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Chapter 9 Antibiotics ant' Vaccines The production of antibiotics and vaccines is a further type of microbial processing that may be of great importance to developing countries. Antibiotics are antimicrobial substances produced by living microorgan- isms; many are used therapeutically and at times prophylactically in the control of infectious diseases. They act by inhibiting the growth of the infect- ing organisms. Some are effective against a wide range of infectious agents and are known as "broad spectrum," whereas others are more specific. Un- fortunately, for many infecting and disease-producing microorganisms (patho- gens) there are as yet no effective antibiotics. Vaccines, in contrast, are preparations of either dead organisms (or specific fractions thereof) or living attenuated microorganisms that may be admin- istered to man or animals to stimulate their immunity to infection by the same or closely related organisms. The effectiveness of vaccines in controlling disease can vary widely. For example, smallpox vaccine, commonly prepared from the vaccinia lesions on the skin of inoculated calves or sheep or from the allantoic membranes of inoculated chick embryos, produces a high degree of immunity in vaccinated individuals and has been highly effective in con- trolling the disease. Measles vaccine, also prepared from an attenuated live virus, is likewise highly effective and produces a degree of immunity that is demonstrable by measurement of antibody titers, usually for a period of 8-10 years or more. These two vaccines produce immunity by infection with live virus and thus are long-acting. Influenza, on the other hand, may be prevented by the parenteral injection of vaccines of influenza viruses that have been grown in chick embryos and rendered noninfectious by formalin or ultraviolet irradiation. With such a dead vaccine, the duration of immunity rarely exceeds one year, and, since the causative agent (virus) of influenza is capable of mutating frequently, different vaccines usually must be prepared to combat each mutant strain. . . . . A _ A: 1~: _ `: ~ _ _ ~ :1 ~ _ 1 ~ t 1 I; `~u vaccines are oom use a in modern medicine lo counter infectious diseases. Vaccines are used as prophylactic agents to increase im- munity and to prevent subsequent infection with more virulent strains; anti- biotics are employed most often as therapeutic agents to control disease after its onset, although they may also be used prophylactically against some 158

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ANTIBIOTICS AND VACCINES 159 organisms. There are, in addition, other antimicrobial drugs (not derived from growing microorganisms) which m`ay be used for control of infection. These are generally used therapeutically, although at times, as with malaria, they may be used to prevent infection. In developing countries, the capacity to produce many of these disease- fighting agents may only be realized further in the future than most other processes described in earlier chapters of this report. Local manufacture of drugs or vaccines requires considerable capital, a high degree of technology, and specially trained personnel; the use of these assets to produce antibiotics or vaccines locally must be viewed critically in relation to other needs for the same limited resources. Economies of scale usually make it possible for industrialized countries to produce drugs more cheaply for large markets. Yet, in these industrialized countries, the major portion of research on drugs and vaccines is likely to relate directly to those diseases occurring within these industrialized areas, that is, not to those in the developing countries where the need is greatest. Many diseases of developing countries, including the major tropical dis- eases, have attracted little attention and it may be that these diseases can best be attacked by a concerted research effort in the countries where they are endemic. Moreover, in view of the limited resources in these countries, shar- ing of effort on a regional basis may be desirable at times; but even so, the investment of time and money for this purpose in no way would be justifiable until other necessary elements of the public health system were adequate. These elements include: Public health statistics. Without good information on the principal causes of illness and death, health planning is ineffective and development of a health policy is impossible. A means of disseminating public health informa- tion is a prerequisite for public health programs. Public health programs. The source and mode of transmission of the target disease must be known. Effective programs may require control of nonhuman hosts or their environments. For example, in conjunction with drug administration, molluscicides may be required against snails for control of schistosomiasis, milk pasteurization for control of typhoid fever, or the destruction of mosquito-breeding areas for control of malaria. A health delivery system. An effective delivery system is a prerequisite to achieving health policy objectives. An effective disease-control program cannot be mounted without adequate storage facilities (generally low-temper- ature) and adequate means for drug distribution and administration. Knowledge of the nutritional status of the population and its relation- ship to disease. The interactions between an individual's nutritional state and

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160 MICROBIAL PROCESSES infection must be taken into account in designing an effective disease-control program. This information on the health system will determine the kinds of vaccines or antibiotics required and whether their local manufacture might be econom- ically feasible. In this regard, modern drug development programs use increasingly sophis- ticated and sensitive analytical, chemical, and biochemical techniques. Drug intermediates are frequently extracted from plants or microorganisms and modified chemically to produce active substances. The distinction between microbiologically derived antibiotics and other antimicrobial drugs becomes less important as the criteria of efficacy and economics of production methods determine the extent to which microbes should be employed to synthesize a particular drug. The World Health Organization (WHOJ provides assistance through the establishment of integrated disease-control programs in most countries. The objectives of this program include assistance in: drugs. Developing a consistent approach to health policies; Assuring safety and efficacy of drugs; Achieving optimum utilization of drugs; Providing supplies of drugs; Exchange of data on drug experience among countries; Training of scientific personnel in the health field; and International collaboration in research and development on improved Antibiotics and vaccines can be powerful tools for enhancing the health and well-being of afflicted populations. The virtual eradication of smallpox throughout the world is a fine example of the success of a coordinated disease- control program. With greater use of microbial processes and with worldwide collaboration other successes will follow. Antibiotics Probably no group of substances has been more thoroughly exploited than the antibiotics. Yet no antibiotics exist today for effective treatment of many of the diseases most prevalent in developing countries. This is partly because of greater attention and resources being given to the diseases of industrialized countries; it is also because of the inherent nature of the diseases and their effects on human hosts. To be effective against a disease-producing organism the antibiotic must be able to inhibit its growth

