Antimicrobial Chemotherapy, 4th Edition
Resistance to antimicrobial agents
The problem of resistance
- J. Towner
Definition of resistance
Bacterial isolates have been labelled sensitive or resistant to antimicrobial agents ever since such agents were brought into use. Some of the criteria on which this categorization has been based have been discussed already in Chapter 8, where the concepts of the minimum inhibitory and minimum bactericidal concentrations (MIC and MBC) of an antibiotic have also been described. The decision as to whether a given bacterial isolate should be labelled sensitive or resistant depends ultimately on the likelihood that an infection with that organism can be expected to respond to treatment with a given drug, but microbiologists and clinicians have become accustomed to the idea that an organism is ‘resistant’ when it is inhibited in vitro by an antibiotic concentration which is greater than that achievable in vivo. Unfortunately, making a true judgement is somewhat less straightforward than this traditional working definition, since there is usually no simple relationship between the MIC (or MBC) of an antibiotic and clinical response. Therapeutic success depends not only on the activity of the antimicrobial agent against the infecting organisms, but relies also on the drug reaching the site of infection in sufficient concentration (i.e. its pharmacokinetic behaviour), and the contribution that the host's own defences are able to make towards clearance of the offending microbes.
If whole bacterial species are considered, rather than individual isolates, it is apparent immediately that they are not all intrinsically sensitive to all antibiotics (Table 11.1); for example, a coliform infection would not be treated with erythro-mycin, or a streptococcal infection with an aminoglycoside, since the organisms are intrinsically resistant to these drugs. Similarly, Pseudomonas aeruginosa and
Mycobacterium tuberculosis are intrinsically resistant to most of the agents used to treat more tractable infections. Such intrinsically resistant organisms are sometimes termed insensitive, with the term resistant reserved for variants of normally susceptible species that acquire the protection of resistance traits.
Table 11.1 Effective antimicrobial spectrum of some of the most commonly used antibacterial agents
The most obvious determinant of bacterial response to an antibiotic, and hence intrinsic resistance, is the presence or absence of the target for the drug's action. Thus polyene antibiotics, such as amphotericin B, kill fungi by binding tightly to the sterols in the fungal cell membrane and altering the permeability of the fungal cell. Since bacterial membranes do not contain sterols, bacteria are intrinsically resistant to this class of antibiotics. Similarly, the lipopolysaccharide outer envelope of Gram-negative bacteria is important in determining sensitivity patterns, since many antibiotics cannot penetrate this barrier to reach their intra-cellular target.
Fortunately, intrinsic resistance is often predictable in a clinical situation, and should not pose problems provided that an informed and judicious choice is made of appropriate antimicrobial therapy. Of greater concern is the acquisition or emergence of resistance in previously sensitive bacterial species, sometimes during the course of therapy itself.
Introduction of clinically effective antimicrobial agents has been followed invariably by the rapid emergence of resistant strains of bacteria belonging to species that would normally be considered to be sensitive. This phenomenon of initial success followed by the emergence of resistance has been repeated many times. Acquisition of resistance has seriously reduced the therapeutic value of many important antibiotics, but is also a major stimulus to the pharmaceutical industry in its constant search for new and more effective antimicrobial drugs.
The first systematic observations of acquired drug resistance were made by Paul Ehrlich between 1902 and 1909 while using azo dyes, organic arsenicals, and triphenylmethane derivatives to treat mice infected experimentally with trypanosomes. However, antibacterial chemotherapy really started with the introduction into clinical practice of sulphonamides in 1935 and penicillin in 1941. Within a very few years, micro-organisms described originally as being susceptible to these agents were found to have acquired resistance. Thus, when penicillin came into use in the early 1940s, less than 1 per cent of all strains of Staphylococcus aureus were resistant to its action. By 1946, under the selective pressure of this antibiotic, the proportion of penicillin-resistant strains found in hospitals had risen to 14 per cent. A year later, 38 per cent were resistant, and today, resistance is found in more than 90 per cent of all strains of Staph. aureus. In contrast, over the same period, an equally important pathogen, Streptococcus pyogenes, has remained more or less uniformly sensitive, although there is no guarantee that resistance will not spread to Str. pyogenes in future years.
There is no easy explanation for the marked observed differences in the acquisition of resistance between different species, but it is clear that simple possession of the genetic capacity for resistance does not always explain its prevalence in a particular species. Even when selection pressures are similar, the end result may not be the same. Thus, although about 90 per cent of all strains of Staph. aureus are now resistant to penicillin, the same has not happened to sulphonamide or ampicillin resistance in Escherichia coli under ostensibly similar selection pressure. At the present time, apart from localized outbreaks involving epidemic strains, about 30–40 per cent of Esch. coli strains are resistant to sulphonamides or ampicillin, and this level has remained more or less steady for a number of years. However, since an increasing incidence of resistance is at least partly a consequence of selective pressure, it is not surprising that the withdrawal of an antibiotic from clinical use may often, but not always, result
in a slow reduction in the number of resistant strains encountered in a particular environment.
