Antibiotic Development and Resistance

Diarmaid Hughes, Dan I Andersson, Diarmaid Hughes, Dan I Andersson

• Publisher: CRC Press
• Year: 2001
• Print ISBN: 9780415272179
• eBook ISBN: 9781134484928
• Edition: 1
• Topic: Medicine
• Subtopic: Immunology

The increasing resistance of bacteria towards all current classes of antibiotics is now a serious health problem in both developed and developing countries. Antibiotic Development and Resistance presents 15 chapters that explore the medical issues raised by this development and review the relevant literature. The book begins by reviewing the global

1. : A Global Perspective on Bacterial Infections, Antibiotic Usage, and the Antibiotic Resistance Problem

Lars G.Burman and Barbro Olsson-Liljequist Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden

INTRODUCTION

Antimicrobial agents represent the greatest advance in modern curative medicine. These drugs are reckoned to have extended the life span of the average US citizen by 10 years, whereas curing all cancer would prolong life by 3 years (McDermott, 1982). Recent evidence, however, points to an inexorable increase in the prevalence of microbial drug resistance apparently paralleling the expansion of the antimicrobial usage in various fields. Therapeutic difficulties are now posed by strains of certain bacteria such as enterococci and tuberculosis bacteria, which have the ability to acquire resistance to the most useful and possibly to all agents currently in use. Thus, antimicrobial resistance particularly among bacteria has become an increasingly important problem, which has serious implications for the prevention and treatment of infectious diseases. Nevertheless, it has been estimated that the benefits in real-dollar terms of resulting from the use of developed and marketed antibiotics far outweighs costs of adverse effects, including resistance (Liss and Batchelor, 1987).

History of Antibiotic Resistance

Resistance to antimicrobial agents has existed since before they were introduced into human and veterinary medicine, probably because most of the classes of compounds used clinically are produced also by microorganisms in the environment. Evidence for this are e.g. the presence of drug resistant strains in collections of bacteria dating from before the antibiotic era (Datta and Hughes, 1983; Murray and Moellering, 1978) and in wild animals with no apparent contact with man made drugs (Gilliver et al., 1999).

The introduction and increasing clinical use of each antimicrobial agent has sooner or later been followed by an increasing isolation rate of resistant bacteria. Shortly after the introduction of penicillin after World War II penicillinase production was discovered in Staphylococcus aureus and Escherichia coli and in the early 1950’s the use of the first broad spectrum agents such as chloramphenicol, streptomycin and tetracycline was rapidly followed by resistance in stapylococci and Gram negative bacteria. This was true also for the isoxazolyl penicillins and the occurrence of methicillin resistance in S. aureus (MRSA) apparently as a result of horizontal transfer of the mecA gene from S. sciuri (Wu et al. , 1996). Also, resistance was quick to develop by mutational target alteration against e.g. quinolones, rifampicin, fusidic acid and mupirocin after their introduction into clinical use.

In some cases resistance turned out to be a complicated task and its development took three decades and included a series of sophisticated genetic events until levels of resistance of clinical relevance was obtained (penicillin betalactam resistant pneumococci, PRP; vancomycin resistant entero-cocci, VRE). Also, the resurgence of tuberculosis in the 1980’s was accompanied by an increasing rate of multi-resistant Mycobacterium tuberculosis isolates, defined as those resistant to both isoniazid and rifampicin, with or without resistance to other agents, which markedly increased the risk of therapeutic failure. On the other hand, the continuing universal susceptibility of Streptococcus pyogenes (group A streptococcus) to penicillin and to other betalactam agents represents an unusual example of both poor ability to acquire betalactamase genes and to create mosaic penicillin binding protein genes through the import of DNA from other streptococci, despite the continuing use of penicillin as the drug of choice for cure of streptococcal in fections.

Consequences of Antibiotic Resistance

There is an embarrassing lack of studies estimating the cost of antibiotic resistance in terms of increased morbidity, mortality or cost to hospitals or the society (Liss and Batchelor, 1987). In one rare and much cited study of hospitalized patients receiving empiric antibacterial therapy, resistance of the infecting strain to the drug given resulted in prolongation of the hospital stay by about 2 weeks (Holmberg et al., 1987). Applying this figure to Swedish hospitals and assuming that 5% of the cures were troubled by bacterial resistance, the resulting extra cost of the patients’ care would equal that of all nosocomial infections taken together or outnumber the hospitals expenditures for antibiotics by 5 to 1.

Shortage of New Agents

The resistance problem has traditionally been addressed by the development of new antimicrobials. In recent years, however, there has been a slowing down in the introduction of such agents and no truly novel antibacterial drugs have been marketed for more than 10 years. Problems have arisen in finding effective therapy for a number of pathogens such as MRSA, VRE, PRP, nonfermentative Gram-negative rods and multiply resistant M. tuberculosis.