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ANTIBIOTICS AND VACCINES 161 or its production of toxic substances without having a similar effect on sur- rounding host cells. This may be especially difficult when the organism is localized in a particular tissue (as in the case of tuberculosis or leprosy) where it is necessary to maintain a high concentration of the antibiotic over suffi- cient time without adverse effects on the human or animal host. Further, there is often a need to grow the disease-producing orgarusms out- side the human or animal body, so that experimentation with potential con- trol agents will be possible. With some organisms, this has not yet been achieved. This inability to culture certain infecting organisms in vitro remains a major obstacle to their control. Many antibiotic-producing microorganisms have been isolated from soil by a simple procedure: a soil sample containing millions of microorganisms is suspended in water, the suspension is diluted severalfold, and samples are transferred to Petri plates containing agar media of various nutritive composi- tions. The plates are incubated until growth of the microorganisms occurs in the form of individual colonies. If any of these colonies has produced an antibiotic, it probably will have diffused into the agar and it can be detected by spraying the agar with a suspension of bacteria susceptible to the anti- biotic. The susceptible organisms form a solid lawn (growth) except where the antibiotic has diffused. Where the antibiotic exists, their growth will be arrest- ed and a clear zone will surround the colony that has produced the antibiotic. Figure 9.1 illustrates zone formation for several different antibiotics. Studies then can be carried out to determine the types of organisms in- hibited by the antibiotic. The antibiotic-producing culture is grown in increas- ingly larger volumes (in Erlenmeyer flasks or fermentation vessels) after deter- mining the conditions favoring maximum production of the desired active material. The antibiotic material may then be isolated and tested for potency alla for its ability to produce side reactions or toxicity in animals. Finally it can be prepared in still larger quantities (Figure 9.2~. Although basically FIGURE 9.1 The effectiveness of several antibiotics against a single microorganis can be simultaneously determined. Discs containing a variety of agents are tested to en- able selection (according to zone sizes) of those which might be used in vivo. (Photo- graph courtesy of BBL Microbiology Systems, Division of Becton, Dickinson and Com- pany)

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162 l. Reparation of Motion 2. Agar plate 1:100 1:10000 1: 100008 ,_ ~ ~ it, )C) . . ~ 15 Nil special nutrient medium '~_. ~ ~~' m'4 me my Soil sample 100 ml Interim dist. water 3. Spray apparatus for the spraying of the test organism on the agar plate Tort ^~nor~icn~~ Inhibitory Tect organism Compres.cc~l zone \ / air \ ,/ Inoenium (A ~ ~ in ~ncuba'Dr',~ Puriflcat.<,n: Grown agar plate 6. Suitability test for submerged culture ~6 # . 7 days at 24-27 in the shaken culture 9. MICROBIAL PROCESSES 9 ml Petri dish 5ttri~c dist. water _ Incubator 6 days at 25. 4. Evaluation of the S. Streak test sprayed plate for the determination or the antihacterist spectrum '] Tee< OCR for page 158
ANTIBIOTICS AND VACCINES 163 examples of narrow-spectrum antibiotics that act against only a few bacterial species. The major microbial sources of useful antibiotics are the actinomycetes (Streptomyces, Nocardia, Micromonospora) and molds or fungi (Penicillium, Cephalosporium). Human Diseases Table 9.1 lists major tropical diseases and indicates the availability of vaccines and antibiotics for their treatment. Much research remains to be done to arrest tropical diseases, particularly schistosomiasis, malaria, filariasis, trypanosomiasis (including African sleeping sickness and Chagas disease), onchocerciasis, and leishmaniasis, all common parasitic infections in the trop- ical zone. They are widespread, chronic, and may affect every member of a community. Although they are rare in industrialized countries in the temper- ate zones, the number of people suffering from their effects in the developing tropical regions runs into hundreds of millions. Their impact on individual well-being and productivity, in addition to physical suffering, has a profound effect on economic and social development. Most therapeutically useful antibiotics exert their inhibitory effects only on bacteria. Since many of the tropical diseases are caused by protozoa, multicellular animal parasites, and viruses, other agents must be sought. Methods must be developed for cultivation of the parasites under laboratory conditions and for detection and assay of agents that can inhibit their growth. Although the list of pathogens yet to be brought under control is lengthy, specific drugs and antibiotics discussed below have been developed for a number of widespread diseases. Antifungal Agents Both superficial and systemic diseases result from in- fection of the skin and viscera by pathogenic fungi. Typical skin infections, like chromomycosis and mycetoma, are caused by a diverse group of soil organisms. These infections develop slowly and are usually chronic. Mycetoma has been treated with penicillin and chromo- mycosis with amphotericin B. but surgical excision of small lesions is most effective. Better drugs are needed. Histoplasmosis is a lung disease caused by inhaling spores from soil-borne fungi. The causative organism prefers soils contaminated by bat or bird drop- pings; caves and chicken coops are notorious sources of the infection. Amphotericin B has been used successfully in the treatment of histoplasmosis. Blastomycosis is also a lung disease with secondary infections appearing on the skin. Amphotericin B has been used in the treatment of this disease. Tine a favosa is a fungal infection of the skin and scalp commonly seen in children. Griseofulvin has been shown to produce good curative effects.

