Comparative Efficacy of Ceftaroline with Linezolid Against Staphylococcus Aureus and Methicillin Resistant Staphylococcus Aureus

ORIGINAL ARTICLE

Comparative Efficacy of Ceftaroline with Linezolid against Staphylococcus Aureus and Methicillin Resistant Staphylococcus Aureus Amira Hafeez, Tehmina Munir, Sabahat Rehman, Sara Najeeb, Mehreen Gilani, Mahwish Latif, Maliha Ansari and Nadia Saad

ABSTRACT Objective: To compare the in vitro antimicrobial efficacy of ceftaroline with linezolid against Staphylococcus aureus and methicillin resistant Staphylococcus aureus. Study Design: Quasi-experimental study. Place and Duration of Study: Microbiology Department, Army Medical College, Rawalpindi, from January to December 2013. Methodology: Clinical samples from respiratory tract, blood, pus and various catheter tips routinely received in the Department of Microbiology, Army Medical College, Rawalpindi were innoculated on blood and MacConkey agar. Staphylococcus aureus was identified by colony morphology, Gram reaction, catalase test and coagulase test. Methicillin resistant Staphylococcus aureus detection was done by modified Kirby Bauer disc diffusion method using cefoxitin disc (30µg) and the isolates were considered methicillin resistant if the zone of inhibition around cefoxitin disc was ≤ 21 mm. Bacterial suspensions of 56 Staphylococcus aureus isolates and 50 MRSA isolates were prepared, which were standardized equal to 0.5 McFarland's turbidity standard and inoculated on Mueller-Hinton agar plates followed by application of ceftaroline and linezolid disc (Oxoid, UK), according to manufacturer's instructions. The plates were then incubated at 37°C aerobically for 18 - 24 hours. Diameters of inhibition zone were measured and interpretated as per Clinical and Laboratory Standards Institute (CLSI) guidelines. Results: Out of 106 isolates all of the 56 Staphylococcus aureus (100%) were sensitive to ceftaroline and linezolid. However, out of 50 methicillin resistant Staphylococcus aureus, 48 (96%) were sensitive to ceftaroline whereas, 49 (98%) were sensitive to linezolid. Conclusion: Ceftaroline is equally effective as linezolid against Staphylococcus aureus and methicillin resistant Staphylococcus aureus.

Key Words: Ceftaroline. Methicillin resistant Staphylococcus aureus. Linezolid.

INTRODUCTION infections until now since S. aureus has developed 3 Staphylococcus (S.) aureus is an important cause of increase in resistance to beta-lactams. Vancomycin and infections worldwide. For the last many years Methicillin linezolid are preferred medicines in the USA and Europe Resistant Staphylococcus aureus (MRSA) has become for the treatment of infections caused by MRSA a frequent offender in hospital settings and represents especially nosocomial pneumonia.4 Linezolid is the first about 33% to 55% of all isolated S. aureus strains from oxazolidinone and is bacteriostatic. It has very good hospital and 60% from critical care units.1 Clinicians face clinical results but adverse effects like thrombocytopenia a great challenge while treating patients with MRSA and myelosuppression may occur.5 Although many new infections especially Community Acquired Pneumonia agents to combat MRSA have been introduced during (CAP) because of limited treatment options. MRSA the last decade including, daptomycin, tigecycline, and infections not only cause increased morbidity and telavancin but their usage has been mitigated because mortality but also contributes to increasing healthcare of concerns regarding adverse effects, drug interactions, costs.2 and high drug prices. Newer antimicrobials are needed Cephalosporins have been used for more than 40 years as there is ongoing emergence of multidrug-resistant 6 against Gram-positive and Gram-negative bacterial Gram-positive organisms. Ceftaroline is newer addition in cephalosporin family. It Department of Microbiology, Army Medical College-National has a wide-spectrum antimicrobial activity against University of Science and Technology, Islamabad. Gram-positive and Gram-negative bacteria including Correspondence: Dr. Amira Hafeez, House No. 14, Askari MRSA, which makes it an ideal treatment option for Villas, Chaklala Scheme III, Rawalpindi. complicated Skin and Skin Structure Infections (cSSSI) E-mail: [email protected] and community-acquired pneumonia.7 Ceftaroline is a Received: May 06, 2014; Accepted: February 10, 2015. bactericidal agent and like all other beta-lactam it inhibit

Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (4): 247-249 247 Amira Hafeez, Tehmina Munir, Sabahat Rehman, Sara Najeeb, Mehreen Gilani, Mahwish Latif, Maliha Ansari and Nadia Saad cell wall synthesis. It has high affinity to bind to Penicillin Exact test) was used to compare sensitivity between the binding proteins 2a making it effective against MRSA.8 two groups. P-value of less than 0.05 was considered as By using animal models the in vivo efficacy of ceftaroline significant. has also been demonstrated and results are very promising. These were followed by Phase-III clinical RESULTS trials for treatment of cSSSI and CAP and results are Out of a total of 106 isolates all of 56 isolates of S. aureus 9 very promising. (100%) were sensitive to ceftaroline and linezolid both. Ceftaroline has been placed as a member of a new However, out of 50 MRSA isolates, 48 (96%) were subclass of antimicrobials, cephalosporins with anti- sensitive to ceftaroline, whereas 49 (98%) were MRSA activity by The Clinical and Laboratory Standards sensitive to linezolid. Sensitivities of both the drugs were Institute (CLSI).10 Currently, no data is available on the similar with insignificant statistical difference (p = 1.000). spectrum of activity of this novel antibiotic in our region as the antibiogram of bacteria vary from region to region. DISCUSSION This study was done to compare in vitro antimicrobial It is the need of the hour to discover and develop new efficacy of ceftaroline with linezolid against S. aureus antibiotics to combat the increasing resistance of and MRSA. bacteria to currently available drugs.11 Ceftaroline may be a useful alternative treatment option since there are METHODOLOGY reports of decreased susceptibility to vancomycin and This quasi-experimental study was done in the the report documenting emergence of both chromo- 12 Department of Microbiology, Army Medical College, somal and transferable resistance to linezolid. Rawalpindi, National University of Science and Ceftaroline is currently the only approved beta-lactam Technology, Islamabad. Clinical samples from res- antimicrobial by Food and Drug Administration (FDA) piratory tract, blood, pus and various catheter tips which has activity against MRSA. Although it is indicated received were inoculated on Blood and MacConkey for the treatment of CAP and cSSSI, recent reports agar. These were then incubated at 37°C for 18 - 24 suggest that different infections including osteomyelitis hours. Staphylococcus aureus was identified by its and endocarditis caused by MRSA may also be 13 colony morphology, positive Gram reaction, positive treated. catalase and coagulase test. S. aureus was found to be 100% sensitive to ceftaroline From the isolated S. aureus MRSA was detected by and to linezolid both which showed these to be highly modified Kirby-Bauer disc diffusion method. Isolate effective and promising treatment option. Similar results suspension was applied on Mueller-Hinton agar followed were seen from surveillance studies conducted in by application of cefoxitin disc (30µg) incubated at different parts of the world. A surveillance study 37°C for 18 - 24 hours. The isolates were considered conducted in Canada by Karlowsky et al. showed 100% 14 methicillin resistant if the zone of inhibition around sensitivity of S. aureus to ceftaroline and linezolid both. cefoxitin disc was ≤ 21 mm. Duplicate sample from same Same 100% sensitivity to both was seen in Europe in 2010 by a study done by Farrel et al.15 However, by patient during same episode of illness was excluded. 2013 a surveillance study done in USA conducted by Antimicrobial susceptibility testing of the isolates was Sader et al. reported 98.5% sensitivity of S. aureus to done by Modified Kirby-Bauer disc diffusion method. ceftaroline and 99.93% to linezolid which is lower than Bacterial suspensions of isolated 56 Staphylococcus this study.16 aureus and 50 MRSA equivalent to 0.5 McFarland MRSA showed different results. Out of 50 samples 48 turbidity standard were prepared. Inoculation on MHA isolates i.e 96% were sensitive to ceftaroline and 49 plates was done which was followed by application of isolates 98% sensitivity to linezolid. Different surveillance ceftaroline (30µg) and linezolid (30µg) disc (Oxoid, UK) studies done in different parts of the world showed according to manufacturer's instructions. The plates different results demonstrating the demographic were then incubated at 37°C aerobically for 18 - 24 variation. In a study, conducted by Ge Yigong et al. who hours. Zone diameters were measured and inter- studied isolates from USA and Europe causing CAP pretation was done as per CLSI guidelines. The isolates demonstrated 98% sensitivity of MRSA to ceftaroline were considered resistant to ceftaroline and linezolid if and 98.4% to linezolid.17 Slightly lower sensitivity of the zones of inhibition around the disc were ≤ 20 mm for MRSA against ceftaroline being 97.5% was shown by both and susceptible if zone was ≥ 24 mm for ceftaroline Sader et al. who studied isolates from hospitals in USA and ≥ 21 mm for linezolid respectively. during a period of 2008 - 2011 whereas sensitivity to Data was analyzed using Statistical Package for Social linezolid was 99.93% which was higher than this study.16 Sciences (SPSS) version 21. Frequencies and In another study by Farrel et al. evaluated different percentages were calculated for categorical data like antibiotics against major pathogens causing skin and sensitivity and resistance. Chi-square test (Fisher’s soft tissue infections in Europe documented 88.8%

248 Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (4): 247-249 Comparative efficacy of ceftaroline with linezolid against Staphylococcus aureus and methicillin resistant Staphylococcus aureus sensitivity of MRSA to ceftaroline which is quite low as bacterial organisms isolated from acute bacterial skin and skin compared to the present findings whereas 100% structure infections in United States medical centers (2010- sensitivity to linezolid was documented which was 2012). Diagn Microbiol Infect Dis 2014; 78:449-56. higher than these resutls.18 Higher sensitivities of 11. Barton E, MacGowan A. Future treatment options for Gram- ceftaroline and linezolid was documented by Richter positive infections-looking ahead. Clin Microbiol Infect 2009; et al. to MRSA as compared to these findings of being 15:17-25. 98% to ceftaroline and 99.9% to linezolid.19 In another 12. Jacqueline C, Caillon J, Le Mabecque V, Miegeville AF, Hamel study by Sader et al.20 in which they studied pathogens A, Bugnon D, et al. In vivo efficacy of ceftaroline (PPI-0903), a causing skin and soft tissue infections and Community new broad-spectrum cephalosporin, compared with linezolid Acquired Respiratory Tract Infection (CARTI) from Asia and vancomycin against methicillin-resistant and vancomycin- Pacific Region and South America in 2010 showed quite intermediate Staphylococcus aureus in a rabbit endocarditis model. Antimicrob Agents Chemother 2007; 51:3397-400. low sensitivity to ceftaroline being only 80.6% whereas linezolid showed 100% sensitivity. 13. Iizawa Y, Nagai J, Ishikawa T, Hashiguchi S, Nakao M, Miyake A, et al. In vitro antimicrobial activity of T-91825, a novel anti- MRSA cephalosporin, and in vivo anti-MRSA activity of its CONCLUSION prodrug, TAK-599. J Infect Chemother 2004; 10:146-56. Ceftaroline is as effective as linezolid against S. aureus 14. 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