Capreomycin Classification Essay

ABSTRACT

To study the cost of chromosomal drug resistance mutations to bacteria, we investigated the fitness cost of mutations that confer resistance to different classes of antibiotics affecting bacterial protein synthesis (aminocyclitols, 2-deoxystreptamines, macrolides). We used a model system based on an in vitro competition assay with defined Mycobacterium smegmatis laboratory mutants; selected mutations were introduced by genetic techniques to address the possibility that compensatory mutations ameliorate the resistance cost. We found that the chromosomal drug resistance mutations studied often had only a small fitness cost; compensatory mutations were not involved in low-cost or no-cost resistance mutations. When drug resistance mutations found in clinical isolates were considered, selection of those mutations that have little or no fitness cost in the in vitro competition assay seems to occur. These results argue against expectations that link decreased levels of antibiotic consumption with the decline in the level of resistance.

FOOTNOTES

    • Received 21 August 2001.
    • Returned for modification 27 November 2001.
    • Accepted 24 January 2002.
  • ↵*Corresponding author. Mailing address: Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastr. 30/32, CH-8028 Zürich, Switzerland. Phone: 41-1-634 2684. Fax: 41-1-634 4906. E-mail: psander{at}immv.unizh.ch.
  • ↵† Present address: Division of Mycology and Mycobacteriology, Department of Microbiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

  • American Society for Microbiology

1. Introduction

Tuberculosis (TB) is believed to have been present in humans for thousands of years, as evidenced by the bones of ancient Egyptian mummies showing deformities consistent with the disease. Historically, pulmonary TB was known as the “Great White Plague” (causing about one in four deaths) of the 17th and 18th centuries in Europe, “phthisis” (a Greek term meaning to waste away), “scrofula” (swollen glands of the neck), and “consumption” (progressive wasting of the body) [1]. From 1700 to 1900, it is estimated that TB was responsible for one billion deaths and killed more people than any other disease [1,2]. Prior to the introduction of antibiotics in the 1950s, improved sanitation and living conditions significantly reduced the incidence of TB disease.

TB is transmitted via the respiratory route as a highly infectious aerosol with varying outcomes occurring from this initial Mycobacterium tuberculosis exposure. These outcomes can range from immediate organism destruction by the host’s immune system to infected individuals developing active primary TB disease within 1–3 years [3]. However, the majority of individuals infected with M. tuberculosis have a non-contagious, clinically-latent infection with an absence of clinical symptoms [4]. Latently-infected individuals have a 5–10% risk of developing reactivation TB disease during their lifetime [3], often due to immunosuppressive circumstances, with HIV infection being the greatest identified cause [5].

The discovery of the first antibiotic, streptomycin, to treat TB in 1944 was soon met with the appearance of the first antibiotic-resistant M. tuberculosis isolates [6]. A rapid succession of additional anti-TB agents was discovered in the late 1940s through the 1950s, with the last, rifampin, discovered in the 1960s [7]. To circumvent the development and emergence of drug resistance, a multidrug chemotherapeutic approach for treating TB was also introduced in the 1960s [8,9,10]. The concomitant emergence of HIV in 1980s further complicated and worsened the ongoing TB epidemic [11], and the global TB/HIV coinfection epidemic continues today with TB infecting one-third of the 33.2 million people living with HIV [12]. Continued evolution and exacerbation of the drug resistance problem has led to extensively drug-resistant TB, or XDR-TB, which is resistant to first-line and second-line TB antibiotics [13,14]. MDR and XDR forms of TB are extraordinarily difficult to treat, particularly in immunocompromised patients, and pose serious threats to global health.

2. Global Incidence, Prevalence, and Mortality of TB

Worldwide, TB is the second leading cause of death from a single infectious agent. Highlighting its success as a human pathogen, the World Health Organization (WHO) declared TB a global emergency in 1993 and warned that the disease could kill 30 million people over the next decade if effective control efforts were not implemented. While significant epidemiological, treatment, and control strategies have been employed over the past decade, the WHO estimate of nearly 30 million deaths was relatively accurate, with TB continuing to be one of the world’s major infectious diseases. Globally, one-third of the world’s population is infected with TB, with over nine million incident cases of active TB disease and an estimated 1.3 million deaths occurring per year [15]. Regionally, the majority of TB cases in 2008 existed in Asia (55%) and Africa (30%), with significantly lower proportions of cases in the Eastern Mediterranean (7%), Europe (5%), and the Americas (3%) [16]. Given the vast number of individuals who succumb to the disease each year, long-term actions to fight this public health challenge must be and are aimed at reducing global mortality and eliminating the disease [17,18].

