KLİNİK ÖRNEKLERDEN İZOLE EDİLEN METİSİLİNE DİRENÇLİ STAPHYLOCOCCUS AUREUS İZOLATLARINA KARŞI SEFTOBİPROLÜN TEK BAŞINA VE KOMBİNE HALDE IN VITRO ETKİNLİĞİ

Year 2025, Volume: 88 Issue: 4, 329 - 337, 30.10.2025

Müge Tepe Fındık , Lütfiye Öksüz

https://doi.org/10.26650/IUITFD.1716566

Abstract

Amaç: Metisiline dirençli Staphylococcus aureus (MRSA) enfeksiyonları tedavi seçeneklerinin azalmasına, hastanede kalış sürelerinin uzamasına, sağlık hizmetleri maliyetlerinin artmasına neden olur ve toplum sağlığı için küresel bir tehdit oluşturur. MRSA izolatlarında vankomisin (VAN) duyarlılığının azalması ve daptomisine (DAP) direncin ortaya çıkması yeni tedavi seçeneklerini gerekli kılmıştır. Bu çalışmada, klinik örneklerden izole edilen 100 MRSA izolatı üzerinde seftobiprolün (BPR) tek başına ve kombinasyon halinde in vitro aktivitesi araştırılmıştır.

Gereç ve Yöntemler: Rutin olarak kullanılan antibiyotikler için duyarlılık testleri disk difüzyon yöntemi ile gerçekleştirilmiştir. BPR, DAP ve VAN için minimum inhibitör konsantrasyon (MİK) değerleri sıvı mikrodilüsyon yöntemi ile belirlenmiştir. Heterojen dirençli vankomisine orta duyarlı S. aureus'un (hVISA) varlığı makro gradiyent test yöntemi ile araştırılmıştır. BPR dirençli izolatlarda BPR-DAP ve BPR-VAN kombinasyonlarının etkinliği dama tahtası yöntemi ile araştırılmıştır.

Bulgular: BPR duyarlılığını saptamada kullanılan disk difüzyon ve sıvı mikrodilüsyon yöntemleri arasındaki kategorik uyum %100 idi. Sıvı mikrodilüsyon yöntemi ile dört izolatın BPR'ye ((%4; MİK: >2 µg/ml), başka dört izolatın da DAP'a (%4,12; MİK: >1 µg/ml) dirençli olduğu bulundu. VAN-dirençli S. aureus (VRSA), VAN-orta duyarlı S. aureus (VISA) ve hVISA varlığı tespit edilmedi. BPR dirençli izolatlarda BPR-DAP ve BPR-VAN kombinasyonları indiferens etki gösterdi.

Sonuç: BPR'ye karşı direnç oranı nispeten düşük olmasına rağmen, BPR için MIC₉₀ değerinin 2 mg/L olması BPR'ye direncin zamanla artacağı endişesini doğurmaktadır. Farklı antibiyotik kombinasyonları ile yapılacak çalışmalar, BPR dirençli izolatların neden olduğu ciddi enfeksiyonları tedavi etme potansiyeline sahiptir.

Keywords

Metisiline dirençli Staphylococcus aureus , sefto biprol , daptomisin , vankomisin , antibiyotik kombi nasyonları

IN VITRO EFFECTIVENESS OF CEFTOBIPROLE ALONE AND IN COMBINATION AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS ISOLATED FROM CLINICAL SPECIMENS

Abstract

Objective: Methicillin-resistant Staphylococcus aureus (MRSA) in fections cause reduced treatment options, longer hospital stays, increased healthcare costs and pose a global threat to public health. Decreased susceptibility to vancomycin (VAN) and the emergence of daptomycin (DAP) resistance in MRSA isolates have necessitated new treatment options. The in vitro activity of ceftobprole (BPR) alone and in combination against 100 MRSA isolates was investigated in this study.

Material and Methods: The susceptibility tests for routinely used antibiotics were performed using the disk diffusion method. The minimum inhibitory concentration (MIC) values for BPR, DAP, and VAN were determined by the broth microdilution method. The presence of heteroresistant-VAN-intermediate S. aureus (hVISA) was investigated using the macrogradient test method. The effec tiveness of the BPR-DAP and BPR-VAN combinations in BPR-resis tant isolates was investigated using the checkerboard method.