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164 MICROBIAL PROCESSES TABLE 9.1 Availability of Antibiotics, Chemicals, or Vaccines for Treatment or Preven- tion of Various Tropical Diseases (x = reported successful use; ? = possible use or testing) Diseases Antibiotics Chemicals Vaccines Protozoan Diseases Amebiasis (Amebic dysentery) x Quinolines Leishmaniasis (Kala-azar) ? Antimonials Malaria ? Quinolines Trypanosomiasis (Sleeping sickness) Amidines, Suramin Fungal Diseases Blastomycosis Chromomycosis Histoplasmosis (Darling's disease) Mucormycosis Mycetoma Rhinosporidiosis Sporotrichosis Tinea favosa (Favus) Tinea imbricata (Tokelau) Bacterial Diseases x x x x Sulfas x x x Iodides Brucellosis (Undulant fever) x Cholera x x Cutaneous Diphtheria x Gonorrhea x Leprosy ? Sulfones Leptospirosis (Weil's disease) x ? Relapsing Fever x Arsenicals Shigellosis (Bacillary dysentery) x Syphilis x Tetanus x Tuberculosis x Isoniazides x Typhoid Fever Yaws Rickettsial Diseases Boutonneuse Fever Epidemic Typhus Murine Typhus Scrub Typhus x x x x x x x x x Mucormycosis is an infection of the intestines, lungs, and central nervous system, or skin. It is caused by one of a class of opportunistic fungi that generally do not infect the normal host but may cause disease in debilitated patients. For example, mucormycosis of the lung is associated with leukemia and mucormycosis of the intestines with malnutrition. In some instances, amphotericin B has been effective. Antibacterial Agents Many drugs are available for the treatment and con- trol of tuberculosis, a disease of bacterial etiology that is still highly prevalent

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ANTIBIOTICS AND VACCINES TABLE 9.1 Continued 165 Diseases Antibiotics Chemicals Vaccines Viral Diseases Bwamba Fever Dengue Infectious Hepatitis Influenza A&B Measles (Rubeola) Poliomyelitis Rabies Rift Valley Fever Smallpox (Variola) Trachoma West Nile Fever Yellow Fever Zika Fever Helminth Diseases Ancylostomiasis (Hookworm) Ascariasis (Roundworm) Clonorchiasis (Oriental liver fluke) Dipetalonemiasis Dipylidiasis Dracunculiasis (Dragonworm) Fascioliasis (Sheep liver fluke) Filariasis (Elephantiasis) Gastrodisciasis Gnathostomiasis (Creeping eruption) Hydatid disease Hymenolepiasis (Dwarf tapeworm) Loiasis (Eyeworm) Onchocerciasis (River blindness) Paragonimiasis (Oriental lung fluke) Schistosomiasis (Bilharziasis) Strongyloidiasis Taeniasis (Tapeworm) , ~ ... . rlcnmosls Trichostrongyliasis Trichuriasis (Whipworm) ? x x x x Sulfonamides Benzimidazoles Benzimidazoles Phenolics Pyrazines Salicylamides Pyrazines Phenolics Pyrazines Benzimidazoles Pyrazines Salicylamides Pyrazines Pyrazirles Phenolics Nitroim~dazoles Benzimidazoles Salicylamides Benzimidazoles Benzimidazoles Benzimidazoles x x in developing countries. When properly used, isoniazid and rifampin in com- bination with either streptomycin, p-aminosalicylic acid, or thiacetazone are highly effective therapeutic agents. Effective control of tuberculosis has been achieved, however, only in those countries where public health practices per- mit early detection of the disease by tuberculin testing and chest X-radiog- raphy, and by early treatment of all those who have had contact with those who are infected. Continuing control has been successful only where long- term drug administration can be assured. Leprosy is a chronic infectious disease caused by Mycobacterium leprae. General treatment includes enhancement of personal and environmental hygiene and an ample, well-balanced diet. Although the sulfones (particularly

