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Antimicrobial Agents and Chemotherapy, February 2002, p. 321-326, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.321-326.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Cephalosporin RWJ-54428 (MC-02479) against Multidrug-Resistant Gram-Positive Cocci

Alan P. Johnson,^* Marina Warner, Michael Carter, and David M. Livermore

Antibiotic Resistance Monitoring and Reference Laboratory, Central Public Health Laboratory, Colindale, London NW9 5HT, United Kingdom

Received 16 May 2001/ Returned for modification 11 September 2001/ Accepted 13 October 2001

Top Abstract Introduction Materials and Methods Results Discussion References

 
RWJ-54428 (MC-02479) is a novel cephalosporin that binds to penicillin-binding protein (PBP) PBP 2' (PBP 2a) of methicillin-resistant staphylococci. Its in vitro activity was assessed against 472 gram-positive cocci, largely selected as epidemiologically unrelated isolates with multidrug resistance. The MIC at which 50% of isolates are inhibited (MIC₅₀) and MIC₉₀ of RWJ-54428 for methicillin-resistant Staphylococcus aureus (MRSA) were 1 and 2 µg/ml, respectively, whereas they were 0.5 and 0.5 µg/ml, respectively, for methicillin-susceptible S. aureus. The MIC₅₀ and MIC₉₀ were 1 and 4 µg/ml, respectively, for methicillin-resistant coagulase-negative staphylococci (MRCoNS), whereas they were 0.25 and 1 µg/ml, respectively, for methicillin-susceptible isolates. The highest MICs for MRSA and MRCoNS isolates were 2 and 4 µg/ml, respectively. The MIC₅₀ and MIC₉₀ of RWJ-54428 for Enterococcus faecalis were 0.5 and 1 µg/ml, respectively, but they were 4 and 8 µg/ml, respectively, for Enterococcus faecium. For penicillin-susceptible, -intermediate, and -resistant pneumococci, the MIC₉₀s of RWJ-54428 were 0.03, 0.25, and 0.5 µg/ml, respectively, with the highest MIC for a pneumococcus being 1 µg/ml, recorded for a strain for which penicillin and cefotaxime MICs were 8 and 4 µg/ml. MICs for Lancefield group A, B, C, and G streptococci were 0.008 µg/ml; those for viridans group streptococci, including isolates not susceptible to penicillin, were from 0.015 to 0.5 µg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci.

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Resistant gram-positive cocci, including methicillin-resistant staphylococci, penicillin- and macrolide-resistant pneumococci, and glycopeptide-resistant enterococci, are all being encountered with increasing frequencies (10). Surveillance of bloodstream infections in England and Wales between 1990 and 2001 showed that the prevalence of methicillin resistance among Staphylococcus aureus isolates rose from 1.7 to 42% and that the prevalence of vancomycin resistance among Enterococcus faecium isolates rose from 3.4 to 30% (19; Public Health Laboratory Service, data on file). Similar problems have developed in many other countries (5, 7) and are compounded by the fact that isolates with the index drug resistance are often additionally resistant to many other unrelated drugs. Against this background, major efforts have been made to discover classes of drugs with activities against gram-positive organisms, as with oxazolidinones and lipopeptides, and to produce resistance-evading analogues in old classes of drugs. A recent product of the latter approach is RWJ-54428 (MC-02479) (1), a cephalosporin that binds to the low-affinity penicillin-binding protein (PBP; PBP 2' or 2a) of methicillin-resistant staphylococci (S. Chamberland, C. Chan, J. Blais, M. Mathias, F. Malouin, and V. J. Lee, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-178, 1997) and that evades staphylococcal ß-lactamases (Chamberland et al., 37th ICAAC).

We tested the activity of RWJ-54428 against multidrug-resistant gram-positive bacteria from British hospitals. Emphasis was placed on the testing of diverse strains, and the isolates were therefore chosen to include a variety of phage types or serotypes and were from a wide geographical spread of hospitals.

