Antibiotic Susceptibility

Although antibiotic activity against non-P-haemolytic streptococci has long since been known to be poorer than for their P-haemolytic counterparts, the 1990s has witnessed some alarming changes in the susceptibility of non-P-haemolytic streptococcal strains to key therapeutic agents. Early indications of emerging P-lactam resistance came from the United States, Italy and the United Kingdom (Wilson etal., 1978; Bourgault, Wilson and Washington, 1979; Venditti etal, 1989;

Table 2.12 Differential biochemical characteristics of the mutans group

We do not have permission to reproduce the table electronically

Table 2.13 Differential biochemical characteristics of the S. bovis/S. equinus complex

S. bovis/S. equinus subsp. gallolyticus subsp. pasteurianus subsp. macedonicus subsp. infantarius subsp. coli

Hydrolysis of Aesculin Gallate Production of P-Glucosidase P-Glucuronidase a-Galactosidase P-Galactosidase (P-GAR test) P-Galactosidase (P-GAL test)

P-Mannosidase Acid from Starch Glycogen Inulin Lactose Mannitol

Methyl-P-D-glucopyranoside

Raffinose

Trehalose

+, >80% of strains are positive; +/-, 21-79% of strains are positive; <20% of strains are positive. Table adapted from Schlegel et at. (2003a). a Different reactions were observed for isolates formerly assigned to S. equinus or S. bovis.

McWhinney etat., 1993; Renneberg, Niemann and Gutschik, 1997), with further reports emerging throughout the 1990s from almost all continents, indicating emerging penicillin resistance.

Within Europe, many reports from the late 1980s, and continuing throughout the 1990s, observed an increase in the numbers of antibiotic-resistant non-P-haemolytic streptococcal strains implicated in severe disease in neutropenic and other patient groups. Research from Barcelona, Spain, based on non-P-haemolytic streptococcal strains causing bacteraemia in neutropenic patients collected between 1987 and 1992 documented such an emergence of penicillin resistance (Carratala etat, 1995). The strain collection was expanded to span from 1986 to 1996, and microbiological analysis revealed a remarkably high number of strains to have reduced susceptibility to penicillin (39%), with resistance to erythromycin and ciprofloxacin being found in just over a third of isolates (Marron etat, 2001). Susceptibility to fourth-generation cephalosporins was also tested in 35 of these isolates, 5 of which were found to be resistant to cefpirome and 12 to cefepime. How widespread this phenomenon of penicillin resistance was is difficult to ascertain, since a study from the opposite side of the Iberian Peninsula (Lugo), although admittedly based on a small collection of anginosus group bacteraemic strains (1988-1994), found all to be sensitive to penicillin and erythromycin (Casariego etal., 1996). More recent evidence from central Spain (Madrid) also reported a high proportion of non-P-haemolytic streptococci isolated from blood culture between 1998 and 2001 to be to erythromycin (42%), tetracycline (35%) and clindamycin (25%) resistant (Rodriguez-Avial etal, 2003). Researchers also found evidence of cross-resistance between erythromycin and tetracycline, with resistance to one agent being associated with the occurrence of the other. Also of note is that 3 of the 111 isolates tested by Rodriguez-Avial etal. (2003) were found to be resistant to the streptogramin quinupristin/ dalfopristin.

