I've appended an editorial from this week's NEJM on spreading antibiotic resistance. Right now CBST and MCDE (and perhaps XOMA) are the pure plays on antibiotic resistance. (A strong dark horse here is Paratek, still private).
CBST, if they hadn't in-licensed daptomycin, wouldn't be much further advanced than MCDE. Dapto is looking pretty good however, and CBST is where I currently hold stock.
CBST has been excessively weak the last few months, perhaps because of a warning letter from the FDA grumbling about excessive promotion. (Unusual in a product that isn't yet approved). I would regard the warning as a buying opportunity myself. Details (as well as some copies of dapto presentations) are at:
fda.gov
Here is the NEJM editorial:
The New England Journal of Medicine -- December 28, 2000 -- Vol. 343, No. 26
Managing Antibiotic Resistance
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One hundred years ago, the three major causes of death in the United States were tuberculosis, pneumonia, and gastrointestinal infections. Subsequently, the advent of antibiotics resulted in a major decline in the incidence of life-threatening infections in the developed world. By the end of the 20th century, only lower respiratory tract infections still ranked among the top 10 causes of death. As we approach January 2001, however, the unforgiving rise in the frequency of multidrug resistance among leading pathogens should cause great concern and incite a commitment to act responsibly.
The pneumococcus is arguably the most important cause of community-acquired pneumonia, meningitis, and bacteremia. Recently, an epidemiologic study of three counties in West Virginia showed that despite declines in case fatality rates, the incidence of bacteremic pneumococcal pneumonia increased substantially from the period 1978 through 1982 to the period 1993 through 1997. (1) Among children younger than 4 years of age, the annual rates increased from 21 per 100,000 to 45 per 100,000, and among those who were 70 to 79 years of age, the rates increased from 15 per 100,000 to 39 per 100,000.
A recent population-based study in San Francisco found that over 50 percent of cases of invasive pneumococcal disease occurred in patients who were infected with the human immunodeficiency virus (HIV). (2) The mortality rates were 7.8 times as high among HIV-positive patients infected with pneumococcal strains that were highly resistant to penicillin (minimal inhibitory concentration of penicillin, greater than or equal to 2 µg per milliliter in vitro) as among those infected with susceptible strains (minimal inhibitory concentration, less than or equal to 0.06 µg per milliliter) or strains with intermediate levels of resistance (minimal inhibitory concentration, 0.1 to 1.0 µg per milliliter). (3) Furthermore, surveys of pneumococcal isolates in the United States (4) and Europe (5) showed that strains with increased levels of resistance to penicillin also had an increased likelihood of resistance to multiple antibiotics. Thus, the interactions between old and new pathogens (the pneumococcus and HIV, respectively) and the increased incidence of multidrug-resistant strains have set the stage for a serious public health problem.
Within our nation's 5400 acute care hospitals, the three leading causes of nosocomial infections of the bloodstream are coagulase-negative staphylococci (80 percent of which involve strains resistant to methicillin), Staphylococcus aureus (30 percent of which involve strains resistant to methicillin), and the enterococci (20 percent of which involve strains resistant to vancomycin). The crude mortality rates associated with these infections are 21 percent, 25 percent, and 32 percent, respectively. (6) Although the contribution of resistance to the outcome of such infections is unclear, nosocomial infections of the bloodstream may represent the eighth leading cause of death in the United States, (7) and the relentless rise of antibiotic resistance has markedly curtailed options for therapy.
In this issue of the Journal, two articles focus on important aspects of antibiotic resistance. Whitney and colleagues present data from a national surveillance system showing that in 1998, 24 percent of isolates of Streptococcus pneumoniae were highly resistant or had intermediate resistance to penicillin and that 15 percent were resistant to cefotaxime, 16 percent to meropenem, 16 percent to erythromycin, and 29 percent to trimethoprim-sulfamethoxazole. (8) Donskey and colleagues found that antianaerobic therapy promoted high-density colonization with vancomycin-resistant enterococci (approximately 8 log organisms per gram of stool). (9) The nearby environment of the patients with high stool concentrations (e.g., bedding and clothing) was also found to be contaminated with vancomycin-resistant enterococci, posing an infection-control hazard. The findings of these two studies have urgent policy implications that must put an end to the national complacency about antibiotic resistance.