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Bacteria. Staphylococci, pneumococci, enterococci, and streptococci were chosen from among those submitted between 1997 and 1999 to the Antibiotic Resistance Monitoring and Reference Laboratory, which is the national reference laboratory for resistant bacteria in England and Wales. The collection was selected to overrepresent bacteria resistant to established antibiotics and to include epidemiologically distinct strains on the basis of their sources and (where available) their phage types or serotypes. Phage types of S. aureus were determined by the Laboratory of Hospital Infection, Central Public Health Laboratory (CPHL), London, United Kingdom, with a standard bacteriophage set (18); serotypes of pneumococci and M and T types of streptococci of Lancefield groups A, B, C, and G were determined by the Streptococcus and Diphtheria Reference Unit, CPHL, by standard methods (4, 6, 12–14).

Antibiotics. RWJ-54428 was obtained from the R. W. Johnson Research Institute, Raritan, N.J. The comparator drugs tested varied with the test organism and are listed in Table 1; most were obtained from Sigma (Poole, United Kingdom), with the exceptions being teicoplanin and quinupristin-dalfopristin (both from Aventis, West Malling, United Kingdom).

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Table 1. MICs of RWJ-54428 and other agents for test strainsa

MICs. MICs were determined at 35°C on Mueller-Hinton agar (Oxoid, Basingstoke, United Kingdom) with inocula of 10⁴ to 10⁵ CFU/spot. For tests with ß-lactams against staphylococci, the medium was supplemented with 2% NaCl, while the medium for streptococci was supplemented with 5% sheep blood (TCS Microbiology, Buckingham, United Kingdom). All cultures except those of pneumococci were incubated in air; pneumococci were incubated in an atmosphere enriched with 5% CO₂. The results were read after 24 h. Except for the use of solid media and 5% CO₂ with pneumococci, these methods corresponded to those of NCCLS, whose breakpoints (15, 16) were used.

Mutant selection. Approximately 10⁹ CFU from overnight broth cultures of each of five isolates of methicillin-resistant S. aureus (MRSA), methicillin-susceptible S. aureus (MSSA), Enterococcus faecalis, and E. faecium were spread onto plates of Mueller-Hinton agar containing doubling concentrations of RWJ-54428 from 0.5 to 8 times the MIC. NaCl (2%) was included in the plates for MRSA. Growth was inspected after incubation for 24 and 48 h at 35°C.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Summary MIC statistics on the activity of RWJ-54428 and its comparator drugs are shown in Table 1, while the distributions of the MICs of RWJ-54428 are shown in Fig. 1.

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FIG. 1. Distributions of RWJ-54428 MICs. (A) S. aureus: MRSA, black bars; MSSA, white bars. (B) CoNS: MRCoNS, black bars; MSCoNS, white bars. (C) Enterococci: E. faecium, black bars; E. faecalis, white bars; E. gallinarum, grey bars. (D) Pneumococci: penicillin-resistant pneumococci, black bars; penicillin-intermediate pneumococci, grey bars; penicillin-susceptible pneumococci, white bars.

Staphylococci. The staphylococci tested included 95 isolates of S. aureus and 95 coagulase-negative staphylococci (CoNS). The former comprised 32 MSSA isolates from 26 hospitals and 63 MRSA isolates from 52 hospitals. The MSSA isolates, 84% of which were penicillin resistant, comprised 17 phage types, with four minor variants of 1 type, whereas the MRSA isolates were divided into 22 groups on the basis of their reactions with bacteriophages. Nevertheless, 61% of the MRSA isolates were phage type variants of epidemic MRSA (EMRSA) strain EMRSA-15 (28%) or EMRSA-16 (33%), which are hugely predominant in the United Kingdom (11). Most MRSA isolates were resistant to erythromycin and ciprofloxacin, as is characteristic of EMRSA-15 and EMRSA-16. Resistance to gentamicin was noted in only 17% of the MRSA isolates, and the teicoplanin MIC for one isolate was 8 µg/ml, whereas the MIC at which 90% of isolates were inhibited (MIC₉₀) was 2 µg/ml for the MRSA isolates as a group. Among the CoNS isolates, 34 were methicillin-susceptible CoNS (MSCoNS) isolates and 61 were methicillin-resistant CoNS (MRCoNS) isolates. The MSCoNS isolates were from 27 hospitals and included isolates resistant to penicillin, erythromycin, gentamicin, and teicoplanin, but not vancomycin. The 61 MRCoNS isolates were from 42 hospitals; many were resistant to erythromycin, gentamicin, and teicoplanin, with substantial minorities also being resistant to ciprofloxacin and rifampin.