Results: The categorical agreement between the disk diffusion and broth microdilution methods used to determine the BPR sensi tivity was 100%. Four isolates were found to be resistant to BPR (4%; MIC: >2 µg/ml) and another four isolates were found to be resistant to DAP (4.12%; MIC: >1 µg/ml) by the broth microdilution method. The presence of VAN-resistant S. aureus (VRSA), VAN in termediate S. aureus (VISA), and hVISA was not detected. BPR-DAP and BPR-VAN combinations in BPR-resistant isolates exhibited an indifference effect.

Conclusion: Although the resistance rate to BPR was relatively low, the MIC₉₀ value for BPR was 2 mg/L, raising concerns that resis tance to BPR would increase over time. Future studies on different antibiotic combinations can treat serious infections caused by BPR-resistant isolates.

Keywords

Methicillin-resistant Staphylococcus aureus , ceftobiprole , daptomycin , vancomycin , antibiotic combinations

References

• Lakhundi S, Zhang K. Methicillin-Resistant Staphylococcus aureus: Molecular characterization, evolution, and epidemiology. Clin Microbiol Rev 2018;31(4):e00020-18. google scholar
• Vestergaard M, Frees D, Ingmer H. Antibiotic Resistance and the MRSA Problem. Microbiol Spectr 2019;7(2):10.1128/microbiolspec.gpp3-0057-2018 google scholar
• Cong, Y, Yang S, Rao X. Vancomycin resistant Staphylococcus aureus infections: A review of case updating and clinical features. J Adv Res 2020;21:169-76. google scholar
• Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis 2011;52(3):e018-55. google scholar
• Kern WV. New antibacterial agents on the market and in the pipeline. Der Internist 2015;56(11):1255-63. google scholar
• De Oliveira DMP, Forde BM, Kidd TJ, Harris PNA, Schembri MA, Beatson AA, et al. Antimicrobial Resistance in ESKAPE Pathogens. Clin Microbiol Rev 2020;33(3):e00181-19. google scholar
• Jorgensen SCJ, Zasowski EJ, Trinh TD, Lagnf AM, Bhatia S, Sabagha N, et al. Daptomycin Plus beta-Lactam Combination Therapy for Methicillin-resistant Staphylococcus aureus Bloodstream Infections: A Retrospective, Comparative Cohort Study. Clin Infect Dis 2020;71(1):1-10. google scholar
• Leonard SN, Rolek KM. Evaluation of the combination of daptomycin and nafcillin against vancomycin-intermediate Staphylococcus aureus. J Antimicrob Chemother 2013;68(3):644-7. google scholar
• Heidary M, Khosravi AD, Khoshnood S, Nasiri MJ, Soleimani S, Goudarzi M. Daptomycin. J Antimicrob Chemother 2018;73(1):1-11. google scholar
• Humphries RM, Pollett S, Sakoulas G. A current perspective on daptomycin for the clinical microbiologist. Clin Microbiol Rev 2013;26(4):759-80. google scholar
• Syed YY. Ceftobiprole medocaril: a review of its use in patients with hospital-or community-acquired pneumonia. Drugs 2014;74(13):1523-42. google scholar
• Lupia T, Pallotto C, Corcione S, Boglione L, De Rosa FG. Ceftobiprole Perspective: Current and Potential Future Indications. Antibiotics 2021;10(2):170. google scholar
• Zhanel G.G, Kosar J, Baxter M, Dhami R, Borgia S, Irfan N, et al. Real-life experience with BPR in Canada: Results from the CLEAR (CanadianLEadership onAntimicrobialReal-life usage) registry. J Glob Antimicrob Resist 2021;24:335-9. google scholar
• Pfaller MA, Flamm RK, Mendes RE, Streit JM, Smart JI, Hamed KA. Ceftobiprole activity against gram positive and negative pathogens collected from the United States in 2006 and 2016. Antimicrob Agents Chemother 2019;63(1):e01566-18. google scholar
• Muller AE, Gyssens IC. Daptomycin. In: Grayson ML, editör in chief. Kucers' The Use of, A. Antibiotics: A Clinical Review of Antibacterial, Antiparasitic, and Antiviral, and Drugs. CRC Press: Boca Raton London Newyork; 2017.p.866-907. google scholar
