High ceftaroline non-susceptibility in Staphylococcus aureus isolated from acute skin infections in 15 tertiary hospitals in China

Ceftaroline is a novel, semisynthetic, N-phosphono prodrug cephalosporin with broad-spectrum activity. As ceftaroline possesses high binding affinity for the mecA-encoded penicillin-binding protein 2a (PBP2a) due to structural differences, this drug has excellent activity against both meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-sensitive S. aureus (MSSA). Furthermore, ceftaroline possesses good activity against penicillin-resistant pneumococci and exhibits similar activity against Gram-negative pathogens to third-generation cephalosporins (Jones et al., 2010; Richter et al., 2011; Saravolatz et al., 2011). This new antibiotic was approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia by the US Food and Drug Administration (FDA) in October 2010. However, there has yet to be a report on testing the activity of ceftaroline against S. aureus isolates collected in China to date.

In the present study, in vitro activity of ceftaroline and 13 other antimicrobials, cefoxitin, ceftriaxone, cefepime, ciprofloxacin, levofloxacin, moxifloxacin, erythromycin, clindamycin, trimethoprim–sulfamethoxazole, linezolid, vancomycin, norvancomycin and teicoplanin, was evaluated against a collection of S. aureus isolates causing ABSSSIs in China. A total of 315 S. aureus isolates were obtained from the Surveillance by Etest and Agar Dilution of Nationwide Isolate Resistance (SEANIR), a nation-wide surveillance programme encompassing 15 tertiary/teaching hospitals distributed across 15 major cities in China.

All S. aureus isolates were referred to the central laboratory (Division of Clinical Microbiology, Peking Union Medical College Hospital, Beijing, China) for identification confirmation. MICs for isolates were determined by the broth microdilution method according to Clinical and Laboratory Standards Institute (CLSI) guidelines (CLSI, 2009), and S. aureus ATCC 29213 was used as quality control. Testing results were interpreted as per CLSI documents M100-S22 (CLSI, 2012); for antimicrobials without CLSI interpretive criteria, norvancomycin was interpreted with reference to breakpoints of vancomycin, and FDA breakpoints were applied for ceftaroline (susceptible, ≤1 mg l⁻¹). Susceptibilities of isolates with ceftaroline MIC >1 mg l⁻¹ were tested twice by broth microdilution, and a third time by the agar dilution method (CLSI, 2009) for confirmation. Statistical analysis for comparisons of categorical variables was performed using a chi-square or Fisher’s exact test as appropriate by spss software version 12.0, and a P-value less than 0.05 was considered significant.

Of 315 S. aureus isolates collected, 65.1 % were isolated from male patients, 93.7 % were recovered from hospital inpatients [surgical wards 51.1 %, medical wards 11.7 %, intensive care units 2.5 % and other wards (e.g. paediatric, dermatology) 28.3 %] and 6.3 % were from outpatients/emergency department. By testing of cefoxitin, 166 isolates were identified as MSSA and 149 were MRSA. MRSA was more commonly isolated from surgical wards compared to MSSA (75.2 % versus 29.5 %, P<0.001).

The overall susceptibility rates to each antimicrobial for MSSA and MRSA are given in Table 1. Generally, cephalosporins (excluding ceftaroline) and fluoroquinolones showed good activity against MSSA (>85 % susceptible) but not against MRSA (≤2 % susceptible). The activity of erythromycin and clindamycin was poor, but most S. aureus isolates tested remained susceptible to trimethoprim–sulfamethoxazole (susceptibility rate of 94.0 % for MSSA and 81.2 % for MRSA). No S. aureus isolate exhibited resistance to vancomycin, norvancomycin, teicoplanin or linezolid.

All isolates had ceftaroline MICs ≤2 mg l⁻¹. For MSSA, the ceftaroline MIC₅₀ and MIC₉₀ values were 0.25 mg l⁻¹, which were identical to those in earlier studies (Jones et al., 2010; Richter et al., 2011). However, only 70 of 121 (63.8 %) MRSA isolates studied were susceptible to ceftaroline according to FDA breakpoints, with MIC₅₀ = 1 mg l⁻¹ and MIC₉₀ = 2 mg l⁻¹. The ceftaroline non-susceptible isolates were all with linezolid MIC of 1 mg l⁻¹ (33.3 %) or 2 mg l⁻¹ (66.6 %). In addition, ceftaroline non-susceptible isolates were more commonly recovered from surgical wards (25.5 %, P<0.001) and less commonly from outpatients/emergency department (5.0 %, P<0.001). Further, MICs of 90.0 % (63 of 70) of ceftaroline-susceptible MRSA isolates were 1 mg l⁻¹. The ceftaroline MIC₅₀ and MIC₉₀ values of MRSA isolates tested in the present study were higher than those reported in the US (0.5 and 1 mg l⁻¹, respectively) (Jones et al., 2010; Richter et al., 2011) but identical to those of isolates from a European collection (1 and 2 mg l⁻¹, respectively) (Jones et al., 2010); however, the ceftaroline non-susceptibility rate of the current Chinese MRSA collection (36.2 %) was higher than that of the previous European collection (17.4 %). As the results were out of the ordinary, those isolates with ceftaroline MIC >1 mg l⁻¹ were tested twice by broth microdilution, then a third time by the agar dilution method for confirmation, and identical results were obtained. We suppose that the geographical difference in ceftaroline susceptibility may be explained by the difference in major MRSA clones that have spread in mainland China (ST239-t030/t037-MRSA-III followed by ST5-t002-MRSA-II) compared to the major clones that have spread in the US and European countries.

In conclusion, we report for what we believe to be the first time the activity of ceftaroline against a multi-centre collection of S. aureus isolates causing ABSSSIs in China. Our study found that the MRSA isolates collected exhibited higher non-susceptibility rates to ceftaroline than those in previous studies, although no isolate was detected with a ceftaroline MIC ≥4 mg l⁻¹. Further analysis is pending on investigating the potential relationship between the reduced ceftaroline susceptibility and molecular typing results of MRSA isolates.