Evaluation of in vitro activity of ceftaroline on methicillin resistant Staphylococcus aureus blood isolates from Iran
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Abstract
Background and Objectives: Ceftaroline (CPT) is a novel cephalosporin with potent activity against methicillin-resistant Staphylococcus aureus (MRSA). Despite its recent introduction, CPT resistance in MRSA has been described worldwide. We aimed in the current study to evaluate the in vitro activity of CPT against 91 clinical MRSA and 3 MSSA isolates.
Materials and Methods: Susceptibility of isolates to CPT was tested using E-test and disk diffusion (DD) method. The nucleotide sequence of the mecA gene and molecular types of isolates with reduced susceptibility to CPT were further studied to identify resistance conferring mutations in PBP2a and the genetic relatedness of the isolates respectively.
Results: Overall, 92.5% of isolates were found to be CPT susceptible (MICs≤1mg/l) and 7 MRSA isolates were characterized with MIC=2mg/l and categorized as susceptible dose dependent. Compared to E-test, DD revealed a categorical agreement rate of 93.6% and the obtained rates for minor, major /very major error were found to be 6.3% and 0% respectively. The MRSA isolates with increased CPT MICs (n=7), belonged to spa types t030 (n=6) and t13927 (n=1) and all carried N146K substitution in PBP2a allosteric domain, except for one isolate which harbored a wild-type PBP2a.
Conclusion: While resistance to CPT was not detected we found increased CPT MICs in 7.69% of MRSA isolates. Reduced susceptibility to CPT in the absence of mecA mutations is indicative of contribution of secondary chromosomal mutations in resistance development.
1. Khan A, Rivas LM, Spencer M, Martinez R, Lam M, Rojas P, et al. A multicenter study to evaluate ceftaroline breakpoints: performance in an area with high prevalence of methicillin-resistant Staphylococcus aureus sequence type 5 lineage. J Clin Microbiol 2019;57(9):e00798-19.
2. Pinho MG, Filipe SR, de Lencastre H, Tomasz A. Complementation of the essential peptidoglycan transpeptidase function of penicillin-binding protein 2 (PBP2) by the drug resistance protein PBP2A in Staphylococcus aureus. J Bacteriol 2001;183:6525-6531.
3. Fernandez R, Paz LI, Rosato RR, Rosato AE. Ceftaroline is active against heteroresistant methicillin-resistant Staphylococcus aureus clinical strains despite associated mutational mechanisms and intermediate levels of resistance. Antimicrob Agents Chemother 2014;58:5736-5746.
4. Andrey DO, Francois P, Manzano C, Bonetti EJ, Harbarth S, Schrenzel J, et al. Antimicrobial activity of ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2013–2014 at the Geneva university hospitals. Eur J Clin Microbiol Infect Dis 2017;36:343-350.
5. Harrison EM, Ba X, Blane B, Ellington MJ, Loeffler A, Hill RL, et al. PBP2a substitutions linked to ceftaroline resistance in MRSA isolates from the UK. J Antimicrob Chemother 2016;71:268-269.
6. Kelley WL, Jousselin A, Barras C, Lelong E, Renzoni A. Missense mutations in PBP2A affecting ceftaroline susceptibility detected in epidemic hospital-acquired methicillin-resistant Staphylococcus aureus clonotypes ST228 and ST247 in Western Switzerland archived since 1998. Antimicrob Agents Chemother 2015;59:1922-1930.
7. Sader HS, Flamm RK, Jones RN. Antimicrobial activity of ceftaroline tested against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin from U.S. hospitals, 2008 to 2011. Antimicrob Agents Chemother 2013;57:3178-3181.
8. Saravolatz L, Pawlak J, Johnson L. In vitro activity of ceftaroline against community-associated methicillin-resistant, vancomycin-intermediate, vancomycin-resistant, and daptomycin-nonsusceptible Staphylococcus aureus isolates. Antimicrob Agents Chemother 2010;54:3027-3030.
9. Zhong NS, Sun T, Zhuo C, D'Souza G, Lee SH, Lan NH, et al. Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial. Lancet Infect Dis 2015;15:161-171.
10. Scott LJ. Ceftaroline fosamil: a review in complicated skin and soft tissue infections and community-acquired pneumonia. Drugs 2016;76:1659-1674.