• United State, Food Drugs Administration. Novel Drug Approvals for 2024 (cited as 2023 January). https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2024. google scholar
• Morosini MI, Diez-Aguilar M, Canton R. Mechanisms of action and antimicrobial activity of ceftobiprole. Rev Esp Quimioter 2019;32(Suppl 3):3-10. google scholar
• Dandan Y, Shi W, Yang Y, Yonggui Z, Zu D, Yan G, et al. Antimicrobial activity of ceftobiprole and comparator agents when tested against gram-positive and -negative organisms collected across China (2016-2018). BMC Microbiol 2022;22(1):282. google scholar
• 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(5):2960-3. google scholar
• Bazan JA, Martin SI, Kaye KM. Newer beta-lactam antibiotics: doripenem, ceftobiprole, ceftaroline, and cefepime. Infect Dis Clin North Am 2009;23(4):983-96. google scholar
• Flamm RK, Duncan R, Hamed KA, Smart JI, Mendes RE, Pfaller MA. Ceftobiprole activity against bacteria from skin and skin structure infections in the United States from 2016 through 2018. Antimicrob Agents Chemother 2020;64(6):e02566-19. google scholar
• Canton R, Hamed K, Wiktorowicz T, Redder N, Jemmely N, Quevedo J, et al. In vitro activity of ceftobiprole and comparator antibiotics against contemporary European isolates (2016-19). JAC-Antimicrob Resist 2022;4(2):1-7. google scholar
• Barber KE, Werth BJ, Ireland CE, Stone NE, Nonejuie P, George Sakoulas G, et al. Potent synergy of ceftobiprole plus DAP against multiple strains of Staphylococcus aureus with various resistance phenotypes. J Antimicrob Chemother 2014;69(11):3006-10. google scholar
• Campanile F, Bongiorno D, Mongelli G, Zanghi G, Stefani S. Bactericidal activity of ceftobiprole combined with different antibiotics against selected Grampositive isolates. Diagn Microbiol Infect Dis 2019;93(1):77-81. google scholar
• Deresinski S. Vancomycin in combination with other antibiotics for the treatment of serious methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2009;49(7):1072-9. google scholar
• Leber AL. Clinical Microbiology Procedures Handbook. ASM, Washington DC:2016. http://lccn.loc.gov/2016009711 google scholar
• European Committee on Antimicrobial Susceptibility Testing (EUCAST). Breakpoint tables for interpretation of MICs and zone diameters. Version 13.0 (cited as 2023 January). https://www.eucast.org/. google scholar
• Miklasinska-Majdanik M. Mechanisms of Resistance to Macrolide Antibiotics among Staphylococcus aureus. Antibiotics (Basel) 2021;10(11):1406. google scholar
• Thapa D, Pyakurel S, Thapa S, Lamsal S, Chaudhari M, Adhikari N, et al. Staphylococcus aureus with inducible clindamycin resistance and methicillin resistance in a tertiary hospital in Nepal. Trop Med Health 2021;49(1):99. google scholar
• Manandhar S, Shrestha R, Tuladhar RS, Lekhak S. Inducible Clindamycin resistance and biofilm production among staphylococci ısolated from Tertiary Care Hospitals in Nepal. Infect Dis Rep 2021;13(4):1043-52. google scholar
• Directorate General of Health Services Ministry of Health and Family Welfare Government of India. Standard Operating Procedure for Antimicrobial Resistance Surveillance National Antimicrobial Resistance Containment Surveillance Network (NARS-Net), January 2023. https://ncdc.mohfw.gov.in/wp-content/uploads/2024/03/58495493521681880873.pdf google scholar
• Lee AS, de Lencastre H, Garau J, Kluytmans J, Malhotra-Kumar S, Peschel A, et al. Methicillin-resistant Staphylococcus aureus. Nat Rev Dis Primers 2018;4:18033. Centers for Disease Control and Prevention. Antibiotic Resistance and Patient Safety Portal 2021 (cited as January 2023). https://arpsp.cdc.gov/profile/ antibiotic-resistance google scholar
