By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates; Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
The First 80 Hours in TB Treatment
Source: Gumbo T, et al. Isoniazid's bactericidal activity ceases because of the emergence of resistance, not depletion of Mycobacterium tuberculosis in the log phase of growth. J Infect Dis 2007;195:194-201.
In patients with M. Tuberculosis infection, the emergence of chromosomally mediated resistance to INH is a stochastic process, meaning it is the sum of the product of the spontaneous mutation rate (10-6) and the total bacterial load. In other words, if a patient has a small pulmonary infiltrate, with an estimated bacterial load of 10 + 4, the risk of INH-resistant organisms being present is about 1 in 100 (10-2). However, in a patient with a large cavitary infiltrate, with an estimate bacterial load of 10+ 9, the potential number of INH-resistant organisms is closer to 1000 (10+ 3). This rate of spontaneous mutation may occur in the absence of selective pressure, and may therefore be present prior to initiation of treatment, although it is well below the levels of detectability for most laboratories (> 1% of colonies).
For this reason, the information from Gumbo and colleagues is especially important. While clinicians have long believed that antimicrobial killing of TB stops at about 3-4 days of INH therapy because of depletion of organisms in the exponential growth phase, Gumbo and colleagues' data suggests otherwise. During the first 3 days of INH therapy, a rapid decline in colony counts (~ 2 logs) was observed, due entirely to the killing of INH-susceptible organisms. At that point, the number of organisms started to increase again, largely due to the exponential phase growth of the small INH-resistant population, which began to outnumber the declining INH-susceptible population.
Increases in both the low-level and high-level INH-resistant population were observed at various daily dosages of INH. Similar data was observed for either fast or slow acetylators (INH half-life 1.8 vs 4.2 hrs) - bacterial growth resumed at about 80 hours.
Resistance was primarily due to typical katG mutations, a single point mutation in the catalase-peroxidase gene, and the induction of multidrug resistant efflux pumps.
These data are important to consider in the context of the activity of other antimycobacterial agents. While cidal activity during the first 2 days is largely due to INH, rifampin and pyrazinamide affect a much slower decline in bacterial colony counts, beginning at about day 3 to day 14. Critically, this is just the point where killing from INH wanes. Administration of moxifloxacin is associated with about a one-third log reduction between days 0 and 2, and then a 0.24 log drop between days 2 and 7. The age-old practice of starting TB therapy one drug at a time is no longer advisable. Based on these data, one can see why.
More on XDR-TB: A Looming Crisis
Source:ProMED-mail, January 28, 2007; firstname.lastname@example.org
An increasing amount of lay press is illuminating the emergence of an exceptionally drug-resistant strain of M. tuberculosis (XDR-TB) (resistant to 6-10 second line agents) in South Africa - and the growing controversy surrounding that government's response.
Since XDR-TB was first detected in 53 persons (52 HIV+ patients quickly died) in KwaZulu-Natal Province in South African in May 2005, at least 300 additional cases have been identified in 39 hospitals in 8 other provinces in S. Africa. Experts at the WHO, and a spokesman for a consortium of South African and American AIDS researchers have expressed alarm that not enough is being done to identify and isolate cases, and that the infection is quickly spreading, threatening the large number of HIV-infected South Africans (estimated to exceed 20% of the population).
Active cases probably represent the tip of the iceberg, and many more persons have likely been exposed. Because of cross-border traffic of migrant workers and refugees, it is feared the infection has crossed into Mozambique, Swaziland, Lesotho and Zimbabwe- nations that have even fewer health care dollars to deal with this looming disaster. Experts are concerned that, since learning about the first outbreak in May 2005, the South African government is doing too little too late to identify and isolate cases. Sadly, treatment for many is not an option, given the extreme drug-resistant profile.
The Director of South Africa's National TB Program, Dr. Lindiwe Mvusi, disagrees with these concerns, contending that sufficient hospital beds are available, and new facilities are under construction.
The cost of routine TB treatment in Africa is estimated at about $15 dollars per case; about 10 times the health dollars available per person in some countries. However, the estimated cost of treating a single case of MDR-TB, including isolation, is about $150 per person. Some countries do not even have sufficient laboratory support to manage this problem, especially when you consider that one laboratory technician can process about 20 sputum specimens for AFB smear and culture per day.
Hemorrhaging Doctors and Nurses
Source: Mullan F. Doctors and Soccer players - African Professionals on the Move. N Engl J Med. 2007; 356:440-442.