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166 MICROBIAL PROCESSES DDS, 4, 4' - diamino diphenyl sulfone) have been the most effective class of drugs against leprosy, recent studies with the antibiotic rifampin at the WHO laboratories in Caracas have shown promise. The widespread use of antibiotics in the treatment of bacterial infection has resulted in the emergence of numerous highly resistant pathogens. Drug resistance has developed through selection and transfer of genetic information (plasmids, extrachromosomal DNA) in microorganisms. Prevalence of drug- resistant strains makes it imperative that new drugs be developed for treat- ment of certain infectious diseases, particularly those caused by Haemophilus influenzee, Neisseria gonorrhoeae, and pathogenic Enterobacteriaceae. Other Antimicrobial Agents Of the rickettsial diseases, epidemic typhus occurs in Africa and Europe. It is caused by Rickettsia prowozekii and can be controlled with chloramphenicol. Boutonneuse fever, a disease of the spotted fever group common in Africa, is caused by R. conorii. Chlortetracycline and chloramphenicol have produced favorable results in patients with this disease. The protozoa! disease amebiasis (amebic dysentery) is an infection by the ameba Entamoeba his tolytica. Although amebiasis is not confined to the tropics, its incidence is determined in part by the level of sanitation in a given area. The majority of antibiotics showing activity against this ameba act in- directly through their bacteriostatic activity rather than directly against this parasite. However, two of them, oxytetracycline and fumagillin, appear to act directly as amebacides and at times have been found effective in the treatment of acute amebic dysentery. Malaria may be the most serious widespread protozoa! disease. The organ- isms, Plasmodium sp., are difficult to culture and are controlled only slowly by the tetracyclines. The disease is currently controlled by chemicals (mair~ly chloroquine derivatives) administered prophylactically and is treated chemo- therapeutically by a variety of substances chemically related to quinine. WHO has cautioned against widespread use of antibiotics for treatment of malaria because of the risks of developing resistance in pathogenic bacteria, and recommends antibiotics only in areas where chloroquine-resistant strains of plasmodia are found. Antitumor Agents The use of products of microorganisms has also been extended to the area of cancer chemotherapy. Antibiotics with antitumor properties are produced by some micro- organisms and a few of these may be used therapeutically (i.e., adriamycin, bleomycin, actinomycin D, mithramycin, mitomycin C). The antitumor antibiotics are not a homogeneous group of compounds. Their antibacterial and antitumor activities are not correlated, but some cor- relation has been found between activities against transplantable tumors and human tumors.

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ANTIBIOTICS AND VACCINES 167 Antihelminths The only effective therapeutic agents as yet developed against infestations ~ man and animals are chemical agents derived by other than microbial processes (see Table 9.1~. Animal Diseases The most prevalent diseases of animals occurring in developing countries are trypanosomiasis (sleeping sickness), Newcastle disease, rinderpest, African swine fever, gastrointestinal parasitism, pasteurellosis, bovine pleuro- pneumonia, heartwater, sheep pox, babesiosis, brucellosis, hog cholera, and foot-and-mouth disease. Trypanosomiasis occurs principally in Africa where the tsetse fly, by which it is spread, is found in 700 million hectares of land and prevents the raising of cattle. It is estimated that this vast area could support 125 million cattle and an equal number of sheep and goats. There are no drugs or vaccines for this parasitic disease, and development of effective ones is critically needed. Gastrointestinal parasitism occurs worldwide in cattle, sheep, goats, swine, and poultry. A number of parasites are involved, although the helminths (roundworms) are the ones of prime importance. No vaccines are available, but there are effective drugs for control of some of these parasites. Pasteurellosis also occurs worldwide but is important primarily in Africa and Asia. This bacterial disease affects cattle and buffalo and has a major impact on draft animals. Vaccines and antibiotics are effective against the disease, but delivery to the field in many countries presents difficulties. Brucellosis occurs in naturally infected domestic animals in all parts of the world. Brucellosis is a serious cause of abortion in cattle, and to a lesser degree in sheep, goats, and swine. Vaccines and antibiotics are available for both prevention and cure of this bacterial disease. Hog cholera is a highly contagious viral disease. Although there are no effective drugs, vaccines are available for control. Foot-and-mouth disease is widespread in Europe, South America, the Middle East, and Mexico. Although vaccines may be used for control of this viral disease, they are type specific. To limit the spread of an outbreak, the enzootic strains must be determined and specific vaccines prepared for use against them. Control in many countries is through maintenance of quarantine along with supervised vaccination. Newcastle disease occurs worldwide and affects poultry, a major protein source in developing countries. Although there are vaccines available for some forms of this viral disease, they are not effective in all field situations. There are no effective drugs. Antibiotics as Growth Stimulants In some geographic areas, antibiotics are now used extensively in animal feeds to promote weight increases of young animals. In developed countries,

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168 MICROBIAL PROCESSES the use of such additives is economically important to farmers. When added to the feed of livestock and poultry in low concentrations (20-50 g per ton of feed), the animals are healthier, grow more rapidly, and reach marketable weight faster than those not fed antibiotics. In the United States, six antibiotics are used extensively for growth- promoting effects on poultry, swine, cattle, and dairy calves: bacitracin, chlor- tetracycline, oxytetracycline, monensin, procaine penicillin, and tylosin. Improved growth rates and feed utilization are in the range of 2-15 percent for broilers, 2-13 percent for swine, 3-4 percent for beef cattle, and 10-30 percent for dairy calves. Production of these antibiotics by a low-level "non- sterile" manufacturing process (see below), if one could be developed, would significantly increase their usefulness as feed supplements by decreasing their cost. The complication introduced by the appearance of mutant pathogenic microorganisms with multiple resistance to broad-spectrum antibiotics has led to consideration of banning of such feed additives in Great Britain and the United States. An antibiotic task force has questioned their use in feeds because of 1) development and dissemination of drug-resistant microorgan- isms, 2) increased shedding of salmonellae in animal dung, and 3) ingestion of antibiotic residues in human food, which may cause bacteriological and pharmacological hazards. The possible spread of drug-resistant microorganisms through transfer of extrachromosomal genetic material (DNA) is now of international concern to scientists and governments. Because of this concern, the use of antibiotics as food preservatives has already been discontinued in the United States and England. Plant Diseases Hundreds of bacterial and fungal species and a few viruses that cause plant diseases are known to be suppressed by antibiotics. However, the use of antibiotics to control plant pathogens is carried out on a large scale only in Japan. Streptomycin, the tetracyclines, cycloheximide, and griseofulvin have been used most extensively, but all have serious drawbacks, including plant toxicity and high production costs Blasticidin S and kasugamycin are widely used instead of mercurial fungicides to control the sheath blight of rice plants. These antibiotics are applied at very low concentrations, and the amount sprayed is 1-10 percent of that of conventional pesticides. This low concen- tration and the eventual biodegradation of the antibiotics lowers the pos- sibility of environmental pollution. However, the emergence of resistant microorganisms reduces the attractiveness of the procedures.

