Synergistic effect of some antibiotics against multidrug resistant clinical isolates Acinetobacter baumannii

G. F. Karim; A. H. Mohamed; E. J. Ibrahem; O. Darweesh

doi:10.15421/0225180

G. F. Karim University of Kirkuk
A. H. Mohamed University of Kirkuk
E. J. Ibrahem Cihan University-Sulaimanya
O. Darweesh Al-Kitab University

Keywords: synergistic effect, antibiotics, Acinetobacter baumannii, CRAB, ISAba1 gene, colistin.

Abstract

Synergistic antibiotic combinations might offer an approach to overcome microbial resistance mechanisms. This work i n vestigated genetic determinants of resistan ce to antibiotics. and evaluated in vitro the impacts of several different antibiotic combinations on a panel of carbapenem-resistant Acinetobacter baumannii (CRAB) and the extended drug-resistant A. ba u mannii (XDR – A. baumannii ) strains. Clinical samples were obtained from patients hospitalized in the Intensive Care Unit (ICU) from August 1, 2024, to August 31, 2025. The "BD Phoenix Automated System" was employed to identify isolated bacteria at species-level, and for determination of the blaOXA-51-like gene. The isolates were screened for some c arbapen e mase genes and the IS A ba1gene using PCR. The fractional inhibitory concentration index (FICI) was used to detect the effect of the various antibiotics used in combination. The study used 24 strains of A. baumannii . All tested antibiotics, except for coli s tin (CL), were ineffective against the isolates. The major mechanism of resistan ce to carbapenems was the coexistence of blaOXA -51-like and IS A ba 1 genetic elements in 24(100%) isolates, foll owed by isolates carrying the blaOXA-24-like and blaNDM-1 genes, accounting for 16 (66.7%) and 8 (33.3%) of all isolates respectively. A single effective combination of CL and tigecycline (TGC) exhibited the maximum rate (100%) of synergy against th e A. baumannii sample s . The s ynergistic effect of CL in combination with TGC was confirmed , which may confer therapeutic benefits against XDR- A. baumannii . This fin d ing is valuable and emphasizes the necessity to discover novel combination therapies that are effective against virtually untrea t able XDR- A. baumannii infections. However, further clinical trials are required to verify the efficacy.

References

Acman, M., Wang, R., van Dorp, L., Shaw, L. P., Wang, Q., Luhmann, N., Yin, Y., Sun, S., Chen, H., Wang, H., & Balloux, F. (2022). Role of mobile genetic elements in the global dissemination of the carbapenem resistance gene blaNDM. Nature Communications, 13(1), 1131.

Al Hadeedy, U., Mahdi, N., & Al Jebory, I. (2019). Isolation and diagnosis of Acinetobacter bumannii recently isolated from patients in Kirkuk hospitals and study their antibiotics resistance. Kirkuk University Journal – Scientific Studies, 14(3), 155–173.

Al-Khafaji, A. M. K., & Al-Fatlawy, H. N. K. (2025). Molecular genotyping of gyrA, blaOXA-51, and blaOXA-23 genes in multidrug-resistant Acinetobacter baumannii isolated from childhood asthma patients in Iraq. Egyptian Journal of Medical Microbiology, 34(4), 1658.

Al-Khafaji, A. M. K., & AL-Fatlawy, H. N. K. (2025). Prevalence of resistance genes Gyr B, Ade-B and NDM-1 in Acinetobacter baumannii from asthmatic children. Kufa Medical Journal, 21(1), 297–308.

Al-Masoudi, K. K., Al-Saffar, J. M., & Kendla, N. J. (2015). Molecular characteristics of multidrug resistant Acinetobacter baumannii isolated from Baghdad hospitals. Iraqi Journal of Science, 56(2B), 1394–1399.

Al-Salihi, S. S., Karim, G. F., Al-Bayati, A. M. S., & Obaid, H. M. (2023). Prevalence of methicillin-resistant and methicillin sensitive Staphylococcus aureus nasal carriage and their antibiotic resistant patterns in Kirkuk City, Iraq. Journal of Pure and Applied Microbiology, 17(1), 329–337.