RWJ-54428 was consistently active against methicillin-susceptible staphylococci, with MICs from 0.06 to 1 µg/ml. These values were no higher for penicillin-resistant organisms than for penicillin-susceptible organisms, thus supporting the ß-lactamase stability reported by Chamberland et al. (Chamberland et al., 37th ICAAC). RWJ-54428 was two- to fourfold less active against MRSA and MRCoNS than against MSSA and MRCoNS, a much narrower differential than for any ß-lactam available. The actual MICs of RWJ-54428 for MRSA and MRCoNS isolates never exceeded 2 and 4 µg/ml, respectively, even on media containing 2% NaCl, which is conducive to the expression of methicillin resistance in staphylococci (8).

Enterococci. Ninety-four enterococcal isolates were tested, comprising 42 E. faecalis isolates from 22 hospitals, 45 isolates E. faecium from 35 hospitals, and 7 Enterococcus gallinarum isolates from 3 hospitals. Over half of the E. faecalis isolates had high-level resistance to either gentamicin or streptomycin, or to both drugs, and 67% were intermediate or (mostly) resistant to vancomycin; 45% of the E. faecalis isolates had the VanA phenotype and 21% had the VanB phenotype. None of these E. faecalis isolates was resistant to ampicillin, but all were resistant to quinupristin-dalfopristin. Eighty-four percent of the E. faecium isolates were resistant to vancomycin; 51% of these isolates had the VanA phenotype and 33% had the VanB phenotype. As is typical of the species, all the isolates of E. gallinarum had the VanC phenotype, with low-level resistance to vancomycin (MICs, 8 µg/ml) but not teicoplanin (MICs, 0.5 to 1 µg/ml).

The MICs of RWJ-54428 for the E. faecalis isolates were mostly from 0.12 to 0.5 µg/ml and were about fourfold lower than those of ampicillin. RWJ-54428 was less active against E. faecium than against E. faecalis, with MICs clustering around 4 to 8 µg/ml; nevertheless, the activity of RWJ-54428 against E. faecium was considerably better than that of ampicillin, which had an MIC₅₀ and an MIC₉₀ of 128 µg/ml. The MICs of RWJ-54428 for the E. gallinarum isolates were from 0.5 to 1 µg/ml, whereas those of ampicillin were 1 to 8 µg/ml.

Pneumococci. Ninety-three isolates of Streptococcus pneumoniae were tested, of which 22 (from 20 hospitals) were penicillin susceptible, 55 (from 39 hospitals) were intermediately penicillin resistant (MICs, 0.12 to 1 µg/ml), and 16 (from 14 hospitals) were fully resistant (MICs, 2 µg/ml). The penicillin-susceptible, -intermediate, and -resistant isolates comprised 13, 11, and 4 serogroups or serotypes, respectively. About half of the penicillin-nonsusceptible isolates were resistant to erythromycin and/or tetracycline, whereas all the penicillin-susceptible isolates remained susceptible to these agents.

The MICs of RWJ-54428 were related to but were lower than those of penicillin. Values for penicillin-susceptible pneumococci were in the range 0.008 to 0.06 µg/ml, whereas those of penicillin and cefotaxime were 0.015 to 0.06 and 0.015 to 0.125 µg/ml, respectively. For the penicillin-intermediate and -resistant groups, RWJ-54428 had MIC₉₀s of 0.25 and 0.5 µg/ml, respectively, and so was more active than either penicillin or cefotaxime. The highest MIC of RWJ-54428 for any pneumococcus was 1 µg/ml, which was recorded for a single isolate for which penicillin and cefotaxime MICs were 8 and 4 µg/ml, respectively.

