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Addressing the problem of increased antibiotic resistance

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Jennifer Kelly, BA (Hons), MSc, RN, DipN, Dip Ed.

Senior Lecturer, Homerton College, Cambridge

The discovery of penicillin in 1928 by Alexander Fleming led to the antimicrobial era and great optimism that infection had been conquered. However, although antibiotics have improved the mortality and morbidity associated with infectious diseases, they are losing their effectiveness. This is mainly because of antibiotic mismanagement, which has caused bacteria to develop resistance to them. The problem has become increasingly serious and is now seen as a major public health threat (DoH, 1999).

The discovery of penicillin in 1928 by Alexander Fleming led to the antimicrobial era and great optimism that infection had been conquered. However, although antibiotics have improved the mortality and morbidity associated with infectious diseases, they are losing their effectiveness. This is mainly because of antibiotic mismanagement, which has caused bacteria to develop resistance to them. The problem has become increasingly serious and is now seen as a major public health threat (DoH, 1999).

In order to deal with this threat a co-ordinated approach is needed (Gerding and Martone, 2000), and nurses must be part of that effort. Nurses need to understand how and why micro-organisms develop resistance to antibiotics so that they can be more effective in their role of preventing the spread of drug-resistant micro-organisms, including teaching patients and their families about infection control and antibiotic management (Glover, 2000).

Antibiotic resistance is not a new problem. In 1944 penicillin resistance was reported in Staphylococcus aureus and, by 1952, 75% of hospital isolates were found to be resistant to penicillin (Finland, 1955).

Currently the chief drug-resistant nosocomial pathogens are methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci, vancomycin-resistant Enterococcus faecalis and Enterococcus faecium and multidrug-resistant species Pseudomonas aeruginosa and Stenotrophomonas maltophilia. In May 1996 the first documented case of infection caused by a strain of Staphylococcus aureus with intermediate levels of resistance to vancomycin was reported in Japan, and it is expected that strains of Staphylococcus aureus with full resistance to vancomycin will emerge soon (Domin, 1998).

Health-care professionals are thus beginning to witness the development of nosocomial pathogens for which there are no antibiotic treatments available (Valigra, 1994).

The wider picture
The problem of resistance is not confined to hospitals. In the community the main bacterial problems are multidrug-resistant Mycobacterium tuberculosis, Neisseria gonorrhoea, salmonella, and penicillin-resistant Streptococcus pneumoniae (Swartz, 1997). Globally, multidrug-resistant cholera has arisen in Ecuador, while Shigella dysenteriae is a serious problem in Africa as one strain has become resistant to all the usual microbial treatments and is only susceptible to the fluoroquinolones, which are potentially toxic (Godfrey, 1997).

Resistant organisms do not stay in their country of origin, as demonstrated by multi-resistant Salmonella typhi, which has spread around the world (Rowe et al, 1997). Furthermore, resistance to antimicrobials is not confined to bacteria but is found in all groups of microbes. Examples of resistance in other organisms include: fungi (fluconazole-resistant Candida species), viruses (zidovudine-resistant HIV) and parasites (metronidazole-resistant Trichomonas species and chloroquine-resistant Plasmodium falciparum) (Cohen and Tartasky, 1997). The latter accounts for the resurgence of malaria in the past 20 years (Kain, 1993).

Antibiotic resistance
A micro-organism can be defined as resistant if it is not inhibited or killed by a drug at concentrations achievable in the body after normal dosage (Mims et al, 1993). Some species of bacteria are naturally resistant to some families of antibiotics because they lack the target that the drug is aimed at, or because they are impermeable to the drug. For example Pseudomonas aeruginosa has always been resistant to flucloxacillin (Neal, 1997). Natural resistance is not a problem, and it allows specific antibiotics to be chosen to treat specific bacterial infections without destroying all the bacteria in the body.

Many bacteria found on the human body are not pathogenic and form a symbiotic relationship with us, protecting us from harmful microbes. For example, Doderlein's bacillus lives in the vagina of most women and the lactic acid it produces protects against fungal infection. It is therefore desirable when treating a patient with an infection not to kill these symbiotic bacteria and so a selective, rather than broad-spectrum, antibiotic is preferable.

The development of resistance
Bacterial cells are very different from human cells, and it is these differences that antibiotics target. If there were no differences between bacterial and human cells, it would be very difficult to kill the bacteria causing the infection without harming the person in which they are growing.