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ANTIBIOTICS AND VACCINES Nonsterile Production of Antibiotics 169 Since the large-scale production of antibiotics requires considerable capital investment and includes steps (maintenance of cultures, fermentation) that must be carried out under scrupulously clean conditions, their manufacture in the developing countries should be considered only in exceptional situations. To set up low-level, low-cost production of carefully selected antibiotics for plant or animal disease control might be possible under less rigid conditions than those currently in use. The production of feed-quality chlortetracycline on cereal solids, which was developed in Czechoslovakia, is an example of the potential of this simplified technology. Vaccines There are many vaccines available for the prevention of infections in human beings. They differ considerably in their composition, effectiveness, and duration of protection. Some are live attenuated viruses; others consist of whole killed bacteria. Still other preparations consist of viral or bacterial components or of modified products of bacterial toxins (or toxoids). A list of diseases for which relatively effective vaccines or immunogenic agents are available is shown in Table 9.1. The characteristics and future possibilities for some of these agents are shown in Table 9.2. Vital statistics obtainable from a number of countries suggest that utiliza- tion of many of the available vaccines is less than optimal. From the stand- point of public health and for the welfare of the population at large, it is important that nations establish effective programs for immunization against highly communicable infectious diseases. Such programs can be carried out only if the vaccines are available in adequate supply, with proper facilities provided for their storage and for protection of their potency, and only if the public can be educated about the benefits of immunization and a system of effectively delivering the vaccine can be developed and maintained. Identi- fication of vaccine failures, especially where the use of live vaccines is con- cerned, is important in detecting flaws in the methods of vaccine storage or administration. Certain vaccines offer a high degree of protection against the diseases for which they were developed. All children should be protected by immuniza- tion against measles, whooping cough, diphtheria, tetanus, and poliomyelitis. There has not been a naturally acquired case of smallpox reported in over a year anywhere in the world. If the disease is eradicated, then there will no longer be a need to vaccinate against it. Yellow fever vaccine has also proved highly effective and should be used in areas where the disease is endemic. Vaccines of the capsular polysaccharides of meningococcal Groups A and C

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170 TABLE 9.2 Current and Future Vaccines and Protective Agents Current Vaccine Disease or Protective Agent Cholera Killed whole organism MICROBIAL PROCESSES Possibilities in 5-10 Years 1. Toxoid vaccine 2. Oral attenuated 3. Oral killed Diphtheria Toxoid-absorbed Tetanus and diphtheria toxoids Tetanus Toxoid-absorbed have been effectively used via Pertussis Killed bacteria or the respiratory tract for bacterial fraction booster unmunization (con- cern exists for allergic re- actions in the lung) Veal hepatitis Type A Passive immune Killed or attenuated serum globulin (ISG) vaccines Type B Passive immune Specific high-titered serum globulin (ISG) ISG vaccine Influenza Egg-grown virus, formalin in- 1. Live attenuated vaccine activated, highly purified 2. Aerosol killed vaccine-fair by zonal ultracentrifugation protection, absence of side effects. Mumps Vaccine 3. Tissue culture-grown virus Measles Live attenuated virus, (rubeola) chick embryo or canine tissue-culture grown Plague Formaldehyde-inactivated Yersinia pestis Poliomyelitis Inactivated virus Attenuated virus monovalent or trivalent Rabies Active: (1) B-propiolactone- Live attenuated vaccine inactivated virus grown in embryonated duck eggs (2) phenol-inactivated virus grown in rabbit brain Passive: equine hyper- Lmmune serum Rubella Vaccine Typhoid Whole organism killed by Oral killed or attenuated vaccines several different techniques have been tested and seem to be more effective with fewer side~ffects Typhus Formaldehyde-inactivated Rickettsia prowazekii Dowry in embryonated eggs Yellow fever Live attenuated virus prepared in chick embryo: Dakar strain or 1 7D strain Source: Robert H. Waldman. 1978. Immunization procedures. In Clinical concerns of infectious diseases, L. E. Cluff, and J. E. Johnson, eds. Baltimore: Williams & Wilkins. Co.

