Risk Factors
Drug Use in Humans
The evolution of drug resistance is facilitated by a number of factors, including increasing use of antibiotics and antimalarials; insufficient controls on drug prescribing; inadequate compliance with treatment regimens; poor dosing; lack of infection control; increasing frequency and speed of travel, which lead to the rapid spread of resistant organisms; and insufficient incentives for patients, physicians, or even governments to care about increasing resistance. It is important to distinguish between risk factors for the emergence of resistance (de novo resistance) and those for the spread of resistance (primary resistance).
The molecular basis of resistance may give a clue to the likelihood of resistance emerging. If a single DNA base pair mutation leads to the development of resistance, then its selection is likely to be widespread, especially if the biological fitness cost of the mutation is low. De novo or acquired resistance results in the appearance of a resistant strain in a single patient. Subsequent transmission of such resistant strains from an infectious case to other persons leads to disease that is drug resistant from the outset, a phenomenon known as primary resistance (IUATLD 1998). Independent, cumulative events result in multidrug-resistant bacteria or tuberculosis (MDR-TB). Both the creation and the transmission of drug resistance contribute to its prevalence in a given population. This mechanism also holds true in the case of antimalarials; that is, resistance develops when malaria parasites encounter drug concentrations that are strong enough to eradicate the susceptible parasite population, but they fail to inhibit the multiplication of naturally occurring resistant strains. Commonly used antimalarial drugs are not mutagenic.
In the case of tuberculosis, spontaneous mutations leading to drug resistance occur rarely in Mycobacterium tuberculosis, and multidrug regimens can prevent the emergence of clinical drug resistance (Cohn, Middlebrook, and Russell 1959). Resistance is thus an avertable phenomenon resulting from inadequate treatment, which, in turn, is often the result of an irregular drug supply, prescription of inappropriate regimens, or poor adherence resulting from a lack of supervision. In the case of malaria, the widespread misuse of chloroquine as prophylaxis is believed to be an important factor in the emergence and spread of resistance to this drug.
Despite conventional wisdom, the highest rates of antibiotic resistance in the pneumococcus bacterium globally are not for penicillins or macrolides, which usually require multiple DNA mutations or the import of foreign genes, respectively, but for sulfamethoxazole-trimethoprim, which can be selected from among a population of susceptible pneumococci by a single base change in the dihydrofolate reductase gene (Adrian and Klugman 1997). The direct selection of resistance following exposure of children carrying pneumococci has been shown in a prospective study in Malawi to occur in 42 percent of children exposed to sulfadoxine-pyremethamine for a week and in 38 percent of children a month after exposure to drug treatment for malaria (Feikin and others 2000).
Evolutionary biology suggests that drug selection pressure is an important factor in the emergence and spread of drug resistance. Although the relationship between antimicrobial use and drug resistance (in the pneumococcus, for example) is well established in developed countries (Bronzwaer and others 2002), direct evidence to support this hypothesis is less forthcoming in developing countries because of a lack of data on antibiotic use. Resistance to antimicrobials is less likely to arise in the poorest developing countries simply because of the lower levels of antibiotic use associated with poorer socioeconomic status. For instance, India—a large country with scant control over antibiotic prescribing—has very low rates of resistance among systemic isolates of pneumococci, at least in rural areas (INCLEN 1999). These low rates exist despite wide antibiotic availability, probably because extreme poverty limits the duration of antibiotic exposure for the treatment of acute pneumococcal infections. Rising incomes and increased affordability of antibiotics will likely change this low incidence of resistance; the same may be true of quinolones, which are widely available at relatively affordable prices, even in semirural and rural populations. This trend may be responsible for the emergence of nalidixic acid resistance to Shigella in Bangladesh and fluoroquinolone resistance to Salmonella typhi in India.
Recent evidence suggests that shorter courses of antibiotics may select for less resistance in the pneumococcus compared with longer courses (when patients comply with those courses) (Schrag and others 2001). Very low levels of resistance have also been found in isolated rural African communities (Mthwalo and others 1998). This observation, however, should not lead to complacency. Increased access to antibiotics in developing countries, without controls on over-the-counter use, has led to some of the highest rates of resistance in the world, as was seen with penicillin resistance in Vietnam. Relatively wealthy countries such as the Republic of Korea and Japan also have lax control and even greater access to funds to purchase antibiotics (Song and others 1999). Patterns of resistance differ by antimicrobial class, and resistance to several classes has been linked to particular patterns of use in developing countries. Macrolide use in children in China may be preferred to the use of beta-lactams, which are known to be associated in rare instances with serious anaphylactic reactions, and in Beijing and Shanghai, the highest global rates of macrolide resistance are encountered in nasopharyngeal isolates from children (Wang and others 1998; Yang, Zhang, and McGee 2001). Tetracycline use remains widespread in developing countries, and poor African countries, such as the Central African Republic, may have higher rates of resistance to tetracycline than to beta-lactams or macrolides (Rowe and others 2000).
