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In depth

Antibiotic resistance: how it arises, the current position and future strategies

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A detailed review of the current position regarding antibiotic resistance, and an outline of future strategies to tackle this problem

Authors

Authors Christine Perry, MSc, RN, is assistant chief nurse and director of infection prevention and control; Carly Hall, PhD, BSc, RN, is senior infection control nurse; both at University Hospitals Bristol Foundation Trust.

Abstract

Perry, C., Hall, C. (2009) Antibiotic resistance: how it arises, the current position and future strategies. Nursing Times; 105: 36, early online publication.

After 70 years of antibiotic therapy, the threat of untreatable infections is again a reality with resistance to antibiotics increasing in both Gram positive and Gram negative bacteria.

Antibiotic-resistant bacteria cause both community and healthcare associated infections, presenting challenges in treatment and management. The development of new and novel antibiotics, particularly for Gram negative bacteria, is worryingly lacking.

This article reviews the current situation and examines future strategies to tackle the continued threat of bacterial resistance.

Keywords: Antibiotic resistance, Antibiotic treatment, Gram negative infections

Practice points

  • Despite the availability of antibiotics, infections acquired in the community or related to healthcare can still cause significant morbidity and even mortality. 
  • Antibiotic-resistant strains of both Gram positive and Gram negative bacteria present challenges in appropriate treatment and have the potential to cause community and healthcare outbreaks.
  • Gram negative infections are a significant cause of healthcare associated infection despite other infections receiving greater focus.
  • Development of antibiotics for Gram negative infections is currently lacking.
  • Strategies to address antibiotic resistance must focus on: infection prevention measures; novel technologies; financial support for antibiotic development; good surveillance systems; more timely diagnosis of infections; and appropriate prescribing of existing antibiotics.

Introduction

Despite the availability of antibiotics, infections acquired in the community or related to healthcare can still cause significant morbidity and even mortality today.

The emphasis on healthcare associated infections (HCAI) has led to a focus on Gram positive bacterial infections such as MRSA and Clostridium difficile. Gram negative infections, including Pseudomonas aeruginosa andEscherichia coli, have received less attention despite being important causes of HCAIs and community acquired infections.

Antibiotic resistant strains of both Gram positive and Gram negative bacteria exist, causing challenges in appropriate treatment as well as having the potential to cause community and healthcare outbreaks. Resistance to antibiotic treatment is an ever increasing risk that requires novel thinking in antibiotic and other therapies, as well as preventative measures.

This article reviews the development of antibiotics and antibiotic resistance, and the significance and treatment of Gram positive and Gram negative infections, including resistant strains. It also examines what can be done to address the continued threat of antibiotic resistance.

Antibiotics and bacterial resistance

Before antibiotics were introduced, medical treatments for bacterial infections were limited. Lancing, surgical drainage and directly applying antiseptics could be used for superficial or localised infections. However, systemic infections such as bacteraemia were likely to be fatal.

The discovery of antibiotics is generally accredited to Alexander Fleming, who made the accidental discovery of penicillin through the contamination by the mould penicillium of a laboratory plate growing Staphylococci. The first reported clinical use of penicillin was in 1941, with the drug entering widespread use in 1944 after work carried out by Florey and Chain. Following this ‘miracle’ discovery many more antibiotics have been developed from natural substances as well as being synthetically produced.

Antibiotics are either bacteriostatic (prevent bacterial reproduction) or bactericidal (destroy the bacterium). They work in a variety of ways including:

  • Preventing cell wall formation – penicillins, cephalosporins and glycopeptides (such as vancomycin and gentamicin);
  • Altering cell membrane permeability – cyclic peptides, for example, polymyxins;
  • Interfering with protein synthesis – tetracyclines, aminoglycosides, macrolides, fusidic acid and mupirocin;
  • Interfering with nucleic acid synthesis – sulphonamides, rifamycins and nitrofurans.

