INTRODUCTION
The discovery and introduction of penicillin as a chemotherapeutic agent in the 1940s was greeted with great enthusiasm. A 33-year-old woman dying of a streptococcal blood stream infection in a New Haven Connecticut hospital in March 1942 was cured after careful injection of repeated doses of the “miracle” drug; she went on to live to the age of 90[1]. The enthusiasm was short lived; in 1944, Staphylococcus aureus (S. aureus) resistant to penicillin through the production of β-lactamase enzyme emerged. Methicillin, a β-lactamase resistant penicillin, was introduced into the market in 1959, but in 1961, resistance to methicillin also emerged[2]. These strains of S. aureus called Methicillin Resistant Staphylococcus aureus (MRSA) became disseminated worldwide, first as hospital-associated[3], and later as community-associated, pathogens[4].
Today, resistance by microbes has been reported against almost every antibiotic discovered, and is one of the most urgent public health problems, threatening to undermine the effectiveness of infectious disease treatment worldwide[5,6]. The present picture is frighteningly similar to the pre-antibiotic era; nosocomial epidemic spread and intercontinental dissemination of multi-drug resistant bacteria are being reported, and for patients infected with these multi-drug resistant bacteria, there is no magic bullet. The challenges of containing and controlling the threat from antibiotic-resistant pathogens are daunting. This editorial reviews certain bacteria that have evolved and adapted to a point where they pose serious clinical and public health challenge to humans.
METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS
The evolution of MRSA exemplifies the genetic adaptation of an organism into a first-class multi-drug resistant bacterial pathogen. After the introduction of penicillin in 1940s and later, methicillin in 1959, S. aureus quickly developed resistance to these β-lactam compounds, and by 2003, more than 50% of S. aureus isolates recovered in United States hospitals were MRSA[7]. Increased isolation of hospital associated MRSA (HA-MRSA) was also reported by several countries in Europe, Asia, Australia, and Africa, including Nigeria[8-12]. In the early 80s, MRSA gradually emerged as a community-associated pathogen in people without identifiable risk factors. This became so pronounced at the turn of the 21st century that, at present, community-associated MRSA (CA-MRSA) is the leading cause of skin and soft tissue infections seen at US emergency rooms[13]. Such MRSA frequently causes severe infections resembling spider bites, as well as severe necrotizing fasciitis and pneumonia. The infection often produces toxins, such as the panton-valentine leukocidin and cytolytic peptides. MRSA has also acquired genes that may increase its ability to survive. A single clone, USA 300 (ST8-MRSA-IV), is responsible for most CA-MRSA infections in the United States[14]. ST80-MRSA-IV is the predominant clone in Europe, Algeria, and Tunisia, while ST88-MRSA-IV is the predominant clone reported in Nigeria[15,16]. Although such MRSA are usually susceptible to oral antibiotics, such as clindamycin, fluoroquinolones, trimethoprim-sulfamethoxazole, tetracyclines, and rifampicin, some multi-drug resistant strains are emerging[15].
VANCOMYCIN RESISTANT STAPHYLOCOCCUS AUREUS
For approximately 30 years, drugs used to treat MRSA infections were the glycopeptides, vancomycin, and teicoplanin[17]. MRSA then began to develop resistance to glycopeptides, evolving through a largely unknown mechanism as reduced susceptibility to vancomycin, which was associated with thickening of the pathogen’s cell wall and sequestration of glycopeptides at the periphery of the cell. Such isolates were designated vancomycin (or glycopeptide) intermediately resistant S. aureus (VISA or GISA) and were first reported in 1997[18]. VISA is difficult for clinical laboratories to detect, but its presence is associated with therapeutic failures of glycopeptides. The Clinical and Laboratory Standards Institute, therefore, changed the susceptibility breakpoints for vancomycin testing in S. aureus in 2009[19], and has proposed screening tests for VISA; however, debate is ongoing regarding the usefulness of vancomycin in the treatment of serious MRSA infections. Strains of MRSA with true low-level and high-level resistance to vancomycin (Vancomycin Resistant S. aureus or VRSA) emerged in 2002[20]. Such resistance was due to acquisition of the vanA gene operon, originally described in vancomycin resistant enterococci (VRE). Eleven such isolates have been reported world-wide; nine in the US (mainly in the Michigan area), one in India, and one in Iran[21]. Certain biological constraints are believed to be responsible for the current restricted dissemination of these VRSA strains, although the potential for widespread dissemination cannot be completely ruled out. We recently isolated six VRSA isolates from chronic wound infections and osteomyelitis with high level resistance (vancomycin MIC > 256 μg/mL) in patients who had not been previously exposed to glycopeptides (Taiwo et al[22], 4th LAUTECH Research and Development Fair/Exhibition, May 2011; unpublished data). This suggested that VRSA carrying the vanA operon, which is inducible only by glycopeptides, may have disseminated. VRSA, like other strains of HA-MRSA, is often resistant to multiple drugs, including clindamycin, aminoglycosides, trimethoprim-sulfamethoxazole, rifampicin, and fluoroquinolones.