National surveillance data from England and Wales also point to a similar increase in resistant phenotypes (PHLS, 2001, 2002; HPA, 2003a). The numbers of bacteraemic strains reported through routine surveillance as having reduced susceptibility to penicillin increased between 2000 and 2002 for all non-P-haemolytic streptococcal groups, with yearly increases for S. mitis group being particularly pronounced, stepping from 9 reports in 2000 to 33 in 2001 to 73 in 2003. Of the multitude of species that constitute the non-P-haemolytic streptococci, S. mitis, S. sanguis and S. oralis, have been described as most frequently exhibiting reduced susceptibility to penicillin (Alcaide etal., 1995; Mouton etal., 1997; de Azavedo etal., 1999; Wisplinghoff etal., 1999; Gershon etal, 2002). Analysis of streptococcal isolates submitted to the UK national reference laboratories between 1996 and 2000, originating from patients with endocarditis, found one in four of S. mitis isolates to have reduced susceptibility to penicillin (MIC >0.125 mg/l), with one in seven of S. sanguis and one in eight of S. oralis isolates also showing reduced penicillin susceptibility (Johnson etal, 2001). Tetracycline and erythromycin resistance similarly increased over this period, with S. mitis group showing highest frequency of erythromycin resistance and S. bovis group showing the highest frequency of tetracycline resistance (HPA, 2003a). In the light of the common target of activity for streptogramins and macrolides, studies have found evidence of cross-resistance between erythromycin and quinupristin/dalfopristin (Mouton etal, 1997).

Similarly worrying reports of antibiotic resistance in non-P-haemolytic streptococci causing bacteraemia and/or endocarditis emerged from other parts of Europe during this period. Although frequently based on small collections of strains, studies in France, Germany, Sweden and Denmark documented substantial proportions of non-P-haemolytic streptococcal strains as having decreased sensitivity to erythromycin and/or penicillin (Wisplinghoff etal, 1999; Lefort etal, 2002; Westling et al., 2002). Pooled data for 1997-1998 from European countries participating in the SENTRY Antimicrobial Surveillance Programme found 39% of non-P-haemolytic streptococci to be nonsusceptible to penicillin, whereas 30% exhibited reduced susceptibility to erythromycin (Fluit etal, 2000).

Interestingly, two studies from the Far East both showed high levels of macrolide resistance in bacteraemic isolates. Sixty-three per cent of non-P-haemolytic streptococcal strains collection from Taiwan were reported as having reduced susceptibility to erythromycin and clarithromycin, although all strains were sensitive to penicillin, cefotaxime, imipenem, vancomycin and teicoplanin (Teng etal., 2001). Similarly, in Hong Kong, characterization of bacteraemic S. bovis isolates showed all to be sensitive to penicillin, cephalothin and vancomycin, whereas 65% had reduced susceptibility to erythromycin. Forty-one per cent also showed reduced susceptibility to clindamycin (Lee etal, 2003). Subsequent reports from participants in the Asia-Pacific region SENTRY Antimicrobial Surveillance Programme, which includes Hong Kong and Taiwan, documented a frequency of penicillin and erythromycin resistance in non-P-haemolytic streptococci more akin to that documented in Europe and the Americas, possibly due to the effect of pooling data from many countries, including Australia and South Africa (Gordon etal., 2002).

Research from North America began to show a similar pattern of emerging penicillin resistance as that seen in Europe among non-P-haemolytic streptococci. Studies conducted in the United States during the mid-1990s began to report levels of penicillin tolerance (nonsusceptibility) at between 39% and 44% of isolates (Doern etal., 1996; Pfaller etal., 1997). Cases of quinupristin/dalfopristin-resistant S. mitis have also been uncovered in the United States through the SENTRY Antimicrobial Surveillance Programme (Kugler etal., 2000). Similarly, research from the Canadian Bacterial Surveillance Network found levels of penicillin resistance increasing from the mid-1990s (28% of blood culture isolates) to 2000 (37%) (de Azavedo etal, 1999; Gershon etal., 2002). Bigger increases still were seen in the frequency of isolates nonsusceptible to erythromycin, from 29% to 42%, with frequency of reduced clindamycin susceptibility also increasing from 4% to 10%.

Following the mottled array of reports describing the emergence of resistant phenotypes over 1990s, more recent descriptions from the SENTRY global antimicrobial surveillance network suggest that some degree of uniformity of antibiotic resistance may now exist among non-P-haemolytic streptococci causing blood stream infection (Gordon etal., 2002). The increase in resistance in these important pathogens presents a challenge to the treatment and control of infections and warrants further vigilance, especially in the light of the first description of a naturally occurring vancomycin-resistant S. bovis strain (Poyart etal., 1997).

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