Antibiotic resistance is the ability of a microorganism to withstand the effects of antibiotics. This can be intrinsic in that the bacteria already have properties that do not allow the antibiotic to work (for example, vancomycin that prevents cell wall formation in Gram positive bacteria will not be effective against Gram negative bacteria because of cell wall composition).

Resistance can also be acquired in that bacteria that could once have been treated with an antibiotic (commonly referred to as “sensitive”) become resistant (such as Staphylococcus aureus that have become resistant to meticillin – MRSA). Acquired resistance occurs through spontaneous genetic mutation or transfer of genetic material from other resistant organisms. The latter occurs in a variety of ways:

  • Transformation – the acquisition or uptake of resistant genetic material from the environment around the bacteria;
  • Transduction – the transfer of genetic material through infection by a virus (bacteriophage);
  • Conjugation – the transfer of genetic material directly from one bacterium to another through direct cell to cell contact. This is not species-specific, in that resistance can be passed between different strains and species of bacteria. This method of transfer is particularly relevant to Gram negative bacteria that have extended-spectrum beta-lactamase (ESBL) producing enzymes.

The mechanisms by which bacteria can withstand the effects of antibiotics generally fall into four categories (Box 1).

Regardless of the type and method of resistance, the World Health Organization (2001) has recognised this issue as a global problem that needs urgent action. Antimicrobial resistance is a problem in both hospitals and the community that requires a coordinated and multifaceted approach to address this continuing threat.

Box 1. Mechanisms of antibiotic resistance

 The four categories are:

  • Preventing drug entry by altering cell permeability;
  • Preventing the drug from reaching the target site by trapping it within the cell or pumping it back out (efflux pumps);
  • Inactivating or modifying the drug by using enzymes;
  • Altering the drug target site.

Antibiotic resistance in Gram positive bacteria

In 2007, 10 per cent of Streptococcus pneumoniae in Europe were resistant to penicillin and 16 per cent were resistant to erythromycin (European Antimicrobial Resistance Surveillance System, 2008).

S. pneumoniae is a common cause of infection in older people, children and patients with compromised immunity. Infections range from sinusitis and otitis media to invasive bloodstream infection and meningitis.

It is also estimated that 25 per cent of community acquired pneumonia is due to pneumococcal infection, with it accounting for more deaths than any other vaccine-preventable bacterial infection (Todar, 2009). Pneumococcal vaccine is available for children and adults at greatest risk of serious infection.

The first report of meticillin-resistant Staphylococcus aureus (MRSA) in 1961 came only two years after the antibiotic was introduced into general use.

The proportion of S. aureus invasive infections that are due to MRSA ranges from none in some northern European countries to 50 per cent in some southern European ones, with the UK reporting 25–50 per cent as resistant (EARSS, 2008). However, all UK countries are reporting a falling trend in MRSA bloodstream infections including a 34 per cent reduction in one year (Health Protection Agency, 2009).

S. aureuscan cause superficial infections such as boils or styes, but can also cause more serious infections including pneumonia, urinary tract infection, osteomyelitis, endocarditis and bacteraemia.

Community strains of MRSA have spread widely in the US, but in the UK infections from MRSA in the community are still predominantly caused by hospital strains of the bacteria (Rollason et al, 2008). S. aureus resistance to glycopeptides (such as vancomycin) remains rare with only four confirmed cases reported in Europe in 2007 (EARSS, 2008).

Enterococci are normally present in the gut flora of humans and other mammals. Although they are not as likely to cause disease as some other bacteria, they can cause a range of infections including wound and urinary tract infections, endocarditis, bacteraemia and meningitis. The majority of enterococcal infections in humans are caused by Enterococcus faecalis and Enterococcus faecium.

Enterococci are naturally resistant to a wide range of antibiotics, including penicillins and cephalosporins, but a major concern is their high affinity for acquiring resistance by conjugation, transduction and mutation. Transfer of vancomycin resistance from enterococci into S. aureus has been demonstrated and the emergence of MRSA with reduced susceptibility to vancomycin has been reported (Hiramatsu et al, 1997). The reported rates of vancomycin resistance in E. faecalis range from 13-67 per cent and in E. faecium from 0-37 per cent (EARSS, 2008).