Lancefield group A, B, C, and G streptococci. Streptococci of Lancefield groups A (43 isolates from 32 hospitals comprising 14 M types), B (15 isolates from 14 hospitals comprising 4 serotypes), C (8 isolates from 7 hospitals comprising 2 T types), and G (18 isolates from 13 hospitals comprising 7 T types) were tested. Many of the isolates were resistant to erythromycin and tetracycline, but all were highly susceptible to RWJ-54428, penicillin, and cefotaxime, with MICs 0.06 µg/ml. Susceptibility to vancomycin and quinupristin-dalfopristin also was universal.

Viridans group streptococci. Six isolates of Streptococcus oralis and 5 isolates of Streptococcus sanguis were studied. The S. sanguis isolates were broadly susceptible to the comparator antibiotics, but resistance to tetracycline and erythromycin was seen among the S. oralis isolates. Like pneumococci, the viridans group streptococci showed variations in their susceptibilities to ß-lactams, with penicillin MICs being up to 4 µg/ml for S. oralis and 0.5 µg/ml for S. sanguis. The MICs of RWJ-54428 were about fourfold below those of penicillin and cefotaxime.

Selection of resistance. Attempts were made to select for resistance by plating five strains each of MSSA, MRSA, E. faecium, and E. faecalis onto agar containing doubling multiples of the MIC of RWJ-54428. A thin haze of growth was apparent on plates with the MIC of the cephalosporin for enterococci or MRSA and inoculated with 10⁹ CFU and on plates with up to four times the MIC for MSSA. When this film was subcultured onto agar with the same drug level, it did not yield viable individual colonies.

Top Abstract Introduction Materials and Methods Results Discussion References

 
ß-Lactams that overcome target-mediated resistance have long been sought, and during the past 15 years, several analogues with affinity for PBP 2' of MRSA have been described. These include the penicillin BRL45144 (E. J. Catherall, N. R. Eaton, G. K. Hill, D. J. Merrikin, and L. Mizen, Program Abstr. 29th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 90, 1989; P. L. A. Chapman, D. J. Merriken, R. J. Ponoford, and H. Smulders, Program Abstr. 29th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 91, 1989), the cephalosporins TOC-39 (9) and TOC-50 (17), and the carbapenem L-695,256 (2, 20), all of which had MICs for MRSA only two- to eightfold above those for MSSA. Cefathiamidine, developed in China in the early 1980s, had activity against the PBPs of E. faecalis and achieved low MICs (3). Although none of these drugs proved suitable for clinical development, several were active in experimental infections in animals, proving the concept that ß-lactams can be reengineered to overcome pathogens with low-affinity PBPs. RWJ-54428 represents a further attempt to exploit this potential, and the present study assessed its activity against a variety of important gram-positive cocci. Great care was taken to test diverse strains, and to this end, bacteria were selected so as to include a wide spectrum of serotypes or phage types and isolates from a wide range of clinical diagnostic laboratories in Great Britain. The results showed that RWJ-54428 had good activity against most of the organisms tested, including methicillin-resistant staphylococci, E. faecalis, and penicillin-resistant pneumococci, and had moderate activity against E. faecium. Moreover, mutational resistance appeared to be difficult. From our findings and those of others reported recently (1), RWJ-54428 appears to offer promise for clinical investigation as treatment against infections caused by gram-positive cocci resistant to the available drugs.

 
We are grateful to the R. W. Johnson Research Institute for financial support and to Karen Bush for helpful discussions. We are also indebted to Terri Parsons for technical assistance and to colleagues in the Laboratory of Hospital Infection and the Respiratory and Systemic Infections Laboratory for typing data for the staphylococci and streptococci, respectively.

 
* Corresponding author. Mailing address: Antibiotic Resistance Monitoring and Reference Laboratory, Central Public Health Laboratory, Colindale, London NW9 5HT, United Kingdom. Phone: 44-208-200-4400, ext. 4237. Fax: 44-208-358-3292. E-mail: AJohnson{at}phls.nhs.uk.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, February 2002, p. 321-326, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.321-326.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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