Al-Sheboul, S. A., Al-Moghrabi, S. Z., Shboul, Y., Atawneh, F., Sharie, A. H., & Nimri, L. F. (2022). Molecular characterization of carbapenem-resistant Acinetobacter baumannii isolated from intensive care unit patients in Jordanian hospitals. Antibiotics, 11(7), 835.

Ayoub Moubareck, C., & Hammoudi Halat, D. (2020). Insights into Acinetobacter baumannii: A review of microbiological, virulence, and resistance traits in a threatening nosocomial pathogen. Antibiotics, 9(3), 119.

Cikman, A., Gulhan, B., Aydin, M., Ceylan, M. R., Parlak, M., Karakecili, F., & Karagoz, A. (2015). In vitro activity of colistin in combination with tigecycline against carbapenem-resistant Acinetobacter baumannii strains isolated from patients with ventilator-associated pneumonia. International Journal of Medical Sciences, 12(9), 695–700.

Darweesh, O., Kurdi, A., Merkhan, M., Ahmed, H., Ibrahem, S., Al-Zidan, R. N., Meyer, J. C., & Godman, B. (2025). Knowledge, attitudes, and practices of Iraqi parents regarding antibiotic use in children and the implications. Antibiotics, 14(4), 376.

Deolankar, M. S., Carr, R. A., Fliorent, R., Roh, S., Fraimow, H., & Carabetta, V. J. (2022). Evaluating the efficacy of eravacycline and omadacycline against extensively drug-resistant Acinetobacter baumannii patient isolates. Antibiotics, 11(10), 1298.

Ellington, M. J., Kistler, J., Livermore, D. M., & Woodford, N. (2006). Multiplex PCR for rapid detection of genes encoding acquired metallo-lactamases. Journal of Antimicrobial Chemotherapy, 59(2), 321–322.

Evans, B. A., & Amyes, S. G. B. (2014). OXA β-Lactamases. Clinical Microbiology Reviews, 27(2), 241–263.

George, M. D., David, R. B., & Richard, W. C. (2001). Berge’s manual of systemic bacteriology. 2nd edition. Springer, New York.

Hama Radha, S., Tawfeeq, A., & Mohamed, S. (2024). Pediatric urinary tract infection: Evaluation antibiotic susceptibility and biofilm formation dynamics. Kirkuk Journal of Medical Sciences, 12(2), 50–59.

Jesudason, T. (2024). WHO publishes updated list of bacterial priority pathogens. The Lancet Microbe, 5(9), 100940.

Kaase, M. (2012). Carbapenemasen bei Gramnegativen Erregern in Deutschland. Bundesgesundheitsblatt – Gesundheitsforschung – Gesundheitsschutz, 55(11–12), 1401–1404.

Karaiskos, I., Lagou, S., Pontikis, K., Rapti, V., & Poulakou, G. (2019). The “old” and the “new” antibiotics for MDR Gram-negative pathogens: For whom, when, and how. Frontiers in Public Health, 7, 151.

Karaoglan, I., Zer, Y., Bosnak, V. K., Mete, A. O., & Namıduru, M. (2013). In vitro synergistic activity of colistin with tigecycline or β-lactam antibiotic / β-lactamase inhibitor combinations against carbapenem-resistant Acinetobacter baumannii. Journal of International Medical Research, 41(6), 1830–1837.

Karim, G. F., Al-Salihi, S. S., Atya, Q. M., & Abass, K. S. (2019). Aerobic and anaerobic bacteria in tonsils of different ages with recurrent tonsillitis. Indian Journal of Public Health Research and Development, 10(9), 132–136.

Kempf, M., & Rolain, J.-M. (2012). Emergence of resistance to carbapenems in Acinetobacter baumannii in Europe: Clinical impact and therapeutic options. International Journal of Antimicrobial Agents, 39(2), 105–114.

