Antimicrobial Chemotherapy, 4th Edition

Resistance to antimicrobial agents


Control of the spread of resistance

  1. M. Emmerson

Over 50 years of antibiotic use have brought great benefits to mankind. Foremost among these is the saving of life and relief of suffering by therapeutic use. Many of the killing bacterial diseases which were rife in the early years of this century have been successfully combated almost to the point of extinction. Pneumococcal pneumonia, tuberculosis, and streptococcal puerperal sepsis, for example, used to kill many hundreds of young people every year. Deaths from these and many other bacterial diseases are now rare in young adults, at least in developed countries, although this may change.

Substantial amounts of antibiotics are also used outside normal therapy for prophylaxis and growth promotion in animal husbandry, and even in plant protection in agriculture. These wider uses have been very important in controlling losses due to infectious disease and in helping to meet growing demands for animal protein for food. The economic benefits of antibiotic use in food production are very large indeed, but the price to pay may be too high.

Compared with most other drugs of similar potency, antibiotics are remarkably safe, and they are also remarkably effective. This has inevitably led to liberal, even lavish use, and concern has frequently been expressed that excessive and inappropriate use of these agents is the chief cause of the widespread emergence of resistant organisms which threatens the continued effectiveness of antimicrobial therapy.

Attention has repeatedly been drawn to the world-wide public health problem of the spread and persistence of drug-resistant organisms, and there have been frequent calls for regulation to curb the unnecessary use and flagrant misuse of antimicrobial drugs in some countries. The following practices have been clearly identified as largely contributing to the present situation:

  • dispensing antibiotics without prescription
  • using clinically useful antibiotics as growth promoters in animal feeds and on agricultural crops


  • prescribing antibiotics for ailments for which they are ineffective
  • misleading consumers by advertising antibiotics as ‘wonder drugs’, especially in areas where dispensing is not regulated
  • using different labelling and advertising to sell the same product in different parts of the world.

Consumers, prescribers, dispensers, manufacturers, and government regulatory agencies are all involved in different ways, and all need to be convinced of the vital importance of prudent antibiotic use.

Availability of antibiotics

In the UK, successive Acts of Parliament have provided a comprehensive system of control of the manufacture, importation, distribution, sale, supply and description of medicinal products, including antibiotics, for human and veterinary use. The intention of this legislation is to give health and agriculture ministers powers that will ensure that all medicinal products offered for sale or supply in the UK are adequately tested for safety, quality and efficacy, and enable them to prohibit the retail sale or supply of medicinal products except on the prescription of a doctor, dentist, or veterinarian. The ministers are advised by authoritative advisory committees and individuals, and exercise their powers by a system of Product Licences (see p. 380). There is, however, at present no body charged with advising specifically on antibiotics and antibiotic use, and there probably should be. There is no other example in therapeutics in which local misuse of an effective agent brings about a general diminution in its effectiveness.

Similar legislation covers much of continental Europe and the US. Indeed, the American Federal authorities have been more often criticized for delaying the introduction or restricting the use of valuable agents than for permitting their indiscriminate use. In the rich, developed world the sale and distribution of antibiotics are fairly tightly controlled, but the poorer, but numerically much larger, developing world provides a much bigger market in which the sale and distribution of these agents are largely unrestricted.

Paradoxically, the use of antibiotics in the developing countries needs to be extended, not restricted, if standards of health are to be brought up to those of the developed world. However, this clearly needs to be done in a controlled manner, and over-the-counter availability of antimicrobial drugs is, in the end, going to create more problems than it solves. It was no great surprise that chloramphenicol-resistant typhoid bacilli first emerged in South America and penicillin-resistant gonococci in south-east Asia.

The onus of providing the necessary legislation obviously rests with individual governments, with the advice and support of international agencies such as the World Health Organization (WHO). However, pharmaceutical companies also have a part to play in ensuring that their products are advertised and marketed to the same standards as those they apply in the countries of the developed world.



