Community acquired infections and bacterial resistance

Streptococcus pneumoniae

Infection with S pneumoniae is the biggest cause of potentially life threatening, community acquired diseases such as meningitis and pneumonia. It is also the leading bacterial cause of otitis media and sinusitis. However, this pathogen has evolved to reach unexpected levels of resistance to antibiotics. Before the early 1990s most pneumococci isolated in the European Union and the United States were susceptible to penicillin, with minimum inhibitory concentrations of <0.1 mg/l1; this concentration of penicillin killed these organisms rapidly. Since then, resistance to penicillin has increased substantially in certain European countries and in the United States. 2 3

Unfortunately, different authors have used different inhibitory concentrations to define penicillin resistance. However, susceptibility to penicillin is defined by many authors as a minimum inhibitory concentration of <0.1 mg/l; penicillin resistance is classed as intermediate when the minimum inhibitory concentration for S pneumoniae is 0.1-1.0 mg/l, and high when the minimum inhibitory concentration is 2.0 mg/l. Treatment regimens have been proposed for different pneumococcal diseases based on these minimum inhibitory concentrations. 4 5 These cut off points were selected on the basis of the efficacy of penicillin in treating S pneumoniae meningitis. Thus, penicillin and other β lactam antibiotics may still be effective in treating non-meningitis pneumococcal infections caused by penicillin resistant strains.5

In Europe, there are discrepancies in penicillin susceptibility even among adjacent countries despite increasing international travel. Penicillin resistance is rare in northern Europe and the Netherlands; high prevalence rates have been reported in Spain (45%) and France (25%). Resistance rates of 5% to 10% have been reported in the United Kingdom, Germany, Belgium, and Italy; most of these strains have intermediate levels of resistance to penicillin.2 Molecular studies have shown that resistant clones have been imported to countries with low prevalence rates, suggesting that local conditions may affect the emergence of resistance.6 Risk factors for the development of penicillin resistance in communities include having many patients who have recently been treated with antibiotics, poor compliance with the treatment regimen, and children's attendance at day care facilities. 5 7

A surveillance study has found that penicillin resistance in S pneumoniae developing among those receiving outpatient care is an important problem in the United States.3 It has also been shown that resistance is no longer limited to isolates taken from paediatric patients with otitis media.7 Clearly, resistant strains have now also spread to the adult population. Since cross resistance occurs with cephalosporins, reduced susceptibility can be expected to extend to this class of antibiotics as well. Of great concern are reports from the United States of clinical isolates of S pneumoniae that have an intermediate level of resistance to penicillin and are highly resistant to cefotaxime and ceftriaxone.8 Penicillin resistant strains are more frequently resistant to other non-β lactam agents (such as macrolide antibiotics, tetracycline, chloramphenicol, and trimethoprim-sulphamethoxazole) than strains that remain susceptible to penicillin. 2 3 5 Yet the mechanisms of resistance to non-β lactam agents are unrelated to those of penicillin resistance. High rates of macrolide resistance have been reported in the United States (19%), Spain (18%), France (30%), and Belgium (30%). 2 3 5 These rates are higher in strains that are resistant to penicillin, resulting in coselection of these multiresistant pneumococci when β lactams and macrolide antibiotics are used.

Thus, antimicrobial resistance in S pneumoniae has clearly emerged as a serious global problem which is likely to grow. Current recommendations for the empirical treatment of pneumococcal infections will require ongoing evaluation.

Streptococcus pyogenes

S pyogenes is responsible for a variety of community acquired diseases and is probably one of the bacterial pathogens most often encountered in clinical practice. Penicillin is the drug of choice for treatment of infection with S pyogenes, and macrolide antibiotics are recommended as an alternative treatment. In spite of the extensive use of penicillin and other β lactam antibiotics these organisms remain susceptible to these antibiotics. However, high rates of resistance to erythromycin have been reported in Australia (18%), Japan (60%), Finland (20%), the United Kingdom (23%), Italy (81%), and Spain (19%). 9 10 Seppälä et al have shown that macrolide resistance may decline if practitioners follow recommendations for reducing the use of these antibiotics.11

The susceptibility of S pyogenes to penicillin has not been a large clinical and epidemiological problem. The study by Seppälä et al in Finland is one of the best demonstrations of the existence of a link between the development of resistance in a community acquired pathogen and the use of antibiotics.