Three important measures can be used to predict the level of antibiotic resistance in a given nation or in a single hospital: the proportion of resistant organisms introduced from outside the population, the proportion that is selected for spontaneously or enhanced as a result of antibiotic use, and the proportion that is spread from person to person. Epidemiologic studies have traced the introduction into Iceland of a penicillin-resistant pneumococcal clone expressing capsular serotype 6B from Spain (10) and the dissemination of a strain expressing capsular serotype 23 from Spain to the United States, and eventually to Asia and South America. (11) In Iceland, the effect of this strain was dramatic. The percentage of cases of pneumococcal disease among children that was due to penicillin-resistant strains increased from 0 percent in 1989 to 20 percent in 1993. Similarly, Moreno and colleagues recorded the introduction and transmission of a single strain of vancomycin-resistant enterococci, an important nosocomial pathogen, to 32 patients in five hospitals in San Antonio, Texas, over a 19-month period. (12)
"Antibiotic pressure" refers to the crude relations between the extent of the use of drugs and the selection of resistant strains. Each year in the United States, 160 million prescriptions are written for antibiotics and 22.7 million kg (25,000 tons) of antibiotics are prescribed, approximately 50 percent for use by patients and 50 percent for use in animals, agriculture, and aquaculture. (13) In a population of 275 million, this degree of use in terms of exposure is equivalent to nearly 30 prescriptions per 100 persons per year and to 4.1 kg (9 lb) of antibiotics per 100 persons per year. This enormous level of use of antibiotics has great potential for selecting for or enhancing the growth of resistant strains. Probably half of all such uses are inappropriate, as is represented by the needless treatment of viral upper respiratory tract infections, bronchitis, and pharyngitis.
The problem of antibiotic resistance is global. An organism's expression of a novel gene coding for drug resistance in remote communities has implications for the developed world. Once a resistant organism is introduced into a population, it is rapidly disseminated. Physician leaders worldwide need to join public health authorities, the infection-control community, and the pharmaceutical industry to curb the inappropriate use of antibiotics and promote responsible prescribing.
Some encouraging news from Hungary and Iceland suggests that decreasing the use of penicillin can lead to a decline in the proportion of strains of pneumococcus that are resistant to penicillin. (14,15) We endorse the World Health Organization's recommendation that an international surveillance system for resistant strains be established, (16) but we think that it should also monitor drug use and patterns of resistance, the outcomes in patients, and compliance with infection-control measures, such as hand washing in hospitals. Methods of educating prescribers should be tested, and industry should be given incentives to develop rapid diagnostic tests.
The data of Donskey and colleagues imply that the overprescribing of antianaerobic drugs promotes the growth of vancomycin-resistant enterococci. (9) Studies are needed to evaluate whether reducing the number of antianaerobic drugs that are prescribed would lower the rates of vancomycin-resistant enterococci in hospitals. In addition, monitoring of the prescribing practices of physicians and their reasons for the use of antibiotics and providing feedback to them may be helpful.
Whitney and colleagues showed that almost 80 percent of the penicillin-resistant isolates were of serotypes included in the 7-valent pneumococcal protein conjugate vaccine recently tested in children and that almost 90 percent were included in the 23-valent polysaccharide vaccine currently available for adults. (8) In the San Francisco study, 83 percent of the pneumococcal isolates from patients with HIV were included in the 23-valent polysaccharide vaccine, yet only about one third of the patients had received the vaccine. (2) Cost-benefit analyses have shown that vaccination of all infants (17) and all elderly persons (18) would be of value. Routine immunization of infants in the United States would prevent 12,000 cases of meningitis, 53,000 cases of pneumonia, and 110 deaths. (17) In terms of the critical value of prevention in adults, the retrospective analysis of Austrian and Gold in 1964 showed that penicillin had little or no effect on the outcome of pneumococcal bacteremia during the first three days of therapy. (19) In the light of subsequent data, this earlier observation should serve as an impetus for the increased use of both vaccines.
The antibiotic era is barely 60 years old, yet the inappropriate use of these drugs threatens our ability to cope with infections. Looking back, we know that the case fatality rate for pneumococcal pneumonia was 30 to 35 percent among adults in the 1930s and that it fell to 20 to 25 percent with the advent of serum containing anticapsular antibody, to 12 to 15 percent with the availability of sulfonamides, and eventually to 5 to 8 percent with the introduction of penicillin. (20) Looking forward, we need to reassess policies on antibiotic use while changing our approach to include vaccination against pneumococcal infections of all children under the age of 4, all adults over the age of 65, and all people with HIV infection.
Richard P. Wenzel, M.D.
Michael B. Edmond, M.D., M.P.H.
Virginia Commonwealth University
Richmond, VA 23298-0663
Peter |