The relationship between compliance and resistance emergence in the treatment of acute and largely self-limiting infections is less robust than in the case of chronic infections such as tuberculosis (TB). It is likely that resistance selection occurs more readily in the commensal flora (for example, the pneumococcal flora of the nasopharynx) than among the organisms causing the acute infection. Thus, shorter courses (and reduced compliance) may reduce the selection of resistance in commensal flora. In contrast, in TB, selection takes place in the infecting pathogen, and poor compliance is associated with the selection of resistant strains.
Antibiotic Use in Animals
Many developed countries use antibiotics for veterinary uses, both for improving feed efficiency and rate of weight gain (subtherapeutic use) and for disease prevention and treatment (therapeutic use) (Levy 1992). Although the extent of antibiotic use in animals in developing countries is unknown, one study from Kenya reported that tetracyclines, sulfonamides, and aminoglycosides were the most commonly used antimicrobials for veterinary purposes (Mitema and others 2001). Over 90 percent of the antibiotics used were for therapeutic purposes, and there was no evidence of use for growth promotion.
There is strong evidence that the use of antibiotics in farm animals promotes the development of drug-resistant bacteria in animals (Aarestrup and others 2001). Because routes for the movement of these resistant bacteria to humans are available, there is sufficient circumstantial evidence that drug resistance in bacteria associated with food animals can influence the level of resistance in bacteria that cause human diseases (Wegener and others 1999). Furthermore, mathematical models indicate that the effect of subtherapeutic use on resistance in humans is greatest when resistance levels are undetectable (Smith and others 2002). The appearance of drug-resistant strains of Enterococcus faecium in broiler meat products at retail outlets declined after the ban of antimicrobial growth promoters in Denmark (Emborg and others 2003). Salmonella has been recovered from chicken (35 percent), turkey (24 percent), and pork (16 percent) samples obtained from area supermarkets in Washington, D.C. (White and others 2001). There is evidence that dissemination of tetracycline-resistance-encoding plasmids between aquaculture and humans has already occurred in Europe (Rhodes and others 2000). The global nature of this problem became apparent in 2001, when authorities in some European countries found residues of chloramphenicol in tiger shrimp imported from China, Indonesia, and Vietnam (Holmstrom and others 2003).
Transmission of Resistant Pathogens
Once resistance has emerged in a population, it can spread both geographically and between age groups. Unsafe drinking water, unsanitary conditions, and poor infection control in hospitals are risk factors for the transmission of all infections, including resistant ones. The transmission of resistant strains from children to adults has been suggested by anecdotal reports as far back as the 1980s (Klugman and others 1986). That association is strongly supported by the role of conjugate pneumococcal vaccine in reducing antimicrobial resistance among adult pneumococcal bacteremic isolates in the United States (Whitney and others 2003). The association of HIV infection with pediatric serotypes and antimicrobial resistance in pneumococci suggests the potential utility of this approach in reducing the burden of antimicrobial resistance in pneumococci in developing countries where the burden of disease is overwhelmingly associated with HIV infection in both children (Madhi and others 2000) and adults (Jones and others 1998).
Disease Burden
Although no estimates of disease burden are currently available that are specific to drug resistance, the contribution of drug resistance to the burden of infectious diseases is believed to be large. Resistance has emerged in malaria, HIV, TB, and other bacterial infections that together constitute a significant proportion of the burden of disease in developing countries. An indication of the extent of the problem is provided by the burden of diseases for which drug resistance is a problem (table 55.1), as well as by the levels of drug resistance among these pathogens (table 55.2 and figures 55.1 and 55.2).
[Figure
55.1]
[Figure
55.2]
[Table .]
[Table .]
Pneumococci
Surveillance of drug resistance in pneumococci shows several general trends. The numbers of strains that are fully susceptible to penicillin-G, once nearly universal in most of the world, have declined by 30 to 50 percent in many countries and by 75 percent in some, as resistant clones have spread widely but irregularly throughout the world (Sa-Leao and others 2002). At the same time, percentages resistant to macrolides and to sulfamethoxazole-trimethoprim have increased, especially where those drugs have been widely used, and resistance to tetracycline or chloramphenicol has fluctuated widely. Linked resistance to these drugs results in a growing percentage of strains resistant to many or all of them. Resistance to fluoroquinolones is still rare but is beginning to be observed in many places (Ho and others 2001; Quale and others 2002).
Certain Streptococcus pneumoniae clones have been widely disseminated. A penicillin-, chloramphenicol-, and tetracy-cline-resistant clone (and sometimes erythromycin) of Spanish origin (Spain23F-1) has, since its original description, been isolated in other parts of Europe, the United States, South and Central America, South Africa, and East Asia (McGee and others 2001). It is likely that this clone is even more widespread and that the absence of reports from other areas reflects the absence of molecular testing techniques needed to delineate clones, rather than an absence of the organisms themselves. Other globally disseminated S. pneumoniae include specific clones of serotypes 19F, 14, 19A, 9N, 9V, 3, and 6 (McGee and others 2001). Spread of these pandemic clones has continued, even in areas where successful interventions have reduced selective pressure from antimicrobial use (Arason and others 2002). With increasing international travel, the potential of these strains to spread to areas where resistance is uncommon can no longer be considered remote.