The introduction of new antibiotics has also resulted in changes to the predominant spectrum of organisms responsible for infections. Thus the 1960s saw the introduction of the semi-synthetic ‘β-lactamase stable’ penicillins and cephalo-sporins which, temporarily, solved the problem of staphylococcal infections. Unfortunately, Gram-negative bacteria then became the major pathogens found in hospitals, and rapidly acquired resistance to multiple antibiotics in the succeeding years. In the 1970s the pendulum swung the other way with the first outbreaks of hospital infection with multi-resistant staphylococci, which can be resistant to nearly all antistaphylococcal agents. Outbreaks of infection caused by such organisms have occurred subsequently all over the world.
Use of vancomycin in response to this problem provides an excellent illustration of the way in which extensive use of a drug can be a major factor in the spread of resistance. Vancomycin was used infrequently for at least 30 years (partly because it was too toxic in its original impure form) without the development of any significant resistance. Less toxic preparations are now available and the use of vancomycin has increased dramatically. It is thus no great surprise that high-level resistance to vancomycin has now emerged in enterococci, with the potential for spread to Staph. aureus and coagulase-negative staphylococci.
Types of acquired resistance
Two main types of acquired resistance may be encountered in bacterial species that would normally be considered sensitive to a particular antibacterial agent.
In any large population of bacterial cells a very few individual cells may spontaneously become resistant (see Chapter 13). Such resistant cells have no particular survival advantage in the absence of antibiotic, but after the introduction of antibiotic treatment, sensitive bacterial cells will be killed, so that the (initially) very few resistant cells can proliferate until they eventually form a wholly resistant population. Many antimicrobial agents select for this type of acquired resistance in many different bacterial species, both in vitro and in vivo. The problem has been recognized as being of particular importance in the long-term treatment of tuberculosis with antituberculosis drugs.
A more spectacular type of acquired resistance occurs when genes conferring antibiotic resistance transfer from a resistant bacterial cell to a sensitive one. The simultaneous transfer of resistance to several unrelated antimicrobial agents can be demonstrated readily, both in the laboratory and the patient. Exponential transfer and spread of existing resistance genes through a previously sensitive
bacterial population is a much more efficient mechanism of acquiring resistance than the development of resistance by mutation of individual sensitive cells.
Mechanisms by which transfer of resistance genes takes place are discussed in Chapter 13. Here it is sufficient to stress that however resistance appears in a hitherto sensitive bacterial cell or population, resistance will only become widespread under the selective pressures produced by the presence of appropriate antibiotics. Also, the development of resistant cells does not have to happen often or on a large scale. A single mutation or transfer event can, if the appropriate selective pressures are operating, lead to the replacement of a sensitive population by a resistant one. Without selective pressure, antibiotic resistance may be a handicap rather than an asset to a bacterium.
Cross-resistance and multiple resistance
These terms are often confused. Cross-resistance involves resistance to a number of different members of a group of chemically-related agents which are affected alike by the same resistance mechanism. For instance, there is almost complete cross-resistance between the different tetracyclines since tetracycline resistance results largely from an efflux mechanism which affects all members of the group. The situation is more complex among other antibiotic groups. Thus, resistance to aminoglycosides may be mediated by any one of a number of different drug-inactivating enzymes (see p. 150, Table 12.3) with different substrate specificities, and the range of aminoglycosides to which the organism is resistant will depend on which enzyme it produces. Cross-resistance can also be observed occasionally between unrelated antibiotics. For example, a change in the outer membrane structure of Gram-negative bacilli may concomitantly deny access of unrelated compounds to their target sites.
In contrast, multiple drug (multi-drug) resistance involves a bacterium becoming resistant to several unrelated antibiotics by different resistance mechanisms. For example, if a staphylococcus is resistant to penicillin, gentamicin, and tetracycline, the resistances must have arisen independently, since the strain destroys the penicillin with a β-lactamase, inactivates gentamicin with an amino-glycoside-modifying enzyme, and excludes tetracycline from the cell by an active efflux mechanism.
It is not always clear whether cross-resistance or multiple resistance is being observed. Genes conferring resistance to several unrelated agents can be transferred en bloc from one bacterial cell to another on plasmids (see Chapter 13), thereby giving the appearance of cross-resistance. In such cases, detailed biochemical and genetical analysis may be required to prove that the resistance mechanisms are distinct (multiple resistance), although the genes conferring resistance are linked and transferred together on one plasmid.
The clinical problem of drug resistance
Concerns about resistance have been raised at regular intervals since the first introduction of antimicrobial chemotherapy, but awareness of the drug resistance problem has never been greater than it is today. It has been suggested that antibiotic resistance is becoming so commonplace that the new century will resemble the pre-antibiotic era. However, it is important not to overstate the problem; the situation is presently becoming serious, but is not yet desperate since most infections are still treatable with more than one of the currently available agents. Nevertheless, in many less-developed countries of the world the therapeutic options may already be severely restricted for economic reasons. There is no doubt that the resistance problem is global and in future years there is a real possibility that physicians will be faced increasingly with infections for which effective treatment is not available. Some of the organisms in which resistance is a particular problem are summarized below.