VRE
Although less virulent than MRSA, enterococci have presented therapeutic problems initially because of their “tolerance” to penicillin and vancomycin, which inhibit, but do not kill them. Enterococci are the third most common cause of infective endocarditis. The effects of penicillin tolerance on therapeutic outcomes were apparent by the late 1940s, when it became routine to add an aminoglycoside to penicillin to treat the disease. This therapy was effective until 1988, when VRE emerged[23,24]. Since the beginning of the 21st century, in the United States, enterococci have become a major reservoir of antibiotic-resistant genes. VRE has become a major cause of nosocomial infections, especially of the bloodstream, urinary tract, and surgical sites[25]. One major problem is the emergence of multidrug resistant enterococci that correlates with the predominance of a single genetic lineage, which has disseminated worldwide. Members of this lineage have acquired genetic determinants that appear to increase their success in the hospital environment, and some have developed resistance to practically all available antibiotics. In Nigeria, we have isolated multi-resistant VRE strains[26] and strains exhibiting high-level resistance to gentamicin and streptomycin[27]. Another major problem is that enterococci harbor transferable genetic elements, which have an unusually broad host range. They can also be transferred to both Gram-negative and Gram-positive bacteria species by conjugation systems involving plasmids and transposons[28]. Transfer of the vanA operon has been specifically reported in patients co-colonized with VRE and MRSA[29]. The recent isolation of VRSA in Nigeria may implicate VRE, which have been locally present for some time, as the possible source of the vanA operon. No appropriate therapy for VRE endocarditis has been defined[30] and no agent has been approved by the Food and Drug Administration for this indication.
MULTI-DRUG RESISTANT GRAM-NEGATIVE BACTERIA
The antibiotic resistance situation is worse when it comes to nosocomial gram-negative infections, because no new antibiotics against these multi-drug resistant organisms are in the advanced stages of clinical development. Pseudomonas aeruginosa and Acinetobacter spp. are the best-known therapeutic challenges among the gram-negative bacteria. Multi-resistant strains of these, especially Acinetobacter spp., were reported to have caused enormous challenges in soldiers that returned to the US from Iraq and Afghanistan[31]. Resistance to the most potent antibiotics has recently extended to members of the family enterobacteriaceae, including hospital-associated strains of Klebsiella spp., Escherichia coli (E. coli) and Enterobacter spp. Such highly resistant clinical bacteria isolates have been reported in Nigeria[32]. Equally worrying is the fact that these multi-drug resistant gram-negative bacteria have been found in otherwise healthy patients outside of hospitals. For example, urinary tract infections caused by E. coli resistant to trimethoprim-sulphamethoxazole, fluoroquinolones, or both, and that produce extended-spectrum β-lactamases, which are capable of destroying the most potent cephalosporins, have been reported[33]. Recent major outbreaks of food poisoning caused by multi-drug resistant Salmonella were also reported.
Until recently, carbapenems, such as imipenem, were almost uniformly active against resistant gram-negative bacteria. However, some strains have developed very effective ways to deal with the carbapenems, including the production of β-lactamases, designated as carbapenemases, that demolish the carbapenems; changes in outer membrane porins that blocks the entry of the drug; and active pumping of the drug out of the cell using complex efflux pumps. The situation is further complicated by the permeability barrier and efflux mechanisms that also affect other classes of antibiotics, such as quinolones, aminoglycosides, and tigecycline. Moreover, the common presence of these β-lactamase genes of gram-negative bacteria in transferable mobile elements means that these genes could reach virtually any gram-negative bacteria and become a major, global threat to public health in the near future. Recognition of the presence of a carbapenemase in a gram-negative bacterium is of paramount importance, because strict infection-control measures are required to avert hospital epidemics and to prevent the dissemination of these genes to other gram-negative bacteria species[31].