11. Argudín MA, Dodémont M, Taguemount M, Roisin S, de Mendonça R, Deplano A, et al. In vitro activity of ceftaroline against clinical Staphylococcus aureus isolates collected during a national survey conducted in Belgian hospitals. J Antimicrob Chemother 2017;72:56-59.
12. Mendes RE, Tsakris A, Sader HS, Jones RN, Biek D, McGhee P, et al. Characterization of methicillin-resistant Staphylococcus aureus displaying increased MICs of ceftaroline. J Antimicrob Chemother 2012;67:1321-1324.
13. Sanchez EH, Mendes RE, Sader HS, Allison GM. In vivo emergence of ceftaroline resistance during therapy for MRSA vertebral osteomyelitis. J Antimicrob Chemother 2016;71:1736-1738.
14. Long SW, Olsen RJ, Mehta SC, Palzkill T, Cernoch PL, Perez KK, et al. PBP2a mutations causing high-level ceftaroline resistance in clinical methicillin-resistant Staphylococcus aureus isolates. Antimicrob Agents Chemother 2014;58:6668-6674.
15. Fishovitz J, Hermoso JA, Chang M, Mobashery S. Penicillin‐binding protein 2a of methicillin‐resistant Staphylococcus aureus. IUBMB Life 2014;66:572-577.
16. Weinstein MP (2019). Performance standards for antimicrobial susceptibility testing: Clinical and Laboratory Standards Institute.
17. Mahon CR, Lehman DC, Manuselis G (2014). Textbook of diagnostic microbiology-e-book. 5th ed. Elsevier Health Sciences; St. Louis, MO: Saunders 2014.
18. Farahmand S, Haeili M, Darban-Sarokhalil D. Molecular typing and drug resistance patterns of Staphylococcus aureus isolated from raw beef and chicken meat samples. Iranian J Med Microbiol 2020;14:478-489.
19. FDA U. Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems. Rockville, MD: US FDA. 2009. (https://www.fda.gov/media/88069/download)
20. Kahl BC, Mellmann A, Deiwick S, Peters G, Harmsen D. Variation of the polymorphic region X of the protein A gene during persistent airway infection of cystic fibrosis patients reflects two independent mechanisms of genetic change in Staphylococcus aureus. J Clin Microbiol 2005;43:502-505.
21. Jones RN, Holliday NM, Critchley IA. Accuracy of the Thermo Fisher Scientific (Sensititre™) dry-form broth microdilution MIC product when testing ceftaroline. Diagn Microbiol Infect Dis 2015;81:280-282.
22. Mubarak N, Sandaradura I, Isaia L, O'Sullivan M, Zhou F, Marriott D, et al. Non-susceptibility to ceftaroline in healthcare-associated multiresistant MRSA in Eastern Australia. J Antimicrob Chemother 2015;70:2413-2414.
23. Cantón R, Livermore DM, Morosini MI, Díaz-Regañón J, Rossolini GM, Group PS, et al. Etest® versus broth microdilution for ceftaroline MIC determination with Staphylococcus aureus: results from PREMIUM, a European multicentre study. J Antimicrob Chemother 2017;72:431-436.
24. Espedido BA, Jensen SO, van Hal SJ. Ceftaroline fosamil salvage therapy: an option for reduced-vancomycin-susceptible MRSA bacteraemia. J Antimicrob Chemother 2015;70:797-801.
25. Khoshbayan A, Shariati A, Ghaznavi-Rad E, van Belkum A, Darban-Sarokhalil D. Prevalence and molecular epidemiology of ceftaroline non-susceptible methicillin-resistant Staphylococcus aureus isolates, first clinical report from Iran. Acta Microbiol Immunol Hung 2020: 10.1556/030.2020.01273.
26. Morroni G, Brenciani A, Brescini L, Fioriti S, Simoni S, Pocognoli A, et al. High rate of ceftobiprole resistance among clinical methicillin-resistant Staphylococcus aureus isolates from a hospital in central Italy. Antimicrob Agents Chemother 2018;62(12):e01663-18.
27. Abbott IJ, Jenney AW, Jeremiah CJ, Mirčeta M, Kandiah JP, Holt D, et al. Reduced in vitro activity of ceftaroline by Etest among clonal complex 239 methicillin-resistant Staphylococcus aureus clinical strains from Australia. Antimicrob Agents Chemother 2015;59:7837-7841.