Ku, Y.-H., Chen, C.-C., Lee, M.-F., Chuang, Y.-C., Tang, H.-J., & Yu, W.-L. (2017). Comparison of synergism between colistin, fosfomycin and tigecycline against extended-spectrum β-lactamase-producing Klebsiella pneumoniae isolates or with carbapenem resistance. Journal of Microbiology, Immunology and Infection, 50(6), 931–939.

Kuo, L.-C., Lai, C.-C., Liao, C.-H., Hsu, C.-K., Chang, Y.-L., Chang, C.-Y., & Hsueh, P.-R. (2007). Multidrug-resistant Acinetobacter baumannii bacteraemia: Clinical features, antimicrobial therapy and outcome. Clinical Microbiology and Infection, 13(2), 196–198.

Kurdi, A., Al Mutairi, N., Baker, K., M-Amen, K., Darweesh, O., Karwi, H., Seaton, A., Sneddon, J., & Godman, B. (2024). Impact of COVID-19 pandemic on the utilization and quality of antibiotic use in the primary care setting in England, March 2019–March 2023: A segmented interrupted time series analysis of over 53 million individuals. Expert Review of Anti-Infective Therapy, 22(12), 1251–1262.

Lodise, T. P., Nguyen, S. T., Margiotta, C., & Cai, B. (2025). Clinical burden of Acinetobacter baumannii, including carbapenem-resistant A. baumannii, in hospitalized adult patients in the USA between 2018 and 2022. BMC Infectious Diseases, 25(1), 549.

Magiorakos, A.-P., Srinivasan, A., Carey, R. B., Carmeli, Y., Falagas, M. E., Giske, C. G., Harbarth, S., Hindler, J. F., Kahlmeter, G., Olsson-Liljequist, B., Paterson, D. L., Rice, L. B., Stelling, J., Struelens, M. J., Vatopoulos, A., Weber, J. T., & Monnet, D. L. (2012). Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clinical Microbiology and Infection, 18(3), 268–281.

Marchaim, D., Pogue, J. M., Tzuman, O., Hayakawa, K., Lephart, P. R., Salimnia, H., Painter, T., Zervos, M. J., Johnson, L. E., Perri, M. B., Hartman, P., Thyagarajan, R. V., Major, S., Goodell, M., Fakih, M. G., Washer, L. L., Newton, D. W., Malani, A. N., Wholehan, J. M., … & Kaye, K. S. (2014). Major variation in MICs of tigecycline in Gram-negative bacilli as a function of testing method. Journal of Clinical Microbiology, 52(5), 1617–1621.

Mohammed, H., Abdel Monem, S., Hassan, A., & Abdallah, A. (2021). In vitro comparison of colistin- versus tigecycline-based combinations against carbapenem resistant Acinetobacter baumannii intensive care unit clinical isolates. Microbes and Infectious Diseases, 2(2), 333–342.

Muhammed, S. M., & Rasool, A. H. (2025). Molecular analysis and genotyping of drug-resistant Acinetobacter baumannii isolates from clinical specimens. ARO – the Scientific Journal of Koya University, 13(1), 144–152.

Nasr, P. (2020). Genetics, epidemiology, and clinical manifestations of multidrug-resistant Acinetobacter baumannii. Journal of Hospital Infection, 104(1), 4–11.

Ness, D., & Olsburgh, J. (2020). UTI in kidney transplant. World Journal of Urology, 38(1), 81–88.

Obaid, W. A. (2025). Prevalence, antimicrobial susceptibility, and distribution of biofilm associated virulence genes in multidrug-resistant Acinetobacter baumannii isolated from various environmental sources in Baghdad hospitals. Iraqi Journal of Science, 2025, 2756–2775.

Park, S., Jin, Y., & Ko, K. S. (2025). Effect of colistin-tigecycline combination on colistin-resistant and carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii. Microbiology Spectrum, 13(2), e02021–02024.