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ANTIBIOTICS AND VACCINES 171 have been shown to be effective where cerebrospinal meningitis caused b these organisms is epidemic, and their administration is preferable to that of prophylactic antimicrobial drugs. To date, a vaccine effective against Group B meningococcal infection, although needed, has not been developed. Parasitic and Venereal Diseases A number of other widespread diseases still lack vaccines that will enable their eradication or control. These include the parasitic diseases endemic to many developing tropical countries and the venereal diseases, which are in- creasingly common throughout the world. Parasitic Diseases Diseases caused by protozoa and helminths are among the major scourges of mankind. Malaria, trypanosomiasis, leishmaniasis, schistosomiasis, and filariasis afflict millions of people. If vaccination against these and other diseases caused by parasites is contemplated, it will first be necessary to cultivate the causative organisms and identify the significant cell components. The recent in vitro cultivation of malarial parasites in the United States and of the blood form of trypanosomes in Kenya may provide prom- ising leads in the development of vaccines for these prevalent disorders. Venereal Diseases Among the venereal diseases, gonorrhea is a major prob- lem and in many geographic areas the etiological agent of the disease (Neis- seria gonowhoeae) has become resistant to the action of penicillin. There are significant gaps, moreover, in our knowledge of this organism and of the immune response to this infection in humans. Additional research is needed before a prophylactic vaccine can be developed. Meanwhile, antibiotics other than penicillin (for example, spectinomycin) may be effective. Syphilis is amenable to control by case- and contact-finding and by penicillin therapy. A vaccine effective against genital strains of Herpes simplex virus has distinct potential utility. Respiratory Infections In addition to diseases of childhood spread via the respiratory system (measles, rubella, mumps), there are many other infections transmitted in this fashion. Pneumococcal Infections Of the respiratory infections of bacterial origin, those caused by pneumococci are most prevalent and are a problem in some nations where rapid urbanization is in progress. Polyvalent vaccines of pneu- mococcal capsular polysaccharides are currently available and should prevent the majority of pneumococcal pneumonias. A similar vaccine for preventing

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172 MICROBIAL PROCESSES respiratory infection and meningitis in young children caused by Haemo- philus inpuenzoe Type B is under development, but the immune response of infants to this vaccine has been limited, as has the response to several other bacterial polysaccharides in children 12-18 months of age and younger. The need for research on the immunologic responsiveness to vaccines of this kind in children under 18 months is great. Bacterial Otitis Media An infection of the middle ear, bacterial otitis media is prevalent in all societies. If effective vaccines for its prevention could be developed, the damage to hearing that often results from it could be eliminated. Tuberculosis A vaccine of attenuated mycobacteria, scG (Bacille Cal- mette Guerin strain), has been successfully used against tuberculosis in certain societies. Some current opinion supports the view that the effect is nonspecific and that an active public health program of case finding and treatment of each index case and its contacts is a more effective means of controlling tuberculosis. Gastrointestinal Infections Enteric or intestinal infections exact a terrible toll throughout most of the world. The World Health Organization estimates that approximately 70 mil- lion people are afflicted with significant diarrhea! illness during each day of the year. Intestinal infections may be caused by a wide variety of bacteria, viruses, and protozoan parasites. They spare no age group, race, nation, or socioeconomic group. The young, especially infants, are particularly affected. In many countries diarrhea accounts for 25-50 percent of all infant deaths. Overall, enteric infection is the leading cause of mortality in most of the developing world. Much can be done to eliminate diarrhea! disease by sanitary measures, including the provision of good water supplies, sanitary disposal of sewage, and adequate cooking and refrigeration of foodstuffs. In areas where eco- nomic circumstances preclude such provision, vaccines offer a partially satis- factory means of preventing some gastrointestinal infection. Various vaccines have been devised to prevent intestinal illness, and some have been in use since the latter part of the 19th century. Only in the last two decades, however, has their efficacy been properly evaluated by controlled trials. Unfortunately, these trials have shown that the available vaccines against typhoid fever and cholera are limited in their effectiveness, and there are no vaccines available for many other causes of diarrhea. Typhoid Fever Long a scourge throughout the world, typhoid fever runs a protracted course, causing death in 10-20 percent of untreated victims and

