Reduced In Vitro Activity of Ceftaroline by Etest among Clonal Complex 239 Methicillin-Resistant Staphylococcus aureus Clinical Strains from Australia

Abstract

bA total of 421 methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates were tested for ceftaroline susceptibility by Etest (bioMérieux). A multidrug resistant phenotype was found in 40.9%, and clonal complex 239 (CC239) was found in 33.5%. Ceftaroline nonsusceptibility (MIC, >1.0 g/ml) was 16.9% overall. Nonsusceptibility was significantly higher in CC239 (41.1%, 58/141) and in isolates with a multidrug resistant phenotype (35.5%, 61/172) compared with comparators (P < 0.0001). Nonsusceptibility of common multidrug resistant MRSA clones limits the empirical use of ceftaroline for these infections. Ceftaroline, an oxyimino-cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA) due to enhanced affinity for penicillin binding protein (PBP) 2a, was approved for use in Australia in 2013 for the treatment of complicated skin and soft tissue infections (SSTIs) and community-acquired bacterial pneumonia (CABP), following approvals for the same indications in the United States in 2010 and Europe in 2012. S. aureus MIC breakpoints have been set by the Clinical and Laboratory Standards Institute (CLSI) (1) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2). Both report a susceptibility MIC of Յ1.0 g/ml, although they differ in the resistance designation (CLSI, resistant MIC of Ͼ4.0 g/ml; EUCAST, resistant MIC of Ͼ1.0 g/ml). Resistance appears to be associated with decreased PBP2a binding affinity (3-7) and heteroresistance (8). Reports have largely demonstrated minimal resistance, although geographical variation has been noted (4, 7, 9-33) ( Table 1). More recently, in hospital-associated MRSA (HA-MRSA) isolates from China, ceftaroline nonsusceptibility was 33.5% (84/251); most (95.2%) belonged to clonal complex (CC) 8, and sequence type (ST) 239-III was the majority (9). Similarly, ceftaroline nonsusceptible MRSA isolates from Eastern Australia were all ST239-III clones (10). A German study also demonstrated increased ceftaroline MIC 50 and MIC 90 values for isolates of clonal lineages ST228 and ST239 (7).Nonduplicate, consecutive clinical MRSA isolates were tested from patients treated at the Alfred Hospital, a tertiary-care metropolitan hospital in Melbourne, Australia, over two time periods: July to December 2010 and August to November 2013. Ceftaroline was not in use clinically before 2014. Isolates from 2010 and 2013 were identified using Vitek 2 and Vitek MS (bioMérieux), respectively. Susceptibility testing was performed using the Vitek 2 Grampositive susceptibility card (AST-P612), applying EUCAST breakpoints. The multidrug resistant phenotype was defined as resistance to Ն3 non-␤-lactam antibiotics, including ciprofloxacin, erythromycin/clindamycin, gentamicin, co-trimoxazole, and tetracycline. All isolates were assessed for ceftaroline and vancomycin susceptibility by Etest (bioMérieux). Isolates from 2010 that had been frozen were thawed and subcultured twice before testing. Isolates from 2013 were collected and tested in real time. Ceftaroline...

Ceftaroline as Salvage Monotherapy for Persistent MRSA Bacteremia

“…AWARE data from 7 countries in the Asia-Pacific region and Australia state that 78.8% and 83.1%, respectively, of MRSA isolates collected in 2012 tested susceptible to ceftaroline. 30,31 Although resistance rates may appear low in the United States, it is important to recognize and monitor regional differences in resistance trends.…”

“…51 It is also unclear whether ceftaroline will retain durable activity against MRSA with more frequent use because recent reports from Australia and Asia suggest higher rates of resistance than previously reported. 30,31 To date, follow-up data regarding patient outcomes from these case series have not yet been published. Results from a completed cohort study evaluating the safety and efficacy of ceftaroline in those with SAB or persistent MRSAB are expected and may provide more evidence for the use of ceftaroline for these indications.…”

Novel Antibiotics for Multidrug-Resistant Gram-Positive Microorganisms

“…Dosage adjustment is required in renal impairment, specifically for patients with an estimated creatinine clearance at 50 mL/min or less [32]. Dose adjustments are made by reducing the dose instead of the dosing interval, as the efficacy of ceftaroline is mainly determined by free-drug concentration above MIC [36]. The commonest adverse drug events are diarrhea, nausea, and rash, with vomiting, headache, hypokalaemia, increased liver transaminases, and phlebitis also documented (2–3% among patients from four phase III clinical trials) [37].…”

“…An emerging concern with ceftaroline use is the reported decreased susceptibility and increased resistance in certain MRSA clinical isolates collected around the world [36,41,42,43]; especially high regional resistance percentages have been reported from China, Thailand, and Australia [36,43]. In particular, the in vitro study that evaluated MRSA isolates from Melbourne, Australia found significant ceftaroline resistance among MDR phenotype and the CC239 strain making it a non-ideal option for empiric treatment in suspected or known MRSA infections in regions where strain CC239 represents a significant proportion of MRSA [36]. It should be noted however, that most resistance strains have been re-categorized as intermediate with the updated The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints [44].…”

Non-microbial Natural Products That Inhibit Drug-Resistant Staphylococcus aureus

“…Ceftaroline has an enhanced affinity for penicillin binding protein 2a (PBP2a), thus is an ideal antibiotic choice for MRSA infections. This antibiotic is relatively new, and was approved for use in 2010 in the U.S, 2012 in Europe, and 2013 in Australia [36]. However, the emergence of ceftaroline resistance in different parts of the world with a demonstrated decrease of PBP2a binding affinity and heteroresistance, has been documented [37][38][39].…”