28. Sader HS, Flamm RK, Jones RN. Antimicrobial activity of ceftaroline and comparator agents tested against bacterial isolates causing skin and soft tissue infections and community-acquired respiratory tract infections isolated from the Asia-Pacific region and South Africa (2010). Diagn Microbiol Infect Dis 2013;76:61-68.
29. Hashemizadeh Z, Bazargani A, Kalantar-Neyestanaki D, Mohebi S, Hadi N. Determining spa-type of methicillin-resistant Staphylococcus aureus (MRSA) via high-resolution melting (HRM) analysis, Shiraz, Iran. BMC Res Notes 2020;13:97.
30. Moosavian M, Dehkordi PB, Hashemzadeh M. Characterization of SCCmec, spa types and multidrug resistant of methicillin-resistant Staphylococcus aureus isolates in Ahvaz, Iran. Infect Drug Resist 2020;13:1033-1044.
31. Bayat B, Zade MH, Mansouri S, Kalantar E, Kabir K, Zahmatkesh E, et al. High frequency of methicillin-resistant Staphylococcus aureus (MRSA) with SCC mec type III and spa type to30 in Karaj’s teaching hospitals, Iran. Acta Microbiol Immunol Hung 2017;64:331-341.
32. Schaumburg F, Peters G, Alabi A, Becker K, Idelevich EA. Missense mutations of PBP2a are associated with reduced susceptibility to ceftaroline and ceftobiprole in African MRSA. J Antimicrob Chemother 2016;71:41-44.
33. Bongiorno D, Mongelli G, Stefani S, Campanile F. Genotypic analysis of Italian MRSA strains exhibiting low-level ceftaroline and ceftobiprole resistance. Diagn Microbiol Infect Dis 2019;95:114852.
34. Lahiri SD, Alm RA. Potential of Staphylococcus aureus isolates carrying different PBP2a alleles to develop resistance to ceftaroline. J Antimicrob Chemother 2016;71:34-40.
35. Fishovitz J, Rojas-Altuve A, Otero LH, Dawley M, Carrasco-López C, Chang M, et al. Disruption of allosteric response as an unprecedented mechanism of resistance to antibiotics. J Am Chem Soc 2014;136:9814-9817.
36. Chan LC, Basuino L, Diep B, Hamilton S, Chatterjee SS, Chambers HF. Ceftobiprole-and ceftaroline-resistant methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2015;59:2960-2963.
37. Gostev V, Sopova J, Kalinogorskaya O, Tsvetkova I, Lobzin Y, Klotchenko S, et al. In vitro ceftaroline resistance selection of methicillin-resistant Staphylococcus aureus involves different genetic pathways. Microb Drug Resist 2019;25:1401-1409.
2. Pinho MG, Filipe SR, de Lencastre H, Tomasz A. Complementation of the essential peptidoglycan transpeptidase function of penicillin-binding protein 2 (PBP2) by the drug resistance protein PBP2A in Staphylococcus aureus. J Bacteriol 2001;183:6525-6531.
3. Fernandez R, Paz LI, Rosato RR, Rosato AE. Ceftaroline is active against heteroresistant methicillin-resistant Staphylococcus aureus clinical strains despite associated mutational mechanisms and intermediate levels of resistance. Antimicrob Agents Chemother 2014;58:5736-5746.
4. Andrey DO, Francois P, Manzano C, Bonetti EJ, Harbarth S, Schrenzel J, et al. Antimicrobial activity of ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2013–2014 at the Geneva university hospitals. Eur J Clin Microbiol Infect Dis 2017;36:343-350.
5. Harrison EM, Ba X, Blane B, Ellington MJ, Loeffler A, Hill RL, et al. PBP2a substitutions linked to ceftaroline resistance in MRSA isolates from the UK. J Antimicrob Chemother 2016;71:268-269.
6. Kelley WL, Jousselin A, Barras C, Lelong E, Renzoni A. Missense mutations in PBP2A affecting ceftaroline susceptibility detected in epidemic hospital-acquired methicillin-resistant Staphylococcus aureus clonotypes ST228 and ST247 in Western Switzerland archived since 1998. Antimicrob Agents Chemother 2015;59:1922-1930.