Global control efforts over the past decade have resulted in relative stabilization of incident and prevalent cases of TB and reduction in TB deaths (Table 1) [19]. In 2004, global incidence rates peaked at 142 cases per 100,000 population, and the slow rate of decline since 2004 has been at less than 1% per year [19]. Accounting for population growth, the currently estimated 139 incident cases per 100,000 population has remained relatively stable for the past several years [16,19,20]. Prevalence is a direct indicator of the global TB burden, referring to the number of individuals with the disease at a particular time [21,22]. The overall numbers of estimated prevalent cases of TB decreased from 13.9 to 11.1 million from 2006 to 2008, corresponding to a reduction in the number of cases per capita from 210 to 164 per 100,000 population in 2006 and 2007, respectively (Table 1) [16,19]. Globally, TB treatment success rates in 2007 were 86%, thus meeting the 85% success rate target first established by the WHO in 1991 [15,16,18].

Worldwide, TB accounts for approximately one-fourth of HIV-related deaths and is the leading cause of death in HIV-infected adults in developing countries [12,16,22,23]. In 2000, nine percent of all new TB cases and 12 percent of TB cases in adults were attributable to HIV infection [22]. In 2008, the influence of the HIV pandemic on the global burden of TB continued to escalate as an estimated 1.4 million incident cases, representing 15% of the total TB incidence, occurred in HIV-positive patients [16]. While the overall number of HIV-related or HIV-attributed TB deaths has remained relatively stable over the past decade (Table 1), the interlinked TB and HIV epidemics continue to inflect serious morbidity and mortality in sub-Saharan African countries [24]. Approximately 78% of the globally estimated 1.4 million HIV-positive TB patients live in sub-Saharan Africa [12] with 30 to 40% of these HIV-infected individuals dying from TB [25].

Table 1. Estimated global incidence, prevalence, and mortality of TB [16,19,22,26].

2000200620072008
Incidencea8.3 million9.24 million9.27 million9.4 million
Prevalenceb16.6 millionc13.9 million13.7 million11.1 million
Deaths (total)1.8 million1.7 million1.7 million1.8 million
HIV-negative1.6 million1.5 million1.3 million1.3 million
HIV-positive0.226 million0.231 million0.456 milliond0.52 milliond

3. Recommended TB Treatment and the Current Arsenal of TB Antibiotics

The current standard chemotherapeutic regimen for treating new pulmonary TB patients consists of a multidrug combination of the first-line anti-TB drugs-isoniazid, rifampin, pyrazinamide, and ethambutol-administered for an intensive, initial period of two months. A continuation phase of treatment for an additional four months consists of administration of isoniazid and rifampin. In countries reporting high levels of isoniazid resistance occurring in new TB patients or lacking isoniazid drug susceptibility results, ethambutol is administered throughout the four-month continuation phase of treatment [27]. Upon availability of drug susceptibility profiles and confirmed sensitivity of isoniazid, administration of ethambutol may be omitted in the continuation phase [27,28].

The implementation of the Directly Observed Treatment, Short course (DOTS) strategy by the WHO in the 1990s elicited great effectiveness in TB control, achieved cure rates of nearly 80% [29], and was subsequently expanded as an internationally recommended approach for TB control [30,31]. DOTS consists of a broad TB control effort focused upon five principal elements: (i) political commitment for financing; (ii) proper case detection with appropriate microbiological laboratory support; (iii) standard chemotherapeutic treatment with patient support and supervision, which includes directly observed therapy; (iv) consistent availability of effective drugs; and (v) standard monitoring and evaluation system with impact measurements. Supervised administration of antibiotics during the intensive phase of therapy, in accordance with the recommended DOTS strategy, results in a greater than 85% cure rate of new, antibiotic-susceptible TB cases (Figure 1) [30,32]. The DOTS supervised program facilitates patient adherence to the treatment regimen and maximizes the likelihood of treatment completion [28].