Apparently, new agents against resistant cocci will soon be clinically available. However, in the case of quinupristin-dalfopristin (Synercid®) being evaluated for use in humans, a related combination of streptogramins has already been used for many years as an animal feed additive in the EU (streptogramin A+B; Virginiamycin). This has resulted in the development of resistance to Virginiamycin but also to Synercid among entero-cocci from animals. Regrettably, this also applies to everninomycin (SCH 27899), an oligosaccharide and a rare example of a truly new type of antibacterial compound to be introduced into human medicine (Ziracin®). This compound has already been used for many years under the name Avilamycin in animal feeds, thereby creating enterococcal resistance in European industry reared animals.

Another truly novel agent inhibiting multiresist-ant cocci and now being launched is linezolid (Zyvox®), the first representative of the oxazolidinone group of agents to be used in clinical practice. It is unique in this context as bacteria outside of laboratories have so far not seen the agent (Ford et al., 1997). A possible drawback from a resistance aspect is that linezolid is almost completely absorbed after oral administration and that adverse effects are rare. This might invite a widespread use of the agent both in hospitals and in the community, which might lead to the development of resistance in Gram-positive cocci and jeopardize its future usefulness in critical clinical situations.

Current International Activities

The serious potential consequences of a continuing development of resistance to antimicrobial agents among microorganisms has been considered and debated by numerous academic, professional, industrial and Government groups worldwide. Several of these bodies, both in Europe (The Copenhagen Recommendations, 1998; European Commission, 1999) and in the US (Goldmann et al., 1996) as well as the WHO (WHO, 1998) have recently reported findings and issued recommendations on complementary strategies including research efforts to better control the drug resistance problem in the future. Furthermore, several efforts to improve surveillance of antibiotic usage and antibiotic resistance and to analyze their relationship are under way in the US (Flaherty and Weinstein, 1996; McGowan and Tenover, 1997; Shlaes et al., 1997) and in Europe (see further below).

INDICATIONS FOR ANTIBIOTIC USAGE

Major Community Acquired Infections

Respiratory tract infections

In western countries about 75% of all antibiotics are used to treat community acquired respiratory tract infections (Gonzales et al., 1997; Guillermot et al., 1998a; Pennington, 1994). The peak of antibiotic usage occurs in early childhood because of the frequent acute middle ear infections (otitis media) affecting half of pre-school children at least once, and some children repeatedly. Otitis is caused primarily by Streptococcus pneumoniae and less often by Hemophilus influenzae, S. pyogenes and occasionally by Moraxella catarhalis. Otitis becomes relatively uncommon after 6 years of age. Instead, tonsillitis mainly due to S. pyogenes and occasionally accompanied by facial skin infection (impetigo) or generalized skin rash (scarlatina) emerges as a major bacterial upper respiratory tract infection. Streptococcal sore throat shows a peak incidence between 5 to 10 years of age but continues to be relatively common through college age annually affecting 2–3% and totally about 25% of the population (Pennington (ed.), 1994).

A less common upper respiratory tract infection is sinusitis, 90% of affected patients being in the age group 15–65 years and with S. pneumoniae as the dominating causative agent followed by H. influenzae and S. pyogenes. These organisms may also contribute to acute exacerbations of chronic bronchitis whereas acute bronchitis is mainly of viral origin.

Deep infection of the lung, pneumonia, shows an incidence of about 10 episodes per 1000 inhabitants and year. It occurs in small children, less often in teenagers and middle age individuals and shows a marked increase in the elderly. S. pneumoniae is again the dominant causative agent followed by Mycoplasma pneumoniae, especially among younger patients. Other major bacterial pathogens casing pneumonia are H. influenzae, Chlamydia pneumoniae and occasionally Legionella pneumophila, M. tuberculosis or Bordetella pertussis, the causative agent of whooping cough.

Because of the expected spectrum of bacterial pathogens, as outlined above, penicillins, macrolides, tetracyclines and amoxicillin/ clavulanic acid are the major classes of antimicro-bial agents used in community acquired respiratory tract infections. Therapy is usually empiric, i.e. started without a microbiological diagnosis. This is because apart from rapid S. pyogenes tests there are currently no possibilities to differentiate between viruses and bacteria or to identify them and their resistance pattern in the doctors office. The drug selected in each case depends both on the organism expected and its presumed susceptibility to antibiotics. Thus, the type of infection, the age of the patient, local susceptibility patterns, previous exposure to antibiotics and other circumstances such as drug allergy have to be taken into consideration.

Urinary tract infections (UTI)

UTI is the indication for 10–20% of antibiotic prescriptions in primary health care. It shows a peak in early childhood, then occurs as the most common bacterial infection in women in the child-bearing age group, and finally increases among the elderly, both women and men. The leading causative agent is Escherichia coli (80%), usually originating from the patient’s own faecal flora, followed by Staphylococcus saprophyticus (10%), Klebsiella spp, other Gram negative bacteria and enterococci. Therefore, broad spectrum penicillins (amoxicillin, mecillinam), oral cephalosporins, nitrofurantion, trimethoprim, and in recent years phosphomycin and particularly fluoroquinolones, have become frequently used against UTI (see below).