Antibiotic resistance in Gram negative bacteria

Although Gram positive bacteria have attracted much attention in terms of recent infection prevention activities, Gram negative infections are also an important cause of healthcare associated and community acquired infections.

Escherichia coli

Escherichia coli and related Gram negative bacteria are commonly found in the human gut. E. coli is a common cause of community acquired and hospital associated urinary tract infections. They are also a common cause of neonatal meningitis and cause surgical wound infections, abscesses in a variety of organs and bacteraemia; E. coli is now the most frequent cause of bacteraemia in the UK (HPA, 2007).

Resistance to cephalosporins (including cefotaxime and ceftazidime) was reported in up to 12 per cent of E. coli bacteraemias in 2006, an increase from 3 per cent in 2002 (HPA, 2008). Highly resistant strains of E. coli have become widespread in the UK since 2003. These are known as extended-spectrum beta-lactamase (ESBL) producers and are able to break down a wider range of antibiotics including penicillins as well as cephalosporins.

Additional resistance to fluoroquinolones, aminoglycosides, tetracycline and trimethoprim has also been reported, with 2.5 per cent of E. coli in Europe resistant to four types of antibiotics (EARSS, 2008).

Infections with ESBL-producing E. coli have become widespread in the UK, with outbreaks of community and hospital urinary tract infections reported.

Klebsiella pneumoniae

Like E. coli, Klebsiella are commonly found in the human gut, but can also be found in the upper respiratory tract and on the skin of hospital patients.

Klebsiella pneumoniaeinfections occur in both community and hospital patients, commonly causing urinary tract and respiratory tract infections; community acquired respiratory tract infections have a mortality rate of up to 50 per cent. These bacteria can be an important cause of hospital associated infections, particularly in patients with poorer immune functions, causing wound infections, urinary tract infections, pneumonia and bacteraemias.

Klebsiella pneumoniaeare naturally resistant to aminopenicillins (ampicillin) but can also be resistant to multiple antibiotics and have ESBL-producing strains, with transfer of resistance genes via conjugation taking place more readily than with E. coli.

Over 30 per cent of Klebsiella in Europe do not show acquired resistance. However, 14 per cent have resistance to three groups of antibiotics that include fluoroquinolones, cephalosporins and aminoglycosides (EARSS, 2008). Carbapenems (such as meropenem) are the antibiotics often used for life threatening infection in patients with highly resistant Klebsiella infections. Although resistance to carbapenems is uncommon, several European countries have reported resistance with rates varying from 1–42 per cent (EARSS, 2008).

Pseudomonas aeruginosa

Pseudomonas aeruginosais naturally present everywhere, particularly in wet environments. In humans it can infect almost any external site or internal organ. Hospital associated infections are more common than those acquired in the community, ranging from urinary tract infections, chronic wound (such as pressure ulcer) infections to eye and burn infections. P.aeruginosa does not commonly cause pneumonia or bacteraemia but when it does it is often associated with a poor outcome. It is naturally resistant to a number of antibiotics by excluding the drug molecules from entering the cell but can also acquire resistance from the three main sources of transformation, transduction and conjugation, so resistance can readily occur during antibiotic treatment.

In the UK, P. aeruginosa resistance to gentamicin and imipenem decreased in 2008 compared with 2007, while resistance to other antibiotics (including ciprofloxacin, ceftazidime and meropenem) remained stable (HPA, 2008). Across Europe 17 per cent of P. aeruginosa are multiresistant (EARSS, 2008).

Acinetobacter baumannii

Acinetobacter are also ubiquitous in the environment and can be carried on human skin. A. baumannii can cause hospital associated infections including meningitis, pneumonia, wound infections and bacteraemias, particularly in critical care and burns patients.

Multiresistant A. baumannii are resistant to aminoglycosides and cephalosporins: some are also resistant to imipenem or meropenem. Rates of resistance to ceftazidime in Europe range from 15 to 97 per cent and to imipenem from less than 1 per cent up to 85 per cent (Souli et al, 2008).