First-line anti-TB antibiotics target actively replicating M. tuberculosis cells in the lung (Table 2) and significantly reduce transmission rates of M. tuberculosis to other persons within the first two months of treatment. The bactericidal antibiotics, isoniazid and rifampin, are active against dividing cells with rifampin also having activity against dormant bacteria, thus accounting for sterilizing properties during the short-course antibiotic regimen (Table 2) [33,34,35]. Pyrazinamide exhibits greatest activity against dormant organisms localized within macrophages or the acidic environment of the pulmonary caseous lesion [36]. Inclusion of ethambutol in the first-line drug regimen is recommended to prevent rifampin resistance when isoniazid resistance is suspected [28].

Second-line antibiotics are introduced into treatment regimens when resistance to primary antibiotics emerges. However, secondary antibiotics exhibit lower potency and/or greater toxicity [38]. The fluoroquinolone, aminoglycoside, and capreomycin antibiotics target DNA replication and protein synthesis and offer the greatest effectiveness of the second-line anti-TB drugs (Table 3) [39,40]. The remaining antibiotics exhibit bacteriostatic activity (Table 3) and are considerably less potent, more toxic, and more expensive [38]. Fortunately, in 2000, the WHO and its partners established the Green Light Committee Initiative which allows countries access to concessionally-priced, second-line anti-TB drugs for treating individuals with MDR-TB in accordance with WHO guidelines [18,41,42].

Therapy for treating TB has not always been mediated via chemotherapeutic agents. Prior to the availability of effective antibiotics, surgical intervention was an important form of therapy for pulmonary TB [43]. In this day and age with the emergence of MDR- and XDR-TB, surgical pulmonary resection is once again considered effective management for the treatment of patients with drug-resistant TB [43,44,45,46,47,48]. Studies have also shown that administration of antibiotics along with surgical management of pulmonary MDR-TB result in improved outcomes compared to surgical intervention alone [43].

Table 2. First-line anti-TB drugs [37].

First-line antibioticsAntibiotic class/structureDelivery routeActivityMechanism of actionGenes and gene products associated with resistance
IsoniazidPyridine hydrazideOralBactericidalInhibits mycolic acid (cell wall) synthesiskatG; catalase-peroxidase
inhA; enoyl-ACP reductase
ndh; NADH dehydrogenase II
RifampinRifamycinOralBactericidalInhibits RNA synthesisrpoB; β-subunit of RNA polymerase
PyrazinamideNicotinamide analogOralBacteriostatic/ bactericidalDisrupts cell membrane energetics and inhibits membrane transportpncA; nicotinamidase/pyrazinamidase
EthambutolEthylenediamine derivativeOralBacteriostaticInhibits arabinogalactan (cell wall) synthesisembCAB; arabinosyl transferase

4. Emergence and Global Health Impact of XDR-TB

The TB global emergency is further complicated by MDR- and XDR-TB strains that are resistant to our best antibiotics, very difficult to treat, and associated with greater morbidity and mortality than antibiotic-susceptible TB (Figure 1). An individual may develop the drug resistant form of TB via inadequate therapy that enables the selection of drug-resistance (acquired resistance) or infection with a drug-resistant TB strain (primary resistance) [49]. While infection with an exogenous drug-resistant TB strain is related to infection control measures, the development of acquired M. tuberculosis resistance is multi-faceted and can be attributed to various social, political, economic, epidemiological, and pathophysiological factors [50]. Certainly, scientists investigate the cellular and molecular mechanisms to explain the development of drug-resistant TB strains, but other influences including, but not limited to, improper or poor health management practices or infrastructure, inadequate therapeutic regimens, antibiotic misuse, insufficient or unobtainable resources, poor socioeconomic conditions, individual immunocompetence, patient compliance, and complicated personal issues have also played roles in the evolution and progression of antibiotic resistance [38,50,51,52,53,54,55].

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