MULTI-DRUG RESISTANT MYCOBACTERIUM TUBERCULOSIS
In early 2005, physicians at a rural hospital in KwaZulu-Natal, a province of South Africa, were concerned by a high rate of rapid death among patients infected with the human immunodeficiency virus (HIV) who had tuberculosis[34]. A study revealed the presence not only of multi-drug resistant Mycobacterium tuberculosis (MDR TB), but also of what came to be called extensively drug resistant TB (XDR TB). XDR TB is caused by a strain of Mycobacterium tuberculosis that is resistant to isoniazid and rifampicin (which defines MDR TB) in addition to any fluoroquinolone and at least one of the three following injectable drugs: capreomycin, kanamycin, and amikacin. A March 2006 report by the Centers for Disease Control and Prevention and the World Health Organization (WHO) also documented the presence of XDR TB in at least 17 countries. Though not representative at that time, the data showed that 10% of MDR TB isolates were in fact XDR TB. More representative data from the US, the Republic of Korea, and Latvia, showed that 4%, 15% and 19%, respectively, of MDR TB isolates were XDR TB strains[35]. Evidence suggests that XDR TB reflects a failure to implement the measures recommended in the WHO’s stop TB strategy[36]. This strategy, which emphasizes expanding high-quality DOTS programs; addressing HIV-associated TB and drug resistance; strengthening health care systems and primary care services; encouraging all providers to follow good practices; empowering patients and communities to improve health; and enabling and promoting research, requires political commitment and will. However, in many developing countries, health is not a top priority.
A GLOOMY PICTURE
Recently, there has been a dramatic reduction in antibiotic research by pharmaceutical companies, because of the high cost of drug research, although several compounds have been developed or resurrected to treat gram-positive infections[31]. However, the available agents have important limitations. None has been shown to work better than vancomycin against MRSA. Quinupristin-dalfopristin and linezolid have important toxic effects, and resistance of MRSA to each has been observed, including linezolid-resistant VRE in patients who have never received the drug. Daptomycin has sometimes failed against MRSA and enterococci, and resistance to it has emerged. There is little data on the effectiveness of tigecycline for enterococci infection, and the new cephalosporins (ceftobiprole and ceftaroline) are not clinically useful against ampicillin-resistant enterococci. Dalbavancin, televancin, and oritavancin are all limited in their effect on VRSA and VRE; and although iclaprim may have a role in MRSA infections, it is not useful clinically against enterococci infections. The situation for gram-negative infections is worse, as no antibiotic is currently being developed against these pathogens[31]. The resurrected polymyxins (e.g. colistin with or without rifampicin) are often the only available alternative antibiotics for some pan-resistant gram-negatives, particularly Acinetobacter spp.. Renal toxicity is still a major problem and reports of resistance are emerging. Similarly, Mycobacterium tuberculosis and atypical mycobacterium that are totally resistant to all available first and second line anti-tuberculosis drugs, as well as to all fluoroquinolones, have emerged. Some strains of MDR TB have undergone stable mutational changes that enhance their survival, virulence, nosocomial transmission, and worldwide dissemination[37].
CURRENT EFFORTS TO COMBAT ANTIBIOTIC RESISTANT BUGS: PUBLIC HEALTH PERSPECTIVES
The challenge of containing and controlling the threat from antibiotic resistant pathogens is daunting. However, few will argue against preserving the existing antimicrobials for the benefit of current and future generations. A multi-disciplinary approach is required, which must be applied, sustained, and continuously refined. The key components for maintaining effective antimicrobial chemotherapy include better use of existing agents, continuous investment in new and innovative technologies (including diagnostics and vaccines), and new antimicrobial agents.
Sound prescribing principles
While the surveillance of resistant pathogens and patterns of antibiotic prescribing need to be defined more accurately, particularly at local and individual levels, they remain the yardstick to inform strategy, policy, and practice, and are a measure of their effectiveness. To be effective and remain so, the use of antimicrobial agents needs to be supported by rigorous application of sound prescribing principles[38] in a health care environment, which strives to minimize the risks of infection by adherence to good hygiene and housekeeping practices. This is particularly important in many developing countries, where antibiotics are available over-the-counter to the populace and are used without medical authorization. It is equally important to have a sound prescribing principle when there is a serious concern about paucity of novel antibiotics, particularly against multi-drug resistant gram-negative pathogens[37]. This is a global challenge, and initiatives at national and international levels are needed to encourage investment and to strengthen research in this area[39,40]. Linking prudent prescribing and sound clinical practice remains a challenge, especially where prescribing is largely empirical. The importance of rapid diagnostic tests, including near patient testing, is increasingly supported and achievable. However, obstacles to widespread acceptance include not only cost, but also the need for greater flexibility in medical practice to permit their adoption.