The use of antibiotics in animal husbandry

Antibiotic-resistant bacterial populations arise in man and animals following the use of antibiotics, whether for therapy, prophylaxis, or growth promotion. The non-therapeutic uses have come under heavy criticism from those concerned in the treatment of infectious disease, despite their immense value in animal husbandry and food production. The extent to which resistant organisms in animals contribute to resistant organisms in man, as opposed to the recycling by cross-infection of resistant organisms within the human population, is still much in dispute. Accurate figures on antibiotic usage are hard to come by, but it is likely that human medical use contributes more to the resistant bacterial population in man than does non-human use. Nevertheless, it has been shown conclusively that resistant bacteria, both commensal and pathogenic, arising in animal populations do pass to human hosts, and this source of human resistant bacteria cannot be ignored.

The Swann Report

The use of certain antibiotics in restricted amounts to promote growth in live-stock, mainly pigs and poultry, is common practice, and concern about dangers resulting from the reported increase in resistant bacteria has been voiced by both medical and veterinary professions. In the UK this concern led to the setting up in 1968 of the joint Committee on the use of Antibiotics in Animal Husbandry and Veterinary Medicine under the Chairmanship of Professor M. M. Swann, and the production a year later of what has come to be known as the Swann Report. This report presented a masterly analysis of the whole problem of the use of antibiotics in animal husbandry, and made several recommendations, the most important of which were:

  • that permission to supply and use drugs without prescription in animal feeds should be restricted to antibiotics shown to be effective for this purpose, of little or no use for treatment of infections in man or animals, and not likely to cause resistance against therapeutic agents in general use
  • that therapeutic antibiotics should be available for use in animals only when prescribed by a member of the veterinary profession that a single committee should be set up with overall responsibility for the whole field of use of antibiotics and related substances whether in humans, animals, food preservation, or for other purposes.

There were more than 20 further cogent recommendations, some of which were implemented, but efforts to follow the recommendations and intention of the Swann Report met with limited success. The direct commercial use of therapeutically useful antibiotics as growth promoters stopped, but the boundaries


between feed additives for growth promotion, antibiotics prescribed prophylac-tically, and antibiotics used to treat sick animals have always been blurred. There has been widespread diversion of antibiotics properly prescribed for treatment of sick animals into feeds intended for well animals. Antibiotics have been readily available without prescription on an illicit but extensive black market. Also, it has always been unclear how much the use of feed additives contributed to the resistance problem, compared with the equally extensive therapeutic use of antibiotics in veterinary medicine, which there was little attempt to control.

The issues raised by Swann have recently been revisited by several expert committees in the UK and elsewhere (see Recommendations for further reading, p. 389) and the use of antibiotics as growth promoters has been further restricted in the European Union.

Irrational use of antibiotics

Whatever the contribution to the human load of resistant bacteria from the use of antibiotics in animal husbandry, the major selective pressure leading to resistant bacteria in man is the use of antibiotics in human medicine. Often this use is inappropriate and unsupported by laboratory cultures. Several surveys have found that inappropriate prescribing is widespread. Studies in the mid-1970s indicated that 25–30 per cent of patients received antibiotics while in hospital although the reason for such high usage was often obscure. At this time, there was great uncertainty on how to use antibiotics for prophylaxis of infection.

A national survey of infection in 43 hospitals in the UK confirmed that nearly a quarter of hospital patients received antibiotics; this ranged from 8 per cent in obstetric patients to more than 60 per cent of those in intensive care units. However, less than 50 per cent of those patients who were prescribed antibiotics showed any evidence of infection. Another study indicated that most patients receiving antibiotics were treated without bacteriological evidence of the infecting agent; doctors prescribing antibiotics for these patients were unable to specify the pathogen against which treatment was intended in half of the cases. Only 7 per cent of antibiotics prescribed for conventional surgical prophylaxis fulfilled all the criteria used to assess the suitability of choice of drug and the method and timing of its administration.

Much of the irrational prescribing of antibiotics stems from lack of information on likely infecting pathogens. Delays in diagnosis occur through poor or non-existing sampling techniques, delay in transport, slow and laborious laboratory techniques, and unsatisfactory reporting methods. Antibiotic prescribers need rapid, accurate information, and near-patient testing is not yet available in microbiology. A rapid slide test for Streptococcus pyogenes in a throat swab at the bedside would negate the need for antibiotic use in many patients with viral sore throats. Unfortunately those rapid methods presently available have poor specificity or poor sensitivity.