7. Sader HS, Flamm RK, Jones RN. Antimicrobial activity of ceftaroline tested against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin from U.S. hospitals, 2008 to 2011. Antimicrob Agents Chemother 2013;57:3178-3181.
8. Saravolatz L, Pawlak J, Johnson L. In vitro activity of ceftaroline against community-associated methicillin-resistant, vancomycin-intermediate, vancomycin-resistant, and daptomycin-nonsusceptible Staphylococcus aureus isolates. Antimicrob Agents Chemother 2010;54:3027-3030.
9. Zhong NS, Sun T, Zhuo C, D'Souza G, Lee SH, Lan NH, et al. Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial. Lancet Infect Dis 2015;15:161-171.
10. Scott LJ. Ceftaroline fosamil: a review in complicated skin and soft tissue infections and community-acquired pneumonia. Drugs 2016;76:1659-1674.
11. Argudín MA, Dodémont M, Taguemount M, Roisin S, de Mendonça R, Deplano A, et al. In vitro activity of ceftaroline against clinical Staphylococcus aureus isolates collected during a national survey conducted in Belgian hospitals. J Antimicrob Chemother 2017;72:56-59.
12. Mendes RE, Tsakris A, Sader HS, Jones RN, Biek D, McGhee P, et al. Characterization of methicillin-resistant Staphylococcus aureus displaying increased MICs of ceftaroline. J Antimicrob Chemother 2012;67:1321-1324.
13. Sanchez EH, Mendes RE, Sader HS, Allison GM. In vivo emergence of ceftaroline resistance during therapy for MRSA vertebral osteomyelitis. J Antimicrob Chemother 2016;71:1736-1738.
14. Long SW, Olsen RJ, Mehta SC, Palzkill T, Cernoch PL, Perez KK, et al. PBP2a mutations causing high-level ceftaroline resistance in clinical methicillin-resistant Staphylococcus aureus isolates. Antimicrob Agents Chemother 2014;58:6668-6674.
15. Fishovitz J, Hermoso JA, Chang M, Mobashery S. Penicillin‐binding protein 2a of methicillin‐resistant Staphylococcus aureus. IUBMB Life 2014;66:572-577.
16. Weinstein MP (2019). Performance standards for antimicrobial susceptibility testing: Clinical and Laboratory Standards Institute.
17. Mahon CR, Lehman DC, Manuselis G (2014). Textbook of diagnostic microbiology-e-book. 5th ed. Elsevier Health Sciences; St. Louis, MO: Saunders 2014.
18. Farahmand S, Haeili M, Darban-Sarokhalil D. Molecular typing and drug resistance patterns of Staphylococcus aureus isolated from raw beef and chicken meat samples. Iranian J Med Microbiol 2020;14:478-489.
19. FDA U. Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems. Rockville, MD: US FDA. 2009. (https://www.fda.gov/media/88069/download)
20. Kahl BC, Mellmann A, Deiwick S, Peters G, Harmsen D. Variation of the polymorphic region X of the protein A gene during persistent airway infection of cystic fibrosis patients reflects two independent mechanisms of genetic change in Staphylococcus aureus. J Clin Microbiol 2005;43:502-505.
21. Jones RN, Holliday NM, Critchley IA. Accuracy of the Thermo Fisher Scientific (Sensititre™) dry-form broth microdilution MIC product when testing ceftaroline. Diagn Microbiol Infect Dis 2015;81:280-282.
22. Mubarak N, Sandaradura I, Isaia L, O'Sullivan M, Zhou F, Marriott D, et al. Non-susceptibility to ceftaroline in healthcare-associated multiresistant MRSA in Eastern Australia. J Antimicrob Chemother 2015;70:2413-2414.
23. Cantón R, Livermore DM, Morosini MI, Díaz-Regañón J, Rossolini GM, Group PS, et al. Etest® versus broth microdilution for ceftaroline MIC determination with Staphylococcus aureus: results from PREMIUM, a European multicentre study. J Antimicrob Chemother 2017;72:431-436.
24. Espedido BA, Jensen SO, van Hal SJ. Ceftaroline fosamil salvage therapy: an option for reduced-vancomycin-susceptible MRSA bacteraemia. J Antimicrob Chemother 2015;70:797-801.