Public health initiatives
Public education concerning the appropriate use of antibiotics and the risks from antimicrobial-resistant pathogens requires a repertoire of approaches. One such approach is the widespread use of routine data sets that link clinical outcome data to prescribing. The increasing recognition of the importance of a partnership between prescriber and the patient is significant. Media campaigns have dominated this approach and emphasize the importance of clear and positive messages. A structured educational approach within the context of day care nurseries and children undergoing full-time education, which also involves parents and primary care physicians, has been shown to be an effective strategy[41]. Currently, an ambitious schools educational program (e-Bug) across many European countries and funded by DG SANCO[42] is being conducted.
The European Union (EU) is strongly supportive of public education initiatives, which have been given a boost by the establishment of an annual EU Antibiotic Awareness Day (EUAAD), promoted by the European Centre for Disease Control[43]. The first EUAAD was 18 November 2008, for which each member state developed its own national program of activities. In the UK, a number of events took place within the devolved administrations and in many individual Trusts. The Advisory Committee on Antibiotic Resistance and Healthcare Associated Infections[44] organized an EUAAD symposium in the Science Museum, London entitled “Antibiotic Resistance - Myth Busting” with the objective of reviewing current problems, national surveillance strategies, the professional responses in human and veterinary medicine, and the importance of engaging with the public[45]. In addition, a school poster competition was launched to coincide with the conference, which was well supported[46]. The brief was to design an eye-catching poster to raise public awareness that antibiotics do not work on most coughs, colds, and sore throats. Recent surveillance data suggests that rates of antimicrobial resistance for a few selected pathogens are falling, a phenomenon that, until recently, would not have been considered possible. It is important to be constantly vigilant, particularly in maintaining good prescribing principles.
Social marketing framework for behavioral change
Although combating antibiotic resistance is a war that must be waged on one front by biological scientists and clinicians, social scientists also have a key role to play because of the behavioral aspects of the problem, e.g. not taking entire prescribed regimen, skipping doses, taking antibiotics for viral illnesses, etc. To minimize the development and spread of antibiotic resistance, providers and current patients, as well as those who might be patients or the caretakers of patients in the future, must become sufficiently aware of the issue and engage in appropriate behavior. Although a few behavioral indicators have indicated progress in recent years, such as a decline in the UK and the US in oral antibiotic prescription rates among children[47,48], recent evidence suggests that there are still large hurdles to climb to address the broader issue. For example, although there have been multiple efforts to educate both providers and patients about the prudent use of antibiotics, survey data from a recent national probability sample of 919 US adults showed that misunderstanding continues to exist about the appropriate use of antibiotics. A substantial proportion of the population still engages in behaviors that potentially contribute to the antibiotic resistance problem[49]. The ultimate goal of social marketing is behavior change, which can only be achieved when detailed attention is paid to defining the behavioral focus.
Oligonucleotide therapeutics
There is a pressing need to develop and evaluate novel, alternative strategies to overcome resistance and reduce the morbidity and mortality associated with infections caused by antibiotic resistant bacteria. One strategy is the use of “antisense” or “antigene” agents to inhibit resistance mechanisms at the nucleic acid level. Antisense or antigene oligonucleotides bind mRNA to prevent translation or bind DNA to prevent gene transcription, respectively. Interrupting expression of resistance genes in this manner could restore susceptibility to key antibiotics, which would be co-administered with the antisense or antigene compound. This would extend the life span of existing antibiotics, which offer clinically proven therapies and are often cheaper, more effective, or less toxic than the alternatives.
Antisense molecules that bind complimentary mRNA sequences are a well-established means of modifying gene expression in mammalian systems[50]. Indeed, the manipulation of eukaryotic RNA pathways with small interfering RNAs has revolutionized research in mammalian cell biology, with libraries of custom-made molecules spanning entire genomes now commercially available. Antisense strategies have been used therapeutically in the treatment of human genetic disorders, such as muscular dystrophy and familial hypercholesterolemia[51] or viral diseases (http://www.avibio.com and http://www.isispharm.com), with some clinical trials ongoing. A small number of agents are already licensed for clinical use[52].
CONCLUSION
It is more difficult than ever to eradicate infections caused by antibiotic-resistant microbes and the problem is exacerbated by a dry pipeline for new antimicrobials with bactericidal activity against gram-negative bacteria and enterococci. A concerted effort on the part of academic researchers and their institutions, the pharmaceutical industry, social scientists, the general populace, and the government, is crucial if we are to prevent a global public health disaster.
Peer reviewer: Zainab Al-Doori, BSc, PhD, Glasgow Caledonian University, Glasgow G68 0JA, Scotland
S- Editor Wang JL L- Editor Stewart G E- Editor Zheng XM