This article briskly states another pressing problem for African health care: the loss of their educated health care professionals. A prime example of the "leaky" medical system is Ghana, which has attempted to ramp up the number of trained physicians and the quality of their education, hoping to retain at least some portion of their trained physicians. But the more dollars are pored into improving the quality of medical education, the more trained professionals are lost to the United States, the United Kingdom and Canada. Although Ghana has considerable natural resources, and a larger health care budget than most African nations, it is estimated to have only 13 physicians per 100,000 population, about one-twentieth the number of physicians per person in the United States. At least 20% of the physician work force is practicing outside of Ghana, leaving only about 2,600 doctors inside the country. The situation for nurses is even worse: attempts to establish a training facility for medical assistants failed because too few nurses were available to apply - they had all emigrated.
A major factor cited in this migration was money - a physician can make 6 times the salary in London as in Africa. Various creative measures to retain physicians, such as free cars, subsidized housing, and pay increases are being attempted but may fall short of the anticipated income and life-style of a medical practice in the United States or the United Kingdom. Other considerations, such as academic camaraderie, access to sub-specialty training, and the opportunity to practice a higher standard of medical care may be important factors, and must be compensated for if physicians are to be retained.
What went unstated in this article was the wish for a safer life for physicians and their families. Physicians, especially those who do not refrain from politic activity or social activism, have been run out of their country, or escaped corrupt and violent regimes, and are unable to return. I know of one Kaiser physician from Nigeria who expressed a wish to return to his country one day should the political situation change. And while a medical education may presently be a ticket out of Africa, it is possible these individuals would have found other opportunities to exit.
Improving TB Screening of Immigrants
Source: Varkey P, etal. The Epidemiology of Tuberculosis Among Primary Refugee Arrivals in Minnesota Between 1997 and 2001. J Travel Med. 2007; 14:1-8.
The emergence of increasingly drug-resistant forms of TB is prompting re-examination of TB screening practices of immigrants and refugees in the United States. By 2002, more than 50% of active TB cases in the United States occurred in foreign-born persons.
Minnesota, which has a long tradition of sponsoring immigrants and refugees, has one of the largest populations of Ethiopians and other Africans in the United States, and the third largest Southeast Asian population. (People are often surprised to learn that my medical school classmates and I lived on the inexpensive and delicious Vietnamese food around the University Medical Center in Minneapolis in the early 1980s). From 1979 to 2004, Minnesota accepted over 75,000 refugees. By 1998, 70% of MN TB cases were foreign born, compared with 41% for the rest of the nation.
In order to assess the adequacy of current public health screening procedures for refugees, these authors examined information available for 13,866 refugees who entered MN between 1997 and 2001. All persons were screened with skin testing, and chest radiographs were performed in those with a positive skin test, symptoms consistent with active TB, or an overseas exam or history of active, treated, or old TB. Of those with a documented skin test result, 51% were positive. Of these, 74% were from Africa, 58% were male, and 62% were 19 to 64 years of age.
Chest radiograph results could be located for 88% of those with a positive skin test, 70% of which were normal, 12% were abnormal but inconsistent with TB, 7% as abnormal but without any other information, 5% consistent with "old" TB, 0.8% non-cavitary disease, and 0.1% cavitary disease. Chest radiographs were missing or not performed for about 10% of patients with a positive skin test.
Of those with a positive skin test, 49% received treatment for latent tuberculosis. The remainder was not treated because of age > 35 years, refusal, loss to follow-up, or prior treatment was completed overseas. No data were available on compliance with treatment or successful completion of appropriate therapy.
Refugees have a peculiar status in the United States - because of their political status, many do not receive appropriate screening and vaccination before entry into the country, although they are "encouraged" to get a health care screening within 90 days of arrival. But many do not have ready access to good public health care systems and fall through the cracks. As a result, refugee status is an independent predictor of failure to diagnosis and promptly treat TB. In this survey of refugees entering MN from 1997 to 2001, half of those with positive skin tests did not received appropriate therapy for latent TB. This finding is especially important when rates of reactivation TB are examined across the United States, most of which occur in foreign-born persons. Thus far, INH remains the standard of treatment for TB exposure and latent TB. However, the increasing frequency of drug-resistant strains may diminish the effectiveness of INH for these purposes. Even in our own Santa Clara County, the rate of INH resistance has dramatically risen to 17%, largely because of the presence of a significant Southeast Asian population.