Helicobacter pylori

A relatively new indication for antibiotic usage is H. pylori infection, which is the cause of duodenal ulcer and sometimes gastric ulcer. The association between H. pylori and diffuse stomach discomfort such as dyspepsia is still controversial. Recommended therapy is combinations including metronidazole, amoxicillin, macrolides and sometimes bismuth. Taken together, these patient groups could represent up to 5% of those needing antimicrobial agents outside hospitals. Currently, patients with milder gastric discomfort lacking evidence of ulcer or laboratory diagnosed H. pylori infection are, however, not given antibiotics. It is therefore estimated that currently only about 1% of all antibiotic prescriptions but 10% of the prescriptions of macrolides (e.g. in Sweden) refer to H. pylori infection.

Enterocolitis

In western countries the incidence of the classical enteric infections has become relatively low. Furthermore, only severe infections due to Salmonella, Shigella or Campylobacter spp. and strains of E. coli causing diarrhea (ETEC, EHEC, EIEC etc.) are treated with antibiotics, usually fluoroquinolones, but erythromycin for Campylobacter. In contrast, milder to severe colitis due to overgrowth of toxin producing Clostridium difficile has become a major problem, particularly in hospitals. This is seen as a consequence of the use of modern antibiotics, disrupting the large bowel microflora by virtue of poor absorption, large biliary excretion and unfavorable antimicrobial spectrum. For example, a recent nationwide Swedish survey showed that the incidence of C. difficile disease, almost unknown 20 years earlier, now exceeds that of the domestic cases of Salmonella, Shigella, Campylobacter, Yersinia and parasitic and amoeba diarrhea taken together (Karlström et al., 1998). The specific therapy of C. difficile diarrhea is metronidazole or oral vancomy-cin, but due to the current problems with VRE van-comycin is no longer recommended for C. difficile infections.

Sexually transmitted disease (STD)

Among these syphilis is rare and there has been a reduction of the incidence of gonorrhea in many western countries since the mid-1970’s. Current isolates of Neisseria gonorrhoeae tend to be resistant to penicillins, and antibiotic therapy is preferably selected based on results of in vitro susceptibility testing of the infecting isolate. Despite the decline of gonorrhea there has been a corresponding increase in genital Chlamydia trachomatis infections over the last decades now affecting about 0.5% of the sexually active population every year. The drugs used for genital infection are tetra-cyclines, and in recent years also modern macrolides like azithromycin and sometimes fluoroquinolones.

Other infections

Bone infection or osteomyelitis may occur either spontaneously via the blood stream or after penetrating trau...

Table of contents

• COVER PAGE
• TITLE PAGE
• COPYRIGHT PAGE
• INTRODUCTION
• Contributors
• 1.: A GLOBAL PERSPECTIVE ON BACTERIAL INFECTIONS, ANTIBIOTIC USAGE, AND THE ANTIBIOTIC RESISTANCE PROBLEM
• 2.: TARGET ALTERATIONS MEDIATING ANTIBIOTIC RESISTANCE
• 3.: EVOLUTION OF MULTIPLE ANTIBIOTIC RESISTANCE BY ACQUISITION OF NEW GENES
• 4.: ADAPTIVE RESISTANCE TO ANTIBIOTICS
• 5.: EFFLUX MECHANISMS: MOLECULAR AND CLINICAL ASPECTS
• 6.: BACTERIAL GENETICS AND ANTIBIOTIC RESISTANCE DISSEMINATION
• 7.: MUTATOR BACTERIA AND RESISTANCE DEVELOPMENT
• 8.: LOW-LEVEL ANTIBIOTIC RESISTANCE
• 9.: POSSIBLE IMPACT ON ANTIBIOTIC RESISTANCE IN HUMAN PATHOGENS DUE TO AGRICULTURAL USE OF ANTIBIOTICS
• 10.: FITNESS AND VIRULENCE OF ANTIBIOTIC RESISTANT BACTERIA
• 11.: EVOLUTIONARY CONSEQUENCES AND COSTS OF PLASMID-BORNE RESISTANCE TO ANTIBIOTICS
• 12.: STRUCTURAL INSIGHTS INTO ANTIBIOTIC-TARGET INTERACTIONS
• 13.: NEW TARGETS AND STRATEGIES FOR IDENTIFICATION OF NOVEL CLASSES OF ANTIBIOTICS
• 14.: PEPTIDE ANTIBIOTICS
• 15.: MOLECULAR GENETIC AND COMBINATORIAL BIOLOGY APPROACHES TO PRODUCE NOVEL ANTIBIOTICS