Where highly resistant strains are identified, antibiotic use is limited. However, polymyxins  have good in vitro activity against A. baumannii although information on clinical use is limited as it is no longer routinely used in practice in the UK due to variable clinical outcomes and slight risk of toxicity (Chopra et al, 2008).

Current and future treatment of Gram negative infections

Choice of antibiotic is influenced by the nature of the bacteria causing the infection (for example, Gram negative or Gram positive) the site of infection, and patient factors (such as allergy, pregnancy or severity of infection). Where infection is suspected but the causative microorganism has not been identified, antibiotics with a broader spectrum of antimicrobial activity will be prescribed.

Once a causative microorganism has been identified, antibiotic sensitivity tests will be carried out and prescribing can then be amended if necessary to ensure the antibiotics are targeted appropriately. For an antibiotic to be clinically useful it should have as many of the characteristics outlined in Box 2 as possible.

Box 2. Desirable features of antibiotics

Antibiotics should have as many of the following as possible:

  • Non toxic and without undesirable side effects;
  • Non allergenic;
  • Should not alter the normal bacterial composition of the body;
  • Should be able to reach the part of the body where the infection is located;
  • Inexpensive and easy to use;
  • Chemically stable with a long shelf life;
  • Microbial resistance is uncommon and unlikely to develop.

Source: Todar (2009)

The agents that have mainly been used for treating Gram negative infections are:

  • Aminoglycosides – such as gentamicin and amikacin;
  • Third generation cephalosporins – for example, cefotaxime and ceftriaxone;
  • Other beta-lactams – such as aztreonam;
  • Quinolones – for example, ciprofloxacin and levofloxacin.

However, as noted above, resistance to many of these antibiotics is now evident and alternative antibiotics must be used. For ESBL-producing Gram negative bacteria it is recommended that: urinary tract infections are treated with quinolones; bacteraemias, hospital acquired pneumonia and intra abdominal infections with carbapenems; and meningitis with meropenem (Paterson and Bonomo, 2005).

The carbapenem group of antibiotics includes imipenem, ertapenem, doripenem and meropenem. Administration is intravenously and the mode of action is to interfere with production of the bacterial cell wall, being bactericidal. Resistance to carbapenems already exists in some Gram negative bacteria including P.aeruginosa, Acinetobacter species and K. pneumoniae (Centers for Disease Prevention and Control, 2009). Although resistance currently remains rare, there is concern that carbapenem resistance is increasing in A. baumannii (HPA, 2004). As the route of administration is IV, carbapenems will generally be used in hospital settings for patients with significant infection. In many hospitals their use is restricted to reduce risk of further resistance developing.

Anti-pseudomonal penicillins that can be used for P. aeruginosaas well as some other Gram negative infections include ticarcillin and piperacillin. Piperacillin is combined with tazobactam, and ticarcillin with clavulanic acid. As with the carbapenems, they are both administered IV and will, therefore, be more commonly used in hospital settings. For pseudomonal septicaemia they should be given with an aminoglycoside (such as gentamicin) to achieve a synergistic effect, as the action of the two drugs together gives a greater effect than either of them alone (British National Formulary, 2009).

Tigecycline entered clinical use in 2005. It is the first antibiotic to be launched in the glycylcycline group, which are similar in structure to tetracyclines.

Being bacteriostatic in action, tigecycline inhibits production of protein within the bacterial cell and is administered by the IV route. Although effective against a wide range of resistant Gram negative bacteria, it is of limited use for infections of the urinary tract, the site where most of the ESBL-producing Gram negative bacterial infections are located (Livermore, 2005). It is not effective against P. aeruginosa (Bhattacharya et al, 2009). Resistance to A. baumannii and K. pneumoniae in the laboratory setting and in clinical trials have been reported (Navon-Venezia et al, 2007; Livermore, 2005).