One of the main differences between human and bacterial cells is the genetic material. In mammalian cells, the genetic material is found in the nuclei in the form of chromosomes. Bacteria do not have membrane-bound nuclei and their genetic material is contained in the cytoplasm as chromosomal deoxyribonucleic acid (DNA) and as plasmids. The latter are small circles of DNA containing genetic information not required for growth and replication.

A bacterium may develop resistance either by chromosomal mutation and selection, or by plasmid transfer. Mutation involves a chance change in the genetic code of the chromosome, leading to the formation of an abnormal protein. Usually the abnormal protein is harmful and the bacteria dies. However, bacteria can double in number every 20 minutes, so from the millions of bacteria that can be produced from one parent in a few days, there is a good possibility that one of these mutations gives rise to a useful protein. If this new protein protects the bacterium from a particular anti-biotic, the bacterium is resistant. For example, the production of an altered ribosomal protein accounts for the resistance of some bacteria to streptomycin (Friedland and McCraken, 1994).

Plasmid-determined resistance is more common than chromosomal resistance, possibly because genes located on plasmids may evolve independently of the chromosome, and genes carried on plasmids are intrinsically more mobile than those on chromosomes. Some plasmids are indiscriminate and cross species barriers so that the same resistance gene is found widely in different species. For example, studies by Salyers (Wuethrich, 1994) showed that the gene for tetracycline resistance has been transferred from bacteria that live in the guts of pigs, sheep and cows to distantly related intestinal and periodontal bacteria living in the human gastrointestinal tract.

Plasmid-based resistance may be transferred to other bacteria by three mechanisms: conjugation, transduction and transformation. Conjugation involves cell-to-cell contact whereby DNA is transferred from a donor bacterium to a recipient via a cytoplasmic bridge called a sex pilus. Many Gram-negative and some Gram-positive bacteria, notably streptococci, staphylococci and clostridia are able to conjugate. Conjugation is probably significant in the dissemination of resistance genes among bacteria that are normally found at high population densities and hence are likely to come into frequent contact with each other, such as Enterobacteriaceae.

Transduction is the transfer of genes by bacteriophages, a type of virus that infects bacteria. As part of their replication cycle the virus may pick up pieces of DNA from one bacterium and transfer them to another bacteria, generally a related species. There is evidence that transduction plays a significant role in the natural transmission of resistance genes between strains of Staphylococcus aureus and between strains of Streptococcus pyogenes (Saunders, 1984).

Transformation is a process whereby bacteria are able to take up naked DNA from their environment and incorporate it into their genome. Although transformation occurs naturally in some species, there is no convincing evidence that it is clinically important in the dissemination of resistance (Kelly and Chivers, 1996).

The mechanism of resistance
Bacteria develop resistance to antibiotics by either altering the target site of the drug, inhibiting its access to the target site, or producing enzymes that inactivate the drug (Kelly and Chivers, 1996). For example, in order to damage bacteria, antibiotics usually need to enter the cell to have an effect. Consequently, if the access of the drug can be inhibited the bacteria will be resistant. This can be achieved by increasing the impermeability of the cell wall or by pumping the drug out of the cell. This mechanism is found in Gram-negative cells where beta-lactams, such as penicillins and cephalosporins, gain access to their target enzymes by diffusion through porins in the outer cell membrane. Mutations in porin genes result in a decrease in permeability of the outer membrane and hence resistance. Bacterial strains that have become resistant through this mechanism may exhibit cross-resistance to unrelated antibiotics, which use the same porins.

Another example is methicillin-resistant Staphylococcus aureus (MRSA). These bacteria use enzymes termed 'penicillin-binding proteins' (PBPs), which are important in the final stages of cross-linking the building blocks of the bacterial cell wall. Antibiotics such as penicillin work by blocking these enzymes. Resistant species such as MRSA synthesise an additional penicillin-binding protein that has a much lower affinity for the antibiotics than the normal enzyme, and so can continue to function (Mims et al, 1993).

Selecting for resistance
Once one bacterium has become resistant to an antibiotic, it will spread this resistance on to its offspring, as well as to other bacteria through plasmid transfer. However, making an abnormal protein is often costly to a bacterium and so in straight competition with other bacteria without the abnormal protein it will not survive. However, if antibiotic is added to the environment the resistant bacteria will have a selective advantage. This means that the antibiotic will kill the surrounding non-resistant bacteria, while the resistant bacteria will be free to multiply, without competition for food and space. The resistant bacteria will then become common in the environment. It can thus be seen that our use of antibiotics actively encourages the development of resistant bacteria.