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ANTIBIOTICS AND VACCINES 173 prolonged disability in its survivors. A recent outbreak in Mexico affected thousands of people, demonstrating the continuing threat of this disease. Vaccines against typhoid fever have been in use since 1895. They consist of suspensions of killed typhoid bacilli. Side effects are frequent and include painful swelling at the injection site, fever, and malaise, all of which may persist for several days. Because typhoid fever is generally contracted after ingestion of contami- nated food or water, attempts have been made to stimulate intestinal im- munity by the oral administration of killed typhoid bacilli. But even when these were given in twice the recommended dosage, the protective effect was only 30 percent. A recent attempt at oral immunization involved the use of attenuated typhoid bacilli. Given in multiple large doses to 155 adult volun- teers, this live vaccine caused no side effects and protected 87 percent of individuals from subsequent illness. Cholera Cholera, which ranks with typhoid as a global affliction, is known to have spread in pandemic fashion throughout the world on six occasions during the past two centuries. The seventh pandemic, which is currently affecting much of Asia, Africa, and the European countries bordering the Mediterranean, has been caused by a different type of organism, the so-called El Tor vibrio. The concern caused by the current appearance of the disease is great. Not only can cholera produce mortality rates of 50 percent and more in severely affected and untreated individuals, but it may create considerable panic and economic dislocation throughout a large geographic area. As with typhoid fever, vaccines against cholera have been in use since the turn of the century They have generally been composed of killed micro- organisms administered by one or more injections. Although many claims have been made as to their effectiveness, field teals have demonstrated that vaccine efficacy at best was 76 percent during the first 6 months. Protection waned thereafter, and subsequent booster doses were required. These results were obtained in a population that had had frequent prior exposure to the etiological agent of cholera and presumably possessed considerable immunity prior to vaccination. The vaccine is generally given in mass fashion during fresh outbreaks, although it has never been shown to have prevented an . . . eplaemlc. Promising results have been obtained with a living attenuated mutant of the cholera organism given orally to adult volunteers in the United States. Approximately 60 percent of recipients, given one to four vaccine doses, were protected from illness after subsequent exposure. The protective effect of this oral vaccine appeared to be at least equal to that of the injected vaccines tested in Bangladesh and elsewhere. Indeed, the efficacy of the oral preparation may be better in a true field situation, where the effective dose may prove to be substantially lower than that given to the volunteers of the U.S. study described above. Advantages of the oral product

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174 MICROBIAL PROCESSES are that it avoids the painful side effects of injections and the skill and expense of administering them. Present limitations to this oral vaccine are that it is live and produces small amounts of cholera toxin. Thus the possibility exists that it could revert to a virulent form. Neither this nor any other oral preparation has yet been field tested. Escherichia cold So-called "enteropathogenic" serotypes of E. cold were first discovered in England in the 1940s. They have been considered to be associated primarily with epidemics of severe gastroenteritis in hospital nurseries. Today, many clinical laboratories have the facilities to readily iden- tify these organisms. It has been recognized only recently that other varieties of E. colt, termed "toxigenic" are probably far more important as causative agents of diarrhea! illness. These organisms are similar to those causing cholera in that a toxin elaborated by the bacterium causes the illness, rather than the bacterium itself. They are probably responsible for a significant portion of the familiar traveler's diarrhea. Although epidemiological investigations are in their in- fancy, it seems quite likely that toxigenic E. cold play a substantial role in causing diarrhea throughout the world. Three other bacterial species, Cam- pylobacter fetus, Yersinia enterocolitica, and Vibrio parahemolyticus, have been recognized recently as causes of diarrhea! disease in man. No vaccine is available at present, nor is any mode of therapy definitely established. Shigellosis Bacterial dysentery, or shigellosis, is an endemic problem in many areas of the world and frequently flares up in epidemic form. Striking examples include the large outbreaks in Central America and Bangladesh in recent years. Treatment with specific antibiotics (chloramphenicol, ampicillin, or tetra- cycline) is usually successful, but shigella organisms possess a striking ability to develop resistance to antibiotic agents. An effective vaccine would be highly desirable, but none is commercially available. Viral Diarrhea Various viruses have long been thought to be responsible for diarrhea! illness. Recent studies have incriminated at least the reovirus and rotavirus. In some population groups, the latter agent is believed to be respon- sible for as much as 70 percent of diarrhea! illness in infants. Other studies have found that young children rapidly acquire antibodies against these viruses, an indirect indication of the prevalence of infection. Since work in this area is new, no vaccines are available. With successful cultivation and propagation of these viruses, however, it is reasonable to expect that an effective vaccine will be forthcoming.

