Candidate Bacterial Conditions

M.L. Cohen*

In 1900, infectious diseases -- especially bacterial diseases -- were the leading cause of morbidity and mortality, and diseases such as tuberculosis and pneumococcal infection were called the "Captain of all these men of death". A series of factors that began in the 16th and 17th centuries and extended into the 20th century greatly influenced the frequency of infectious diseases. These factors included improvements in hygiene and sanitation, better housing and nutrition, and safer food and water; the technological advances of the 20th century include use of vaccines and antibiotics. It is important to emphasize that, particularly for bacterial diseases, any reduction in their frequency is multifactorial and related to both specific and nonspecific changes. For example, examination of the estimated and reported mortality for tuberculosis in England from 1700 to 1920 shows a peak around 1770 at a rate of 700 per 100,000 -- carrying a nearly 1% chance per year of dying of tuberculosis. By 1920, the mortality rate had decreased to less than 50 per 100,000. This decline preceded the introduction of BCG and antituberculosis chemotherapy. Thus, factors such as improvements in nutrition, decreased crowding, and better hygiene and sanitation were major contributors to the reduction in the incidence of tuberculosis. As we approach the 21st century, bacterial diseases and infectious diseases in general are no longer the leading causes of death in the developed world, except for certain conditions (e.g. heart disease) which may have a significant infectious etiology, as is currently being discussed. Globally, however, the perspective is different. For example, in 1992, almost 20 million deaths were caused by infectious and parasitic diseases, which WHO estimates to have been the leading cause of death worldwide. Bacterial disease (e.g. tuberculosis and other respiratory and diarrhoeal diseases of bacterial etiology) accounted for more than half of these deaths.

Bacterial diseases are not static but include newly emerging diseases, re-emerging diseases that were once thought to be conquered, and diseases that show changes of antimicrobial resistance. For example, in the last two decades, bacterial diseases have been newly recognized, including Legionnaires' disease, toxic shock syndrome, Lyme disease, campylobacteriosis, Escherichia coli 0157 : H7 infections, helicobacter infections associated with peptic ulcer disease, and Bartonella infections associated with cat scratch disease. Cholera is an example of a re-emerging disease in the Western hemisphere which, since 1991, has caused over a million cases and 10,000 deaths. Other diseases, such as meningococcal infections, Salmonella enteritidis infections associated with shelleggs, foodborne listeriosis, and tuberculosis have increased in frequency, in some instances in both the industrialized and developing world. Antimicrobial resistance, once thought to be primarily a problem of hospital-acquired infections, is also a particular problem among community-acquired infections. In the hospital, there are strains of enterococci and tuberculosis that are essentially untreatable with antimicrobials, and strains of Staphylococcus aureus that have become relatively resistant to vancomycin -- the last effective antimicrobial for many of these strains. In the community, drug-resistant infections with pneumococci, salmonella, shigella, and gonococci have become important public health problems. For example, strains of Shigella dysenteriae 1A in parts of the developing world have become resistant to almost every oral antimicrobial agent. Many strains of multidrug-resistant pneumococci are only susceptible to vancomycin.

One final point involves the often unexpected consequences of changes that either intentionally or unintentionally affect the frequency of bacterial diseases. In the latter part of the 19th century and into the 20th century, efforts were made to improve hygiene and sanitation in many parts of the developed world. In Germany, for example, with increases in the number of homes in Frankfurt-am-Main that were connected to sewers and water mains, the death rate from typhoid fever rapidly decreased. However, an unexpected impact of such improvements in hygiene and sanitation in the developed world resulted in postponement or prevention of the exposure of many parts of the population to poliomyelitis, creating a population susceptible to epidemics and paralytic disease at a later age. Thus, efforts to eliminate or eradicate one disease may have important implications for another.

Based on the responses from the conference participants to identify potential candidates for elimination or eradication, only one bacterial disease -- neonatal tetanus -- was felt to be a strong candidate for elimination. There was relatively little difference in support for other bacterial diseases, including Haemophilus influenzae b infection, leprosy, diphtheria, pertussis, tuberculosis, meningococcal disease, congenital syphilis, trachoma, and syphilis. The low level for most bacterial diseases relates, in part, to various deficiencies in the criteria for elimination or eradication. For many of these diseases, there are either inadequate diagnostic methods or inadequate interventions, or there are reservoirs that persist in the environment or animal populations. Thus, for most bacterial diseases, eradication is not feasible and elimination is extremely complicated.

