73 E. Pérez-Trallero, M. Urbieta, C. L. Lopategui, et al., “Antibiotics in Veterinary Medicine and Public Health,†Lancet 342 (1993): 1371–72.
74 E. Pérez-Trallero, C. Zigorraga, G. Cilia, et al., “Animal Origin of the Antibiotic Resistance of Human Pathogen Yersinia enterocolitica,†Scandinavian Journal of Infectious Diseases 20 (1988): 573.
75 S. D. Holmberg, M. T. Osterholm, K. A. Senger, and M. L. Cohen, “Drug-Resistant Salmonella from Animals Fed Antimicrobials,†New England Journal of Medicine 311 (1984): 617–22.
76 The Salmonella problem was exacerbated by home microwave oven cooking. It turned out that Salmonella could withstand microwaves, and reheated meat dishes often proved dangerously contaminated. See B. D. Gessner and M. Beller, “Protective Effect of Conventional Cooking Versus Use of Microwave Ovens in an Outbreak of Salmonellosis,†American Journal of Epidemiology 139 (1994): 903–9.
77 S. B. Levy, “Playing Antibiotic Pool: Time to Tally the Score,†New England Journal of Medicine 311 (1984): 663–64; Brunton, J. “Drug-Resistant Salmonella from Animals Fed Antimicrobials,†New England Journal of Medicine 311 (1984): 1698–99; and T. H. Jukes, “Drug-Resistant Salmonella from Animals Fed Antimicrobials,†New England Journal of Medicine 311 (1984): 1698–99.
78 J. S. Spika, S. H. Waterman, G. W. SooHoo, et al., “Chloramphenical-Resistant Salmonella newport Traced Through Hamburger to Dairy Farms,†New England Journal of Medicine 316 (1987): 565–70.
79 L. W. Riley, R. S. Remis, S. D. Helgerson, et al., “Hemorrhagic Colitis Associated with a Rare Escherichia coli Serotype,†New England Journal of Medicine 308 (1983): 681–85.
80 S. Ringertz, B. Bellete, I. Karlsson, et al., “Antibiotic Susceptibility of Escherichia coli Isolates from Inpatients with Urinary Tract Infections in Hospitals in Addis Ababa and Stockholm,†Bulletin of the World Health Organization 68 (1990): 61–68; and S. Harnett, “Transferable High-Level Trimethoprim Resistance Among Isolates of Escherichia coli from Urinary Tract Infections in Ontario, Canada,†Epidemiology of Infection 109 (1992): 473–81.
Some remarkable E. coli strains emerged in the early 1990s. For example, outside Cambridge, England, two strains appeared on a hospital transplant ward that were resistant to the antibiotic imipenen, as well as cefotaxime, ceftazidime, ciprofloxacin, gentamicin, ampicillin, azlocillin, coamoxiclav, timentin, cephalexin, cefuroxime, cefamandole, streptomycin, neomycin, kanamycin, tobramycin, trimethoprim, sulfamethoxazole, chloramphenicol, and nitrofurantoin. Only one commonly used antibiotic remained effective: amikacin. If the strains became resistant to that drug, they would be invulnerable to human treatment. See D. F. J. Brown, M. Farrington, and R. E. Warren, “Imipenenresistant Escherichia coli,†Lancet 342 (1993): 177.
In the Netherlands in 1992 a random survey of fecal samples from 310 healthy people yielded 456 E. coli types, nearly all of which bore some level of antibiotic resistance: 89 percent were resistant to ampicillin, 28 percent to trimethoprim, 80 percent to chloramphenicol. Only 19 percent were still susceptible to all eleven frontline antibiotics, and 14 percent were multiply resistant to four or more drugs. See M. Bonten, E. Stobberingh, J. Philips, and A. Houben, “Antibiotic Resistance of Escherichia coli in Fecal Samples of Healthy People in Two Different Areas in an Industrialized Country,†Infection 30 (1992): 258–62.
And it was clear that plasmids and transposons that conferred antibiotic resistance traits in E. coli also commonly carried genes for greater virulence. See J. R. Johnson, I. Orskov, F. Orskov, et al., “O, K, and H Antigens Predict Virulence Factors, Carboxylesterase B Pattern, Antimicrobial Resistance, and Host Compromise Among Escherichia coli Strains Causing Urosepsis,†Journal of Infectious Diseases 169 (1994): 119–26.
81 B. Marshall, D. Petrowski, and S. B. Levy, “Inter- and Intraspecies Spread of Escherichia coli in a Farm Environment in the Absence of Antibiotic Use,†Proceedings of the National Academy of Sciences 87 (1990): 6609–13; and M. Singh, M. A. Chaudry, J. N. Yadava, and S. C. Sanyal, “The Spectrum of Antibiotic Resistance in Human and Veterinary Isolates of Escherichia coli Collected from 1984–86 in Northern India,†Journal of Antimicrobial Chemotherapy 29 (1992): 159–68.