Polymyxin B and colistin are from the polypeptide group of antibiotics developed in the late 1940s but have not been clinically used widely in recent years due to concerns over toxicity (Arnold et al, 2007).

They are rapidly bactericidal and act by altering the permeability of the outer membrane of bacterial cells. They have good activity against most clinically relevant Gram negative bacteria. Resistance to Gram negative bacteria, including P. aeruginosa, E. coli and K. pneumoniae, is reported but remains uncommon due to their infrequent use in recent years (Zavascki et al, 2007). Colistin is available as an IV preparation and as a powder for nebuliser solution and polymyxin B is available in powder form for intramuscular or IV injection.

New developments

While a number of antibiotics are in the latter stages of development for Gram positive infections, the only one imminently expected into worldwide use for Gram negative bacteria is faropenem, with development of an oral carbapenem in progress.

These products, together with the other recently launched antibiotics for Gram negative infections, are related to or derivatives of existing groups of antibiotics in which Gram negative bacterial resistance is also present.

The development of new antibiotics is costly and time consuming, giving limited financial return for the outlay associated with their development. In addition, prudent antibiotic prescribing to reduce risk of other infections (such as C. difficile) and the need for antibiotics with a narrow spectrum of activity means their development is not financially viable for the pharmaceutical industry (Finch and Hunter, 2006). This lack of development of antibiotics for Gram negative bacterial infections is a cause of major concern internationally (Chopra et al, 2008).

Other novel technologies, aimed at preventing rather than curing infections, may be useful to reduce antibiotic use and delay the inevitable development of resistance. Vaccines have proven invaluable in controlling and eliminating a number of serious infections including smallpox. They have also been shown to have an impact outside of the age group being vaccinated. For example, the pneumococcal vaccine given to children also reduced infection rates in older age groups and an associated reduction in macrolide resistance was seen (Stephens et al, 2005).

Clinical trials of vaccination against P. aeruginosa have taken place. Vaccines against other Gram positive and Gram negative bacteria are in the early stages of development (Finch and Hunter, 2006).

Since many infections caused by Gram negative bacteria are opportunistic –affecting people with poor immunity due to underlying conditions – cases of Gram negative bacterial infection are likely to increase as advances in medical treatments lead to increased survival of patients with severe underlying disease. Combining this with increasing resistance to commonly used treatments, all available options to preserve the effectiveness of existing antibiotics need to be deployed.

The future for antibiotics and antibiotic resistance

As new antibiotics are discovered and enter clinical use, it will be a matter of time before resistance to these drugs occurs due to the nature of evolution.

Strategies to ensure infections remain treatable in the future will need to include:

  • Infection prevention measures;
  • Strict control of antibiotic prescribing;
  • Development of new and different antibiotics;
  • Consideration of new technologies.

Developing new antibiotics will require public funding and greater involvement of non-profit making organisations (such as universities), with a focus on the Gram negative bacteria (Chopra et al, 2008). Collaborations between microbiologists and biochemists will be essential in supporting the discovery of new classes of antibiotics.

Increased infection prevention and control measures in healthcare settings will be necessary to reduce the spread of existing resistant bacteria, but also to reduce all HCAIs and, therefore, reduce antibiotic prescribing. Other preventative measures, such as vaccination, should also be pursued, taking the focus back from one of treatment to one of prevention.

Tighter control over antibiotic prescribing is also essential and this can be supported by developing rapid and sensitive diagnostic testing, enabling more timely identification of the bacteria causing infection. This also further supports the use of antibiotics with a small spectrum of activity. Surveillance systems will also be essential for tracking resistance patterns and ensuring that antibiotic policies reflect local antibiotic resistance patterns.

Conclusion

In less than 70 years we have gone from the widespread launch of the ‘wonder drug’ penicillin to considering what the future may be for antibiotics. The challenges are immense. Nurses can play a key role in helping to reduce antibiotic resistance by strict adherence to infection control measures and ensuring antibiotic prescriptions are reviewed regularly by medical staff. However, it will require global initiatives to ensure we do not return to the pre-1940s era.

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