Resistance rates to erythromycin, tetracycline, and ofloxacin of Campylobacter spp isolated from human faeces, Arnhem region, Netherlands. Percentages are 12 month moving averages. Reproduced with thanks to Drs H Nieste (Streeklaboratorium Arnhem) and E Talsma (ISIS)

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Neisseria meningitidis

In children and young adults infection with N meningitidis is an important cause of bacterial meningitis and community acquired septicaemia. Benzylpenicillin is the treatment of choice for infections caused by this organism. Strains of N meningitidis with decreased susceptibility to penicillin (minimum inhibitory concentrations >0.16-1.28 mg/l) have been described worldwide, but the frequency with which such isolates are found varies widely. In Spain the incidence increased from 0.4% in 198512 to 67% in 1996.13 In the United Kingdom the incidence rose to 11% in 199514; in Belgium 6% of meningococcal isolates showed reduced susceptibility to penicillin in 1998.15 From the data, it seems that the prevalence of resistance is low in other parts of the world; in the Netherlands it is still below 2%.16

The clinical importance of infection with strains that have a reduced susceptibility to penicillin is unclear because treatment with high doses has been successful. Also, ceftriaxone remains effective against these organisms.17 Prophylactic treatment of close contacts of an index case usually involves administration of rifampicin or fluoroquinolone drugs. Rifampicin resistance is rare, and resistance to fluoroquinolone drugs has not yet been reported. 14 15 Nevertheless, evidence of the development of resistance to penicillin and to other antibiotics in N meningitidis is mounting.

Thus, although the prevalence of resistance is still low, continued surveillance is necessary to monitor trends in the susceptibility of meningococci to antimicrobial drugs. Eradication of meningococcal disease by vaccination would be the ultimate response to the emergence of resistance.

Bacterial gastroenteritis

Infection with Campylobacter jejuni or Salmonella spp is the most frequent cause of bacterial gastroenteritis. When empirical treatment of gastroenteritis is required, fluoroquinolone drugs are prescribed because they are one of the few classes of drugs with activity against both organisms. They have also been recommended for the management of traveller's diarrhoea.18 However, resistance to fluoroquinolones among Campylobacter spp is increasing worldwide. The figure shows this increase in one region in the Netherlands.

Although the number of resistant isolates varies both between and within countries, resistance rates of more than 50% have been reported in some studies. 19 20 Fluoroquinolone resistance in campylobacter has been responsible for treatment failures.21 There are also indications of reduced susceptibility to fluoroquinolone drugs among non-typhoidal salmonella serotypes in the United Kingdom22 and the United States23 but the prevalence remains low. The use of fluoroquinolones in animal husbandry has contributed to the selection of fluoroquinolone resistant campylobacter and salmonella.24 Thus, although most cases of infection with campylobacter and non-typhoidal salmonella do not require treatment, there is concern about the emergence of fluoroquinolone resistance among these organisms.

Urinary tract infections

Infection with Escherichia coli is responsible for more than 80% of cases of acute uncomplicated cystitis in young women, and fluoroquinolone drugs are among the recommended empirical treatments.25 Several reports have found an increase in the number of E coli isolated from the urinary tract that are resistant to fluoroquinolone drugs. 26 27 Although clinical information is lacking in most of these in vitro studies, it has been shown by others that resistant strains are often isolated from patients previously treated with fluoroquinolone drugs,28 or from patients with urinary tract infections complicated by functional or anatomical disorders of the urinary tract.29 Moreover, after the administration of fluoroquinolone drugs high concentrations of these drugs have been identified in urine.

Thus, despite the development of in vitro resistance to fluoroquinolones these agents may be successful in eradicating E coli from the urinary tract of women with acute uncomplicated cystitis. However, expanded use of these agents may pose a risk for the further selection and spread of fluoroquinolone resistant E coli.

Discussion

Community acquired resistance to antibiotics is increasing and has reached an alarming level for some organisms (S pneumoniae) and certain antibiotics (fluoroquinolones and macrolides). The potentially widespread use of new fluoroquinolone drugs for treatment of respiratory tract infections in the next century and the use of fluoroquinolones in animal husbandry may exacerbate this problem.29 Resistance has been developing in patients in day care centres and long term care facilities, such as nursing homes and rehabilitation centres.30 This resistance has probably emerged in the community as a result of a variety of factors such as clustering and overcrowding, the increasing number of immunocompromised patients, an increase in the number of elderly people, increased travelling, the widespread use of broad spectrum antibiotics, the sale of antibiotics over the counter, self treatment with antibiotics, the inappropriate use of antibiotics, a lack of compliance with treatment, fewer resources for in-service training of health workers, a lack of resources for infection control, and decreased funding for public health surveillance.31 Although the hospital and the community are considered separate ecosystems, their boundaries have become blurred. This trend will continue due to the shift towards shorter hospital stays, the provision of more treatment at home (even of patients with severe and complicated illnesses), the use of more short stay surgical interventions, and the increasing number of transfers of patients from acute hospitals to long term care facilities.32 Nevertheless it is believed that the problem of emerging resistance could be restricted by the appropriate and prudent use of antibiotics.32^–35 Treatment guidelines should be based on the outcome of a reliable surveillance system. Therefore surveillance of bacterial resistance requires a dedicated approach that takes laboratory methods as well as epidemiological princples into account.