82 Several other cases of transmission of E. coli from manure to humans have since been described. See P. R. Cleslak, T. J. Barrett, P. M. Griffin, et al., “Escherichia coli 0157:H7 Infection from a Manured Garden,†Lancet 342 (1993): 367; G. M. Morgan, C. Newman, S. R. Palmer, et al., “First Recognized Community Outbreak of Haemorrhagic Colitis Due to Verotoxin-Producing Escherichia coli 0157:H7 in the U.K.,†Epidemiology of Infection 101 (1988): 83–91; and S. A. Renwick, J. B. Wilson, R. C. Clarke, et al., “Evidence of Direct Transmission of Escherichia coli 0157:H7 Infection Between Calves and a Human,†Journal of Infectious Diseases 168 (1993): 792–93.
83 Centers for Disease Control, “Preliminary Report: Foodborne Outbreak of Escherichia coli 0157:H7 Infections from Hamburgers—Western United States, 1993,†Morbidity and Mortality Weekly Report 42 (1993): 85–87; and S. Deresinski, “From Hamburgers to Hemolysis: Escherichia coli 0157:H7,†Infectious Disease Alert 12 (1993): 81–84.
84 A. D. Russell, “Microbial Cell Walls and Resistance of Bacteria and Fungi to Antibiotics and Biocides,†Journal of Infectious Diseases 168 (1993): 1339–40; and Columbia-Presbyterian Medical Center, Infection Control: A Training Paradigm for Healthcare Professionals (New York, 1994).
85 By 1994 the anti-chlorine sentiment would run so high in the United States that the head of the federal Environmental Protection Agency would advocate a virtual ban on all chlorinated products. Despite objections from industries as diverse as plastics manufacturing, cosmetics, electronics, dry cleaning, and petroleum, the EPA would move vigorously for massive reductions. In addition to public concern about cancer, the EPA would cite evidence that free chlorine ions expelled into the atmosphere acted as ozone scavengers, contributing to the depletion of the ozone layer.
86 I. Amato, “The Crusade Against Chlorine,†Science 261 (1993): 152–54.
87 Cryptosporidium are about 4 to 6 microns in size, just a bit smaller than E. coli. Most water filters could only screen out organisms and particles of 100 microns or more in size. Disinfection was really the only practical way to sterilize the water.
88 E. B. Hayes, T. D. Matte, T. R. O‘Brien, et al., “Large Community Outbreak of Cryptosporidiosis Due to Contamination of a Filtered Public Water Supply,†New England Journal of Medicine 320 (1989): 1372–76.
89 Centers for Disease Control, “Surveillance for Waterborne Disease Outbreaks—United States, 1991–1992,†Morbidity and Mortality Weekly Report 42 (1993): SS5—SS22.
90 K. C. Spitalny, R. L. Vogt, L. A. Orciari, et al., “Pontiac Fever Associated with a Whirlpool Spa,†American Journal of Epidemiology 120 (1984): 809–17; E. J. Mangione, R. S. Remis, K. A. Tait, et al., “An Outbreak of Pontiac Fever Related to Whirlpool Use, Michigan, 1982,†Journal of the American Medical Association 253 (1985): 535–39; and CDC, “Surveillance for Waterborne Disease Outbreaks†(1993), op. cit.
91 E. Geldreich, “Summary Report: Investigation of the Cabool, Missouri, Outbreak for a Water Supply Connection,†U.S. Environmental Protection Agency, Washington, D.C.
92 Natural Resources Defense Council, “Think Before You Drink: The Failure of the Nation’s Drinking Water System to Protect Public Health†(New York: NRDC Publication, 1993).
93 S. B. Levy, “Active Efflux Mechanisms for Antimicrobial Resistance,†Antimicrobial Agents and Chemotherapy 36 (1992): 695–703; and H. Nikaido, “Prevention of Drug Access to Bacterial Targets: Permeability Barriers and Active Efflux,â
€ Science 264 (1994): 382–88.
94 J. Lederberg, speech before the Irvington Trust, New York City, February 8, 1994.
95 Gibbons (1992), op. cit.
96 J. Davies, “Inactivation of Antibiotics and the Dissemination of Resistance Genes,†Science 264 (1994): 375–82; and B. G. Spratt, “Resistance to Antibiotics Mediated by Target Alternatives,†Science 264 (1994): 388–93.
97 M. Raymond, P. Gros, M. Whiteway, and D. Y. Thomas, “Functional Complementation of Yeast ste6 by a Mammalian Multidrug Resistance mdr Gene,†Science 256 (1992): 232–34.