The prevalence of resistance in hospital strains of Enterobacteriaceae has been increasing steadily for the past 30 years, particularly in large units, and although cephalosporins, quinolones, and aminoglycosides have been developed to cope with the problem, significant levels of resistance to these newer compounds have already emerged in many countries. Epidemics of diarrhoeal disease caused by multi-resistant strains of intestinal pathogens, including Vibrio cholerae, shigellae, salmonellae, and toxin-producing strains of Esch. coli, have occurred around the world, especially in south-east Asia and Africa. Widespread resistance is a particular problem in less-developed areas of the world where heavy and indiscriminate use of antibiotics may combine with a high prevalence of drug-resistant bacteria in the faecal flora, poor standards of sanitation, and a high incidence of diar-rhoeal disease to encourage the rapid emergence and spread of multi-resistant strains of enteric bacteria.
These organisms now account for a substantial proportion of endemic nosoco-mial infections, particularly ventilator-associated pneumonia acquired by patients confined to intensive care units. Such infections are usually extremely difficult to treat because of the multiple classes of antibiotic resistance found in these bacteria. Very few antibiotics are now reliably effective for treatment of acine-tobacter infections. The carbapenems currently offer the best therapeutic option, but resistance has already started to emerge and combination therapy is invariably required. Some strains are now effectively untreatable.
Staphylococci and enterococci
Methicillin-resistant Staph. aureus (MRSA) continue to cause outbreaks in many hospitals and nursing homes, and are endemic in others. Some MRSA strains are resistant to all available agents except the glycopeptide antibiotics, and isolates with mutations conferring low-level resistance to glycopeptides have already been reported.
Coagulase-negative staphylococci and enterococci are gaining importance as multi-resistant pathogens causing infections that are difficult to treat. A combination of antibiotics may be required to treat serious enterococcal infections, but the emergence of high-level aminoglycoside resistance may seriously limit this option. Aminoglycoside-resistant enterococci carrying genes conferring high-level resistance to glycopeptides have also been reported. Not only may such isolates be untreatable, but it is probably only a matter of time before the genes responsible find their way into staphylococci.
Another major problem concerns the emergence of resistance in Streptococcus pneumoniae, a common cause of community-acquired pneumonia and other forms of sepsis. This organism used to be combated easily by treatment with penicillin and its derivatives. Unfortunately isolates with resistance to most antibiotics can now be found, albeit infrequently, in most countries of the world. In some countries the situation is serious. Such infections are presently treatable with glycopeptides and broad-spectrum cephalosporins, but the range of alternative treatments is narrowing.
The frequency of resistance in meningococci is increasing gradually. Decreased levels of susceptibility to penicillin are being encountered in many countries, notably Spain, but also including the UK. The emergence of resistance to penicillin in N. meningitidis has removed one of the mainstays of immediate empirical therapy, a development that has important strategic implications because of the need for immediate treatment of the life-threatening infections caused by these organisms.
Strains of M. tuberculosis that are multi-resistant to isoniazid, ethambutol, rifampicin, and streptomycin have been seen mainly, but not exclusively, in HIV-infected patients, and transmission to healthcare workers has also occurred. This problem is continuing to grow because of the general susceptibility to tuberculosis in certain populations, the difficulty of ensuring compliance with the necessary
long-term treatment regimens, and the ineffectiveness of conventional prophylaxis against resistant strains.
Problems of ‘blind’ therapy
In most situations in which antimicrobial agents need to be used, treatment must be started, and is often completed, without the benefit of laboratory help. This is true both in domiciliary practice, where access to the laboratory may be limited, and also in hospitals, where severe infections need treatment urgently and there is often no time to wait for culture (and sensitivity) results from the specimens taken. Even if the infecting organism is recognized to be multi-resistant and therapy is chosen accordingly, treatment failures may still occur simply because such infections tend to be associated with critically ill patients who have impaired host defences or have been subjected to invasive procedures. Such patients have often already received antibiotics, are elderly, or have been confined to hospital for prolonged periods.
Drug resistance is a significant clinical problem because it limits the number of therapeutically effective agents, puts constraints on those that can be used, and sometimes forces the use of more expensive, more toxic, or otherwise more difficult agents than would be chosen normally. In any clinical situation there is therefore a need for knowledge of local resistance trends. Indeed, under circumstances in which access to a microbiology laboratory is difficult or ruled out because of time constraints, such information is vital for a judicious and informed choice of appropriate antimicrobial therapy. It is also of paramount importance that the development and spread of resistance should be contained by sensible prescribing and by the implementation of agreed control of infection policies. Many hospitals now have Control of Infection teams of doctors (normally microbiologists) and nurses who have a roving commission to investigate outbreaks of infection. Such intervention is crucial in the containment of the spread of antibiotic resistance and in the preservation of the rapidly decreasing number of effective antimicrobial agents remaining in the armamentarium (see Chapter 14).