25. Khoshbayan A, Shariati A, Ghaznavi-Rad E, van Belkum A, Darban-Sarokhalil D. Prevalence and molecular epidemiology of ceftaroline non-susceptible methicillin-resistant Staphylococcus aureus isolates, first clinical report from Iran. Acta Microbiol Immunol Hung 2020: 10.1556/030.2020.01273.
26. Morroni G, Brenciani A, Brescini L, Fioriti S, Simoni S, Pocognoli A, et al. High rate of ceftobiprole resistance among clinical methicillin-resistant Staphylococcus aureus isolates from a hospital in central Italy. Antimicrob Agents Chemother 2018;62(12):e01663-18.
27. Abbott IJ, Jenney AW, Jeremiah CJ, Mirčeta M, Kandiah JP, Holt D, et al. Reduced in vitro activity of ceftaroline by Etest among clonal complex 239 methicillin-resistant Staphylococcus aureus clinical strains from Australia. Antimicrob Agents Chemother 2015;59:7837-7841.
28. Sader HS, Flamm RK, Jones RN. Antimicrobial activity of ceftaroline and comparator agents tested against bacterial isolates causing skin and soft tissue infections and community-acquired respiratory tract infections isolated from the Asia-Pacific region and South Africa (2010). Diagn Microbiol Infect Dis 2013;76:61-68.
29. Hashemizadeh Z, Bazargani A, Kalantar-Neyestanaki D, Mohebi S, Hadi N. Determining spa-type of methicillin-resistant Staphylococcus aureus (MRSA) via high-resolution melting (HRM) analysis, Shiraz, Iran. BMC Res Notes 2020;13:97.
30. Moosavian M, Dehkordi PB, Hashemzadeh M. Characterization of SCCmec, spa types and multidrug resistant of methicillin-resistant Staphylococcus aureus isolates in Ahvaz, Iran. Infect Drug Resist 2020;13:1033-1044.
31. Bayat B, Zade MH, Mansouri S, Kalantar E, Kabir K, Zahmatkesh E, et al. High frequency of methicillin-resistant Staphylococcus aureus (MRSA) with SCC mec type III and spa type to30 in Karaj’s teaching hospitals, Iran. Acta Microbiol Immunol Hung 2017;64:331-341.
32. Schaumburg F, Peters G, Alabi A, Becker K, Idelevich EA. Missense mutations of PBP2a are associated with reduced susceptibility to ceftaroline and ceftobiprole in African MRSA. J Antimicrob Chemother 2016;71:41-44.
33. Bongiorno D, Mongelli G, Stefani S, Campanile F. Genotypic analysis of Italian MRSA strains exhibiting low-level ceftaroline and ceftobiprole resistance. Diagn Microbiol Infect Dis 2019;95:114852.
34. Lahiri SD, Alm RA. Potential of Staphylococcus aureus isolates carrying different PBP2a alleles to develop resistance to ceftaroline. J Antimicrob Chemother 2016;71:34-40.
35. Fishovitz J, Rojas-Altuve A, Otero LH, Dawley M, Carrasco-López C, Chang M, et al. Disruption of allosteric response as an unprecedented mechanism of resistance to antibiotics. J Am Chem Soc 2014;136:9814-9817.
36. Chan LC, Basuino L, Diep B, Hamilton S, Chatterjee SS, Chambers HF. Ceftobiprole-and ceftaroline-resistant methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2015;59:2960-2963.
37. Gostev V, Sopova J, Kalinogorskaya O, Tsvetkova I, Lobzin Y, Klotchenko S, et al. In vitro ceftaroline resistance selection of methicillin-resistant Staphylococcus aureus involves different genetic pathways. Microb Drug Resist 2019;25:1401-1409.
| Files | ||
| Issue | Vol 13 No 4 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijm.v13i4.6967 | |
| Keywords | ||
| Ceftaroline; Methicillin-resistant Staphylococcus aureus; Penicillin-binding protein 2a; Minimum inhibitory concentration; mecA | ||
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How to Cite
1.
Abdizadeh N, Haeili M, Samadi Kafil H, Ahmadi A, Feizabadi MM. Evaluation of in vitro activity of ceftaroline on methicillin resistant Staphylococcus aureus blood isolates from Iran. Iran J Microbiol. 2021;13(4):442-448.