One of the major problems in dealing with patients in whom an infection is suspected is distinguishing between infection and colonization. Patients with an undiagnosed fever may well be colonized with potentially pathogenic micro-organisms, but may not be infected. The distinction is not always obvious, and under these circumstances it is understandable for a clinician to prescribe antibiotics. However, good practice dictates that all relevant samples for culture should be collected before treatment.

Rational use of antibiotics

Each prescribing doctor has the responsibility to provide the best possible treatment for the patient, taking into account the risks of adverse effects. The widespread use of antibiotics has led to a marked increase in antibiotic resistance of many hospital-associated pathogens and there is ample evidence of the ways in which antibiotic resistance has imposed serious limitations on the treatment of most of the important bacterial infections.

Every attempt should be made to establish a clinical and microbiological cause of any infection; it is not rational to treat patients merely because they have a raised temperature. Where possible, all appropriate samples should be collected before treatment. The initial choice of antimicrobial therapy will depend on the most likely infecting organism, the severity of the illness, and the type of the patient. If the identity of the organism is known then treatment can be specific and a single, narrow-spectrum antibiotic used. If the infecting organism can be targeted then broad-spectrum antibiotics do not need to be used, thus leaving much of the body's normal flora undisturbed.

Initial (often empirical) therapy is based on good surveillance and prompt guidance from clinical laboratory staff. Therapy is subsequently modified according to the results of pre-treatment samples. The duration of therapy will depend on the type and severity of the illness and the patient's response. Potentially toxic drugs should be monitored accordingly. Infection control staff should be contacted for specialized advice if the patient is infected with contagious pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) or Str. pyogenes.

Control of antibiotic use

The principles which should be followed in deciding which antibiotic, if any, to use in a given situation are discussed in Chapter 15. However, even in relatively straightforward clinical situations there are often several equally effective agents which might be used. Choice may then be determined by a locally agreed set of guidelines for the rational use of antibiotics.



Antibiotic policies (guidelines)

Clinicians do not take kindly to ill-informed interference, least of all with their prescribing habits, but all would agree that a rational approach to prescribing is the basis of medical practice. Guidance on the most appropriate use of antibiotics should not be too restrictive, should reflect local needs, and should be formulated with the agreement of the local users. The basis of most policies is education and communication. The aims of the policy are to offer guidelines for the rational use of antimicrobial agents in an attempt to prevent or delay the emergence of resistant micro-organisms. Advice should also include the most effective treatment for the individual patient. The basis of all sound antibiotic policies is good microbiology laboratory surveillance, which is required to detect important change in bacterial resistance. The policy chosen should be monitored by a clinical microbiologist or by a small enthusiastic subgroup of the drugs and therapeutics subcommittee. Day-to-day control of antibiotic usage can be monitored by the pharmacy department and ward pharmacists, but good communication within the hospital or health area is of the utmost importance.

Clinicians need to be aware of the local and changing patterns of infection and antibiotic resistance in their locality. Information about new agents, together with an assessment of their likely place in therapy, should be available. Involvement of pharmacists and microbiologists as well as clinicians should enable colleagues to reach a consensus on appropriate usage. It may be that the most important function of an antibiotic policy is to provide a vehicle for ensuring that regular discussion among all those concerned in antibiotic prescribing does take place.

Blind faith in a restrictive antibiotic policy is not the answer to control of antibiotic usage since bacterial resistance patterns change over time owing to selective pressure; a flexible system should therefore be used. It is essential that an active infection control programme is also in place, so that patients harbouring multi-resistant bacteria are appropriately treated.

Monitoring antibiotic policies

Laboratory reports should contain information on a restricted number of antibiotic sensitivities; full clinical advice is usually available from the microbiology department. Policies may be tailor-made for individual units, and ward stocks restricted to agents named in the formulary. Ward pharmacists, if they are available, should maintain up-to-date records and maintain stocks; unused drugs should be returned to the pharmacy. Restricted drugs may be available in the emergency cupboard, but a record of all antibiotics removed should be kept. Antibiotics used for surgical prophylaxis should be prescribed for 1 day or less, and treatment courses re-prescribed every 5 days if necessary. Overall scrutiny of antibiotic usage (audit) by ward, unit, or hospital can be carried out by the drugs and therapeutics sub-committee. Computer printouts can be readily scrutinized and


aberrant prescriptions followed up. The policy is based on consensus and voluntary agreement. Cross-sectional surveys are easy to carry out and should be performed at regular intervals: once a month on selected wards. Special attention should be paid to the use of antibiotics for surgical prophylaxis, which should be the subject of regular audit.