• World Health Organization. Proportion of bloodstream infection due to methicillin-resistant Staphylococcus aureus (MRSA). 2021. https://www.who.int/data/gho/data/indicators/indicator-details/GHO/sdg-3. d.2-amr-infect-mrsa. google scholar
• Dundar D, Wilke A, Sayan M, Koç M, Arikan Akan O, Sumerkan B, et al. Epidemiological and molecular characteristics of meticillin-resistant Staphylococcus aureus in Turkey: A multicentre study. J Glob Antimicrob Resist 2016;6:44-9. google scholar
• Gurung RR, Maharjan P, Chhetri GG. Antibiotic resistance pattern of Staphylococcus aureus with reference to MRSA isolates from pediatric patients. Future Sci OA 2020;6(4):FSO464. google scholar
• Oksuz L, Gurler N. Susceptibility of clinical methicillin-resistant Staphylococci isolates to new antibiotics. J Infect Dev Ctries 2013;7(11):825-31. google scholar
• Hassoun A, Linden PK, Friedman B. Incidence, prevalence, and management of MRSA bacteremia across patient populations-a review of recent developments in MRSA management and treatment. Crit Care 2017;21(1):211. google scholar
• Shariati A, Dadashi M, Moghadam MT, van Belkum A, Yaslianifard S, Darban-Sarokhalil D. Global prevalence and distribution of Vancomycin resistant, Vancomycin intermediate and heterogeneously Vancomycin intermediate Staphylococcus aureus clinical isolates: a systematic review and meta-analysis. Sci Rep 2020;10(1):12689. google scholar
• Hodille E, Delouere L, Bouveyron C, Meugnier H, Bes M, Tristan A, et al. In vitro activity of ceftobiprole on 440 Staphylococcus aureus strains isolated from bronchopulmonary infections. Med Mal Infect 2017;47(2):152-7. google scholar
• Li L, Zhou W, Chen Y, Shen P, Xiao Y. In vitro antibacterial activity of ceftobiprole and comparator compounds against nation-wide bloodstream isolates and different sequence types of MRSA. Antibiotics (Basel) 2024;13(2):165. google scholar
• Mirza HC, Şanlı ÖÖ. Evaluation of in vitro activity of ceftaroline, ceftobiprole and their combination with trimethoprim/sulfamethoxazole against MRSA isolates: a two center study. J Chemother 2024;36(6):457-64. google scholar
• Aktas G. Efficacy of vancomycin in combination with various antimicrobial agents against clinical methicillin resistant Staphylococcus aureus strains. Pak J Med Sci 2021;37(1):151-6. google scholar
• Pfaller MA, Flamm RK, Duncan LR, Shortridge D, Smart JI, Hamed KA, et al. Ceftobiprole activity when tested against contemporary bacteria causing bloodstream infections in the United States (2016-2017). Diagn Microbiol Infect Dis 2019;94(3):304-13. google scholar
• Pfaller MA, Duncan LR, Streit JM, Castanheira M, Sader HS. Antimicrobial activity of ceftobiprole and comparator agents when tested against contemporary Gram-positive and -negative organisms collected from Europe (2015). Diagn Microbiol Infect Dis 2018;91(1):77-84. google scholar
• Farrell DJ, Flamm RK, Sader HS, Jones RN. Ceftobiprole activity against over 60,000 clinical bacterial pathogens isolated in Europe, Turkey, and Israel from 2005 to 2010. Antimicrob Agents Chemother 2014;58(7):3882-8. google scholar
• Horner C, Mushtaq S, Livermore DM. Activity of ceftaroline versus ceftobiprole against staphylococci and pneumococci in the UK and Ireland: analysis of BSAC surveillance data. J Antimicrob Chemother 2020;75(11):3239-43. google scholar
• Rouse MS, J.M. Steckelberg JM, Patel R. In vitro activity of Ceftobiprole, daptomycin, linezolid, and vancomycin against methicillin-resistant staphylococci associated with endocarditis and bone and joint infection. Diagn Microbiol Infect Dis 2007;58(3):363-5. google scholar
• 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. google scholar
• 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(1):41-4. google scholar