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ANTIBIOTICS AND VACCINES 175 Parasites There are many parasites that may cause significant diarrhea (Giardia lamblia and Entamoeba histolytica are excellent examples). There is no imminent promise of a successful vaccine against any of these. References and Suggested Reading Anti biotics Beeson, P. B., and McDermott, W., eds. 1975. Textbook of medicine. Philadelphia- London-Toronto: W. B. Saunders Company. Corcoran, J. W., and Hahn, F. E., eds. 1974. Mechanism of action of antimicrobial and antitumor agents. Antibiotic Series, Volume 3. New York: Springer-Verlag. Goldberg, I. H.; Beerman, T. A.; and Poon, R. 1977. Antibiotics: nucleic acids as targets in chemotherapy. In Cancer: a comprehensive treatise, F. F. Becker, ea., Volume 6: Chemotherapy, pp. 427456. New York: Plenum Press. Kurylowicz, W., ed. 1976. Antibiotics-a critical review. Warsaw: Polish Medical Pub- lishers, distributed in the United States of America and Canada by the American Society for Microbiology, Washington, D.C. 20006. Lane, M. 1977. Chemotherapy of cancer. In Cancer: diagnosis, treatment and~prognosis, 5th edition, J. A. Del Regato; H. J. Spjut; and J. Harlan, eds., pp. 105-130. St. Louis, Missouri: C. V. Mosby Company. Maegraith, B. G., 1973. One world. London: Athlone Press, distributed in the United States of America by Humanities Press, Inc., Atlantic Heights, New Jersey. 1974. Tropical medicine: trends and progress. Journal of Tropical Medicine and Hygiene 77:4-7. Reiner, R. 197 7. Antibiotics. In Methodicum chimicum, Vol. 1 1: Natural compounds, Part 2: Antibiotics, vitamines and hormones, Fr. Korte and M. Goto, eds, pp. 2-68. New York: Academic Press. Woodbine, M., ed. 1976. Antibiotics and antibiosis in agriculture with special reference to synergism. London: Butterworths. Zahner, H., and Maas, W. K. 1972. Biology of antibiotics. New York: Springer-Verlag. Zeigler, E.; Moody, W.; Hepler, P.; and Varela, F. 1977. Light-sensitive membrane poten- tials in onion guard cells. Nature 270:270-271. Vaccines American Academy of Pediatrics. 1974. Report of the committee on infectious diseases. 17th edition. Evanston, Illinois: American Academy of Pediatrics. Ashcroft, M. T.; Singh, B.; Nicholson, C. C.; et al. 1967. A seven-year field trial of two typhoid vaccines in Guyana. Lancet 2:1056-1059. Current status and prospects for improved and new bacterial vaccines. 1977. Journal of Infectious Diseases 136: Supplement. Cvjetanovic, E., and Vermura, K. 1965. The present status of field and laboratory studies of typhoid and paratyphoid vaccines: with special reference to studies sponsored by the World Health Organization. World Health Organization Bulletin 32:29-36. Dupont, H. L.; Hornick, R. B.; Snyder, M. J.; et aL 1972. Immunity in shigellosis. II. Protection induced by oral live vaccine or primary infection. Journal of Infectious Diseases 125:12-16. Germanier, R. 1975. Effectiveness of vaccination against cholera and typhoid fever. Monographs in Allergy 9: 217-230. Gilman, R. H.; Hornick, R. B.; Woodward, W. E.; Dupont, H. L.; Snyder, M. J.; Levine, M. M.; and Libonati, J. P. 1977. Evaluation of a UDP-glucose-4-epimeraseless mutant of Salmonella typhz as a live oral vaccine. Journal of Infectious Diseases 136:717-723.

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1 176 MICROBIAL PROCESSES Gorbach, S. L., and Khurana, C. M. 1972. Toxigenic Escherichia coli: a cause of infantile diarrhea in Chicago. New England Journal of Medicine 287:791-795. Hejfec, L. B. 1965. Results of the study of typhoid vaccines in four controlled field trials in the U.S.S.R. World Health Organization Bulletin 3 2:1-14. Honda, T., and Finkelstein, R. 1979. Selection and characteristics of a Vibrio cholerae mutant lacking the A (ADP-Ribosylating) portion of the cholera entero-toxin. Proceedings of the US National A cademy of Sciences. 76: 205 2-205 6. Hornick, R. B., and Woodward, W. E. 1966. Appraisal of typhoid vaccine in experi- mentally infected human subjects. Transactions of the American Clinical and Cli- matological Association 7 8: 70-78. Mel, D. M.; Terzin, A. L.; and Vuksic, L. 1965. Studies on vaccination against bacillary dysentery. 3. Effective oral immunization against Shigella flexneri 2a in a field trial. World Health Organization Bulletin 32:647-655. Mosely, W. H. 1969. The role of immunity in cholera. Texas Reports on Biology and Medicine 27:22?-241. National Academy of Sciences. 1979. Pharmaceuticals for developing countries: con- ference proceedings of the division of interrogational health of the institute of medi- cine. Washington, D.C.: National Academy of Sciences. Rotaviruses of man and animals: Editorial. 1975. Lancet 1:257. Sack, R. B.; Hirschhorn, N.; Brownlee, I.; et al. 1975. Entero-toxigenic Escherichia coli-associated diarrhea! disease in Apache children. New England Journal of Medi- cine 20:1041-1045. Shore, E. G.; Dean, A. G.; Holik, K. J.; et al. 1974. Enterotoxin-producing Escherichia cold and diarrhea! disease in adult travelers: a prospective study. Journal of Infectious Diseases 129 :577-582. Waldman, Robert H. 1978. Immunization procedures. In Clinical concepts of infectious diseases, L. E. Cluff, and J. E. Johnson, eds. Baltimore: Williams & Wilkins Co. Woodward, W. E.; Gilman, R. H.; Hornick, R. B.; et al. 1976. Efficacy of a live oral cholera vaccine in human volunteers. Developments in Biological Standardization 33: 108-1 12. World Health Organization. 1972. Oral enteric bacterial vaccines. Technical Report Series, No. 500. Geneva: World Health Organization. Yugoslav Typhoid Commission. 1964. A controlled field trial of the effectiveness of acetone-dried and inactivated and heat-phenol inactivated typhoid vaccines in Yugo- slavia: Report. World Health Organization Bulletin 30:623-630. Source of Cultures Antibiotics and Vaccines American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. Research Contacts Antibiotics and Vaccines Burton Pogell, School of Medicine, St. Louis University, 1402 South Grand Boulevard, St. Louis, Missouri 53104, U.S.A. Oldrich K. Sebek, Infectious Disease Research Unit, The Upjohn Company, Kalamazoo, Michigan 49001, U.S.A. William E. Woodward, Program in Infectious Diseases and Clinical Microbiology, Uni- versity of Texas Health Science Center, P. O. Box 20708, Houston, Texas 7702S, U.S.A.