Peleg, A. Y., Seifert, H., & Paterson, D. L. (2008). Acinetobacter baumannii: Emergence of a successful pathogen. Clinical Microbiology Reviews, 21(3), 538–582.

Perez, F., Hujer, A. M., Hujer, K. M., Decker, B. K., Rather, P. N., & Bonomo, R. A. (2007). Global challenge of multidrug-resistant Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy, 51(10), 3471–3484.

Poirel, L., & Nordmann, P. (2006). Carbapenem resistance in Acinetobacter baumannii: Mechanisms and epidemiology. Clinical Microbiology and Infection, 12(9), 826–836.

Pournaras, S., Vrioni, G., Neou, E., Dendrinos, J., Dimitroulia, E., Poulou, A., & Tsakris, A. (2011). Activity of tigecycline alone and in combination with colistin and meropenem against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains by time–kill assay. International Journal of Antimicrobial Agents, 37(3), 244–247.

Qader, S., & Ganjo, A. (2023). Detection of carbapenemase in Acinetobacter baumannii enrolled in the relationship between biofilm formation and antibiotic resistance. Zanco Journal of Medical Sciences, 27(1), 74–84.

Qureshi, Z. A., Hittle, L. E., O’Hara, J. A., Rivera, J. I., Syed, A., Shields, R. K., Pasculle, A. W., Ernst, R. K., & Doi, Y. (2015). Colistin-resistant Acinetobacter baumannii: Beyond carbapenem resistance. Clinical Infectious Diseases, 60(9), 1295–1303.

Rajan, V., Vijayan, A., Puthiyottu Methal, A., Lancy, J., & Sivaraman, G. K. (2023). Genotyping of Acinetobacter baumannii isolates from a tertiary care hospital in Cochin, South India. Access Microbiology, 5(11), 662.

Saleem, Z., Mekonnen, B. A., Orubu, E. S., Islam, M. A., Nguyen, T. T. P., Ubaka, C. M., Buma, D., Thuy, N. D. T., Sant, Y., Sono, T. M., Bochenek, T., Kalungia, A. C., Abdullah, S., Miljković, N., Yeika, E., Niba, L. L., Akafity, G., Sefah, I. A., Opanga, S. A., … & Sharland, M. (2025). Current access, availability and use of antibiotics in primary care among key low- and middle-income countries and the policy implications. Expert Review of Anti-Infective Therapy, in press.

Segal, H., Garny, S., & Elisha, B. G. (2005). Is ISABA-1customized forAcinetobacter? FEMS Microbiology Letters, 243(2), 425–429.

Shi, J., Cheng, J., Liu, S., Zhu, Y., & Zhu, M. (2024). Acinetobacter baumannii: An evolving and cunning opponent. Frontiers in Microbiology, 15, 1332108.

Unnikrishnan, S., Khan, M. H., & Ramalingam, K. (2018). Dye-tolerant marine Acinetobacter baumannii-mediated biodegradation of reactive red. Water Science and Engineering, 11(4), 265–275.

Wong, M. H., Chan, B. K., Chan, E. W., & Chen, S. (2019). Over-expression of ISAba1-linked intrinsic and exogenously acquired OXA type carbapenem-hydrolyzing-class D-ß-lactamase-encoding genes is key mechanism underlying carbapenem resistance in Acinetobacter baumannii. Frontiers in Microbiology, 10, 2809.

Woodford, N., Ellington, M., Coelho, J., Turton, J., Ward, M., Brown, S., Amyes, S., & Livermore, D. (2006). Multiplex PCR for genes encoding prevalent OXA carbapenemases in Acinetobacter spp. International Journal of Antimicrobial Agents, 27(4), 351–353.

Zhou, Y.-F., Liu, P., Zhang, C.-J., Liao, X.-P., Sun, J., & Liu, Y.-H. (2020). Colistin combined with tigecycline: A promising alternative strategy to combat Escherichia coli harboring blaNDM–5 and mcr-1. Frontiers in Microbiology, 10, 2957.