98 C. F. Amabile-Cuevas and M. E. Chicurel, “Horizontal Gene Transfer,†Scientific American 81 (1993): 332–41.
99 M. Blot, J. Meyer, and W. Arber, “Bleomycin-Resistance Gene Derived from the Transposon TnS Confers Selective Advantage to Escherichia coli K-12,†Proceedings of the National Academy of Sciences 88 (1991): 9112–16.
100 For an excellent overview of the various genes inside normal bacterial chromosomes that control the absorption and use of mobile DNAs, see D. J. Galas and M. Chandler, “Bacterial Insertion Sequences,†Chapter 4 in Berg and Howe (1989), op. cit.
101 Amabile-Cuevas and Chicurel [(1992), op. cit.] pictured the movement of transposons and plasmids between various families of organisms as a highly fluid and ongoing process. On the basis of organism interactions and the relatedness of various known plasmids and transposons, they came up with the following representation of likely gene swapping.
102 J. D. Boeke, “Transposable Elements in Saccharomyces cerevisiae,†Chapter 13 in Berg and Howe (1989), op. cit.; and H. Varmus and P. Brown, “Retroviruses,†Chapter 3 in Berg and Howe (1989), op. cit.
103 R. Saral, W. H. Burns, O. L. Laskin, et al., “Acyclovir Prophylaxis of Herpes-Simplex-Virus Infections: A Randomized, Double-Blind, Controlled Trial in Bone-Marrow-Transplant Recipients,†New England Journal of Medicine 305 (1981): 63–67.
104 G. J. Mertz, C. W. Critchlow, J. Benedetti, et al., “Double-Blind Placebo-Controlled Trial of Oral Acyclovir in First-Episode Genital Herpes Simplex Virus Infection,†Journal of the American Medical Association 252 (1984): 1147–51; and S. E. Straus, H. E. Takiff, M. Seidlin, et al., “Suppression of Frequently Recurring Genital Herpes,†New England Journal of Medicine 310 (1984): 1545–50.
105 K. E. VanLandingham, B. Marsteller, G. W. Ross, and F. G. Hayden, “Relapse of Herpes Simplex Encephalitis After Conventional Acyclovir Therapy,†Journal of the American Medical Association 259 (1988): 1051–53; A. L. Rothman, S. H. Cheeseman, S. N. Lehrman, et al., “Herpes Simplex Encephalitis in a Patient with Lymphoma: Relapse Following Acyclovir Therapy,†Journal of the American Medical Association 259 (1988): 1056–57; and R. J. Whitley, “The Frustrations of Treating Herpes Simplex Virus Infections of the Central Nervous System,†Journal of the American Medical Association 259 (1988): 1067.
106 W. I. Whittington and W. J. Cates, Jr., “Acyclovir Therapy for Genital Herpes: Enthusiasm and Caution in Equal Doses,†Journal of the American Medical Association 251 (1984): 2116–17.
107 Though acyclovir was first used to treat herpes simplex-2, which caused genital herpes, it soon proved effective in controlling the entire family of herpes viruses, including varicella (chicken pox and shingles), herpes zoster, and herpes simplex-1. All of these viruses had the ability to hide latently inside human nerve cells for years, even decades, only surfacing when immunological conditions in the host favored their survival. For example, the same virus that caused childhood chicken pox would hide for five or six decades, resurfacing to produce often excruciating shingles.
108 L. Seale, C. J. Jones, S. Kathpalia, et al., “Prevention of Herpesvirus Infections in Renal Allograft Recipients by Low-Dose Oral Acyclovir,†Journal of the American Medical Association 254 (1985): 3435–38.
109 D. Parris and J. E. Harrington, “Herpes Simplex Virus Variants Resistant to High Concentration of Acyclovir Exist in Clinical Isolates,†Antimicrobial Agents and Chemotherapy 22 (1982): 71–77.
110 E. Katz, O. Rosenblat, and S. Pisanty, “Isolation and Characterization of Herpes Simplex Virus Resistant to Nucleoside Analogs,†Oral Surgery, Oral Medicine and Oral Pathology 72 (1991): 296–99.
111 H. J. Field and S. E. Goldthorpe, “The Pathogenicity of Drug-Resistant Variants of Herpes Simplex Virus,†Fourth Forum in Virology, 1992, 120–24.
112 K. S. Erlich, J. Mills, P. Chatis, et al., “Acyclovir-Resistant Herpes Simplex Virus Infections in Patients with the Acquired Immunodeficiency Syndrome,†New England Journal of Medicine 320 (1989): 293–96; and R. J. Whitley and J. W. Gnann, Jr., “Acyclovir: A Decade Later,†New England Journal of Medicine 327 (1992): 782–89.