Antibiotic audit should not be a policing exercise and should not imply a threat to the clinician's freedom to prescribe as he or she thinks best. Rather, it should serve as a reminder of the need to justify selection of antimicrobials in the light of critical analysis.

Benefits of monitoring antibiotic use

Formularies are a way of ensuring that drug therapy is cost effective and cost beneficial. Monitoring antibiotic usage should provide ward, unit, and hospital-wide information on prescribing patterns. This should prove useful for trend analysis and allow discrepancies to be identified. Such information lends itself to detailed scrutiny to differentiate between rational, questionable, and irrational antibiotic usage. Clinical efficacy and adverse events can be evaluated. Correlations between antibiotic usage and antimicrobial resistance should be sought, and changes can be made. Prospective, controlled trials on new antibiotics should be carried out and cost–benefit analyses undertaken.

Although there are many benefits of monitoring antibiotic use, such a strategy costs money. Few studies have attempted to cost the total resource put into preparing and monitoring a formulary. The effect (or outcome) of drug utilization review studies is unknown. It is not enough simply to count the total cost of antibiotic consumption; there are too many variables. Although a ‘defined daily dose’ can be used as a standard unit of measurement, the case mix of different wards is so variable that direct comparisons are difficult. Nevertheless, without information on antibiotic prescribing habits it is impossible to control the use of antibiotics effectively.

The next stage on from monitoring antibiotic usage is antibiotic audit, thereby closing the loop (see Table 14.1).

Table 14.1 Audit of antibiotic prescribing


1. What is the most likely anatomical site of the infection?

2. What clinical and radiological evidence, and laboratory findings support the evidence of infection?

3. Have bacteriological investigations been requested?

4. Has the organism responsible for the infection been isolated?

5. If not, what is the suspected organism?

6. Are there any recognized underlying or predisposing conditions relevant to the diagnosis of infection?

7. Was the diagnosis, confirmed, doubtful, or unknown?

8. Should the patient have received an antibiotic?

9. Was the antibiotic an appropriate choice?

10.     Was the dose appropriate?

11.     Was its frequency of dosage appropriate?

12.     Was the route of administration appropriate?

13.     Was the course of treatment of suitable duration?


Control of the emergence of resistance

All antibiotic use creates selective pressures which lead to the emergence of resistant bacterial strains. Antibiotics are vital to the practice of modern medicine; we cannot abandon them, or even unreasonably restrict their use. Resistant bacteria will continue to appear, and to cause problems in the treatment of the infections they cause. Surveillance of the use of antibiotics—locally, nationally, and internationally—coupled with the monitoring of emerging patterns of bacterial resistance will help to influence prescribing practice and the development


of meaningful antibiotic policies, as long as the people collecting the information ensure that it is passed on to the people who use the drugs. Few will recklessly continue to prescribe antibiotics to which local resistance is common, as long as they know that local resistance iscommon.

Control of the spread of antibiotic-resistant bacteria

Effective surveillance is critical to the understanding and control of the spread of resistance. Microbiology laboratories should provide readily available advice on the correct procedure for specimen collection together with a rapid and accurate diagnostic service (see Chapter 10). Clinical advice should be available when needed, and it should be evidence-based. Rapid identification of infecting organisms will encourage early treatment and prompt isolation of patients that are infected or colonized with ‘alert organisms’ (e.g. MRSA or multi-resistant Gram-negative bacilli). Patients may be isolated in single rooms or cohort-isolated in groups of beds (bays) in which those with similar infections can be treated.

There is ample evidence that when infection control measures are strictly enforced, the incidence of infection with resistant organisms can be reduced. Although such measures are time-consuming and sometimes expensive, so are the consequences of the spread of progressively more resistant bacteria. Patients may have to be screened to see if resistant bacteria strains are still present and, if they are, then the carriage rate may have to be reduced or eradicated.