The misuse of antibiotics
The use of antibiotics has greatly increased in recent years particularly in intensive care units (Amyes and Thomson, 1995). This is because developments in medical procedures have advanced at an unparalleled rate, and many of these procedures require the immunosuppression of the patient. Such patients must be protected against infection using antibiotics. However, although there has been a genuine need to increase the antibiotics used, the problem of resistance has been aggravated by the misuse and overuse of antibiotics. For example, a survey in 1974 noted that 24% of patients given antibiotics had no evidence of infection (Cooke et al, 1980), while researchers at the Centre for Disease Control and Prevention have estimated that some 50 million of the 150 million outpatient prescriptions for antibiotics each year are unnecessary (Levy, 1998).

The reasons for antibiotic misuse are varied and examples are given in Box 1.

Antibiotics are not the only antimicrobial substances being overexploited today. Use of disinfectants and antiseptics has also increased, and resistance has developed to antiseptics such as chlorhexidine (Morgan, 1993). Historically these substances have been used in hospitals for cleansing purposes, but more recently substances such as triclocarbon, triclosan and quaternary ammonium compounds such as benzalkonium chloride have been added to soaps, detergents and impregnated into such items as toys, mattress pads and cutting boards for use in the home (Levy, 1998).

Prevention of bacterial resistance
The problem of antimicrobial resistance is not as high on the strategic agenda as it should be, which is surprising given the costs and consequences of infectious diseases due to these micro-organisms (National Audit Office, 2000; Plowman et al, 1999; Goldmann and Huskins, 1997).

Research scientists are working hard to find new drugs to fight infection (Ellis and Pillay, 1996; Gavaghan, 1999), but as there are unlikely to be any completely novel antibiotics on the market in the near future (Amyes and Thomson, 1995) other solutions to the problem of bacterial resistance must be found.

The most effective and least expensive way to prevent and curb resistance is to use antibiotics correctly (Box 2) and for as short a time as possible, thereby reducing their overall selective effects (Levy, 1991). The British National Formulary recommends a maximum course of five days for the treatment of most infections (BMA/RPSGB, 2001). The value of this approach is demonstrated by a hospital that reduced its usage of erythromycin from a total of 3.3kg in 1958 to 0.3kg in 1959. Due to the reduced antibiotic usage, the frequency of erythromycin resistance in Staphylococcus aureus fell from 18% to 3% (Ridley et al, 1970).

Equally important is the early detection of resistant organisms and the prevention of cross-infection by isolation, as barrier precautions prevent spread much more effectively than standard precautions (Farr, 2000). This applies to both infected and colonised patients, as the latter are the main reservoir for the spread of antibiotic-resistant pathogens.

The dedicated use of non-critical-care items such as stethoscopes (Jones et al, 1995), electronic thermometers, pens (French et al, 1998) and scissors (Kelly and Trundle, 2000) for individual colonised or infected patients should form part of the isolation procedure. In addition, the use of occlusive dressings rather than traditional dressings could help to prevent cross-infection as they have been shown to reduce wound infection rates from 7.1% to 2.6% (Hutchinson and McGuckin, 1990).

The simplest method of reducing cross-infection is to return to the principles of the pre-antibiotic era and ensure good environmental and personal hygiene, as outlined in the national evidence-based guidelines (Pratt et al, 2001). Infection control and basic hygiene, especially good handwashing, which is acknowledged as the single most effective and cost-effective intervention, must be at the heart of clinical practice (ICNA, 1997).

This can be achieved by increased education, which must start with pre-registration students so that when nurses qualify they have a good underpinning knowledge of infection control principles, and are competent at effective handwashing and aseptic techniques (Gould, 2000; Little, 2000). This education must be re-enforced at regular intervals for all members of the multidisciplinary team, including the patient, and must include discussion on how to prevent and treat infection correctly (Freeman, 1997).

Furthermore, patients must receive holistic care, including good nutrition, to promote an active immune system, which will prevent infection and minimise the need to use antibiotics. Finally, there must be increased research and development into vaccines, and encouragement to use the vaccines available (Beardsley, 1995), as these offer the best and most cost-effective method of reducing the appalling toll of death from infectious diseases worldwide.

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Walters, J. (1993)How antibiotics work: protein synthesis. Professional Nurse 8: 12, 788-791.

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Valigra, L. (1994)Engineering the future of antibiotics. New Scientist 142: 1923, 25-27.

Wuethrich, B. (1994)Migrating genes could spread resistance. New Scientist 144: 1947, 9.

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