113 Quite unfortunately, the sexual partner refused to cooperate with the study, so Straus was unable to absolutely confirm this hypothesis by performing PCR analysis of his herpes strain. It is a sorry fact that individuals commonly decline to participate in such studies, which could prove of immense good for the community as a whole. Such lack of participation is evident in all types of people. The failure of cooperation in this case—in a gay man—was actually fairly unusual, as the American gay community had proven remarkably open to scientists and their investigations since the onset of the AIDS epidemic.
114 The study is described in R. G. Kost, E. L. Hill, M. Tigges, and S. Straus, “Brief Report: Recurrent Acyclovir-Resistant Genital Herpes in an Immunocompetent Patient,†New England Journal of Medicine 329 (1993): 1777–81.
115 S. Safrin, C. Crumpacker, P. Chatis, et al., “A Controlled Trial Comparing Foscarnet with Vidarabine for Acyclovir-Resistant Mucocutaneous Herpes Simplex in the Acquired Immunodeficiency Syndrome,†New England Journal of Medicine 325 (1991): 551–55; and S. Safrin, “Management of Patients Following Successful Healing of Acyclovir-Resistant Herpes Simplex Infection,†Fourth Forum on Virology, 1992, 125–26.
116 J. M. Pepin, F. Simon, M. C. Dazza, and F. Brun-Vezinet, “The Clinical Significance of in vitro Cytomegalovirus Susceptibility to Antiviral Drugs,†Fourth Forum on Virology, 1992, 126–27; and C. Leport, S. Puget, J. M. Pepin, et al., “Cytomegalovirus Resistant to Foscarnet: Clinicovirologic Correlation in a Patient with Human Immunodeficiency Virus,†Journal of Infectious Diseases 168 (1993): 1329–30.
117 N. S. Lurain, K. D. Thompson, E. W. Holmes, and G. S. Read, “Point Mutations in the DNA Polymerase Gene of Human Cytomegalovirus That Result in Resistance to Antiviral Agents,†Journal of Virology 66 (1992): 7146–52.
118 S. Safrin, S. Kemmerly, B. Plotkin. et al., “Foscarnet-Resistant Herpes Simplex Virus Infection in Patients with AIDS,†Journal of Infectious Diseases 169 (1994): 193–96.
119 M. C. Y. Heng, S. Y. Heng, and S. G. Allen, “Co-infection and Synergy of Human Immunodeficiency Virus-1 and Herpes Simplex-1,†Lancet 343 (1994): 255–58.
120 The literature on AZT resistance is vast and occasionally contradictory on questions of timing of emergence. Key studies include: A. Erice, D. L. Mayers, D. G. Strike, et al., “Brief Report: Primary Infection with Zidovudine-Resistant Human Immunodeficiency Virus Type 1,†New England Journal of Medicine 328 (1993): 1163–65; M. S. Hirsch and R. T. D’Aquila, “Therapy for Human Immunodeficiency Virus Infection,†New England Journal of Medicine 328 (1993): 1686–95; V. A. Johnson, “New Developments in Antiretroviral Drug Therapy for HIV Infection,†Chapter 4 in P. Volberding and M. A. Jacobson, AIDS Clinical Review 1992 (New York: Marcel Dekker, 1992); B. A. Larder, K. E. Coates, and S. D. Kemp, “Zidovudine-Resistant Human Immunodeficiency Virus Selected by Passage in Cell Culture,†Journal of Virology 6 (1991): 5232–36; and H. Mohri, M. K. Singh, W. T. W. Ch
ing, and D. D. Ho, “Quantitation of Zidovudine-Resistant Human Immunodeficiency Virus Type 1 in the Blood of Treated and Untreated Patients,†Proceedings of the National Academy of Sciences 90 (1993): 25–29.
121 M. S. Smith, K. L. Korber, and J. S. Pagano, “Long-Term Persistence of Zidovudine Resistance Mutations in Plasma Isolates of Human Immunodeficiency Virus Type 1 Dideoxyinosine-Treated Patients Removed from Zidovudine Therapy,†Journal of Infectious Diseases 169 (1994): 184–88; and C. P. Conlon, P. Klenerman, A. Edwards, et al., “Heterosexual Transmission of Human Immunodeficiency Virus Type 1 Variants Associated with Zidovudine Resistance,†Journal of Infectious Diseases 169 (1994): 411–15.
122 Z. Gu, Z. Gao, X. Li, et al., “Novel Mutation in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene That Encodes Cross-Resistance to 2’,3’-Dideoxyinosine and 2’3’-Dideoxycytidine,†Journal of Virology 66 (1992): 7128–35; and Z. Song, G. Yang, S. P. Goff, and V. R. Prasad, “Mutagenesis of the Glu-89 Residue in Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2 Reverse Transcriptase: Effects on Nucleoside Analog Resistance,†Journal of Virology 66 (1992): 7568–71.
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