Shigella
In many regions where Shigella, especially Shigella dysenteriae, is prevalent and an important cause of infant mortality, resistance first to sulfamethoxazole-trimethoprim, then to ampicillin, and commonly to tetracycline and chloramphenicol has emerged and, over recent decades, spread to half or more of the strains sampled. In the 1990s, resistance has begun to emerge and spread to fluoroquinolones and third-generation cephalosporins, which in many places are the last effective oral drugs available (Ding and others 1999). In the past two decades, emergence and spread of Shigella dysenteriae type 1 resistant to sulfamethoxazole-trimethoprim, ampicillin, tetracycline, chloramphenicol, and—increasingly—nalidixic acid has reduced the effectiveness of these inexpensive and widely available antimicrobials in the empiric management of epidemic dysentery (Cunin and others 1999; Hoge and others 1995). The alternatives, ciprofloxacin and ceftriaxone, are relatively expensive and not always available. As a consequence, high fatality rates have been observed in a number of recent dysentery outbreaks (Legros and others 1998). The emergence of fluoroquinolone-resistant strains has quickly followed. The unchecked spread of these pathogens could pose a major public health challenge (Sarkar and others 1979).
Gonorrhea
Newly drug-resistant strains of gonococci tend to spread rapidly because of their peculiar epidemiology and the lack of control programs. Therefore, it is important to detect microepidemics of such strains, but this need is rarely met. The past half-century has witnessed the successive emergence and spread of gonococcal strains resistant to each new drug that becomes widely used to treat gonorrhea, including sulfonamides, penicillin, tetracycline, and sulfamethoxazole-trimethoprim (Tapsall 2002). Within less than a decade, such strains have commonly come to account for half or more of the isolates in many regions. The recent emergence of resistance to fluoroquinolones leaves only less available parenteral drugs, such as spectinomycin or ceftriaxone, as the reliable therapy (Ison and others 1998; Palmer, Leeming, and Turner 2001).
Tuberculosis
The emergence and spread of multidrug-resistant tuberculosis, which is defined as combined resistance to isoniazid and rifampicin, threaten the control of TB globally (Kochi, Vareldzis, and Styblo 1993). Patients infected with strains resistant to multiple drugs are very difficult to cure (Espinal and others 2000; Goble and others 1993), particularly if they are HIV-infected or malnourished (Fischl and others 1992), and alternative treatment is much more toxic and expensive (Drobniewski and Balabanova 2002). A patient with MDR-TB may remain infectious much longer than a patient with drug-susceptible organisms. Among new cases, prevalence of resistance to at least one TB drug ranges from 0 percent in some Western European countries to 57.1 percent in Kazakhstan, with a median of 10.2 percent. Multidrug resistance among untreated patients ranged from 0 percent in eight countries to 10.0 to 14.2 percent in six others. In previously treated cases, resistance to at least one drug ranged in different settings from 0 to 82.1 percent, with a median of 18.4 percent. Prevalence of MDR-TB in previously treated cases ranged from 0 to 58.3 percent, with a median of 7.0 percent (WHO 2004).
An estimated 273,000 (at a 95 percent confidence interval [CI]; 185,000 to 414,000) new cases of MDR-TB occurred worldwide in 2000. By simple extrapolation, 70 million people could be latently infected with MDR-TB, and more than 1 million active MDR-TB cases could remain among previously treated patients. Despite its threatening potential, MDR-TB is—and will probably remain—generally rare. Decades after the introduction of TB drugs, the global prevalence of MDR-TB in new patients remains less than 2 percent (Dye and Espinal 2001). Old animal studies (Cohn and others 1954) and recent analyses using molecular epidemiology (Garcia-Garcia and others 2000) suggest that MDR-TB strains might be, on average, less infectious. And unlike most other bacteria, M. tuberculosis replicates rather slowly (low mutation rate) and shares little if any genetic material. Thus, even in the absence of widespread treatment of MDR-TB, its prevalence may not necessarily explode (Kam and Yip 2001).
Malaria
Chloroquine-resistant strains of Plasmodium falciparum malaria appeared a half-century ago in Southeast Asia and South America and spread across Africa, especially East Africa, in the past quarter-century (Wellems and Plowe 2001). The use of molecular markers testing indicates the wide geographical reach of pfcrt polymorphism for chloroquine resistance, and dhfr and dhps polymorphisms for sulfadoxine-pyrimethamine. Current levels of treatment failure of chloroquine are in figure 55.1. There is evidence that malaria mortality, especially in children under the age of five, is rising as a consequence of increasing resistance to chloroquine (Greenberg and others 1989; Trape 2001). In response to increasing treatment failure, many countries, including Malawi, South Africa, and Tanzania, adopted sulfadoxine-pyrimethamine as first-line treatment; however, resistance to this drug too is growing in many parts of Africa. In Southeast Asia, the emergence of multidrug resistance to sulfadoxine-pyrimethamine and mefloquine over the past decade and a half has prompted the use of combination treatments that include artemisinin (Wongsrichanalai and others 2001).