Neonatal tetanus -- the one potential candidate for elimination -- is a devastating illness caused by infection with Clostridium tetani, usually of the umbilical stump. The case-fatality ratio for this infection is greater than 80% and it ranks second only to measles as a cause of childhood mortality among the vaccine-preventable diseases that are included in the Expanded Programme on Immunization. It is estimated that annually there are over 490,000 deaths from neonatal tetanus, accounting for a global mortality rate of 6.5 per 1000 live births. Effective interventions include vaccination coverage with two doses of tetanus toxoid among women of childbearing age in high-risk areas. This approach, coupled with efforts to promote clean delivery and core care practices, as well as evaluation of the role of topical antimicrobial agents, provides a potential to eliminate this disease. Elimination goals have been set by WHO and, between 1980 and 1995, the number of developing countries that eliminated neonatal tetanus increased from 38 to 97.

Haemophilus influenzae is also an important cause of global morbidity and mortality, causing meningitis, pneumonia, and septicaemia. In the USA, prior to the introduction of conjugate vaccines, an estimated 1 in 200 children were affected by age 5 years. At present, the estimates of the global burden of disease range from 380,000 to 600,000 deaths annually in children aged less than 5 years. The potential for elimination or eradication of this disease has been supported by the introduction of effective conjugate vaccines. These vaccines have led to a significant reduction in the incidence of invasive Haemophilus influenzae type B disease in the developed world (e.g. in the USA, .95% reduction). In addition, in several industrialized countries, the vaccine has led to significant reduction in the carriage rate of this organism. Even though these achievements suggest that effective use of the vaccine may lead to global eradication of related disease, several barriers persist, including its high cost and the lack of data on both the effectiveness and the impact on carriage in developing countries compared with the developed world.

Leprosy (Hansen's disease) is an ancient problem whose control has long been complicated by an incubation period that can range from 2 to 40 years. Although the disease appears to have low infectivity, there remain questions about the occurrence of transmission, including the relative importance of person-to-person and environmental transmission. The current prevalence of the disease is greater than 1.1 million, a substantial decline from the 10-12 million in recent years. None the less, 500,000 new cases occur annually, predominantly in 55 countries throughout the world. Perhaps the greatest impact on this disease has been the demonstrated effectiveness that multidrug therapy is curative. In contrast to the previous life-long therapy of patients infected with its causative agent, Mycobacterium leprae, multidrug regimens are curative within 6-12 months. Although these regimens have raised optimism for elimination of leprosy, there are, as with any chronic multidrug therapy, issues of compliance and microbial resistance.

Diphtheria had been under good control in most developed countries until the early 1990s when it resurged, particularly in the Newly Independent States of the former Soviet Union. Although the specific explanation for this resurgence is unclear, continued circulation of toxigenic strains and waning immunity in adults have been postulated as possible explanations. Interventions include an inexpensive and safe toxoid and a pattern of seasonal transmission that presents the opportunity for interruption of transmission. Pertussis is also an important cause of global morbidity and mortality accounting annually for 39 million cases and 355,000 deaths. Although intervention is part of routine infant immunization programmes, immunization does not prevent carriage or circulation of the strain in the community and current schedules do not provide immunization for adults. Thus, waning immunity in adults, continuing carriage, infection and disease limit the effectiveness of interventions. In addition, diagnostic tests are of limited effectiveness and the lack of surrogates for protection complicate the development of new vaccines. Congenital syphilis is another candidate for elimination. There is an estimated 70% probability of transmission from an infected pregnant woman to the fetus. Over 900,000 infected pregnancies occur globally each year, resulting in 360,000 fetal or perinatal deaths and the births of 270,000 infants with serious or permanent impairment. The intervention strategy involves testing of all pregnant women for syphilis and the treatment of all positives with penicillin. Penicillin remains an excellent intervention tool since it is both inexpensive and the spirochaete has not developed resistance. Most of the issues that could affect elimination of this disease are operational.

Bacterial diseases remain an important cause of morbidity and mortality in both the developed and the developing world. The emergence of new and re-emergence of old bacterial diseases, and the development of antimicrobial resistance pose substantive challenges to public health. For most bacterial diseases, eradication is not likely and any plans for elimination are complicated by the characteristics of the disease and limitations in intervention.

* Director, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.

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