depend on antibodies cross-linking small particles that have been tagged with cardiolipin, resulting in the fluid changing from a smooth appearance to a clumpy one. The big difference b
etween the VDRL and the RPR tests is that RPR substrates are cross-linked in such a way as to allow for testing without a microscope. Both of these tests can be used with serum dilutions to quantify the degree of infection (titration or "titer"), and a four-fold decrease in the titer (say from a dilution of 1 part serum to 32 parts of saline to 1 part serum to 8 parts of saline) indicates that the patient is recovering from the disease. The RPR test, in particular, is suitable for rapid screening of blood donations, as well as prenuptial and prenatal testing.

  The VDRL test can be also used with Cerebral Spinal Fluid (CSF—fluid around the brain and spinal cord) obtained by a "spinal tap" for the diagnosis of and evaluation of treatment for neurosyphilis. This is needed because the blood brain barrier, especially if inflamed from infection, will not allow the passage of the antibodies we want the test to find. As a result, someone may have an active, life-threatening neurosyphilis but without active infection elsewhere in the body the serum tests may well be negative.

  The basic serologic tests for syphilis will probably be within 1630's tech after 1633, as the public health authorities will be pressing for their urgent development, to secure the blood supply if for no other reason. I expect that the hemolysis type tests will be used only long enough to develop the easier to use flocculation tests, which should not take more than another year once the cardiolipin is isolated. I am working up a more detailed timeline on serology and blood banking, which will have more detailed information on this subject.