In Vitro Synergistic Activity of Fosfomycin-Colistin Combination Against Carbapenem-Resistant Pseudomonas Aeruginosa from Ventilator-Associated Pneumonia Patients
Abstract
Objective: Infections caused by carbapenem-resistant Pseudomonas aeruginosa (CRPA) are a global health problem due to its multidrug resistance, often leading to treatment failure. This study aimed to assess the synergistic activity of fosfomycin plus colistin combination against clinical CRPA isolates from ventilator-associated pneumonia (VAP) patients.
Material and Methods: This cross-sectional study retrospectively collected clinical data on 40 VAP patients with CRPA infections in 2023. CRPA clinical isolates were obtained between 2022 and 2023 from the sputum of VAP patients as part of the carbapenem-resistant isolate collection. The susceptibility to carbapenems, fosfomycin, and colistin was evaluated on CRPA isolates using the broth microdilution method. The synergistic activity of fosfomycin and colistin combination against CRPA isolates was assessed using the checkerboard assay. The time-kill study was then conducted on CRPA isolates that exhibited treatment synergism with the combination.
Results: The most common comorbidities were chronic pulmonary disease and diabetes mellitus, which were found in 73% and 70% of VAP patients with CRPA infection. Previous carbapenem exposure was observed in 93% of the patients. Since VAP diagnosis, these patients were on a ventilator for a median of 13 days with an interquartile range of 10-22 days. Approximately 92% and 95% of the CRPA isolates exhibited high and low carbapenem and colistin resistance, respectively. In contrast, only 3 (7%) isolates were extremely resistant to fosfomycin, classifying as the non-wild type (bacterial isolates with reduced susceptibility or resistance). Synergism between fosfomycin and colistin was only observed in 2 (5%) isolates. Time-kill kinetics of these 2 isolates revealed a ≥2-log reduction in 1/4 minimum inhibitory concentration of fosfomycin and colistin.
Conclusion: In vitro findings indicate that the synergistic activity of fosfomycin combined with colistin against CRPA isolates was rare. While this combination showed potential activity in these few isolates, further studies are needed to determine its clinical relevance and effectiveness in treating severe CRPA infections.
Keywords
Full Text:
PDFReferences
Kresken M, Körber-Irrgang B, Korte-Berwanger M, Pfennigwerth N, Gatermann SG, Seifert H, et al. Dissemination of carbapenem-resistant Pseudomonas aeruginosa isolates and their susceptibilities to ceftolozane-tazobactam in Germany. Int J Antimicrob Agents 2020;55:105959.
Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2019 (2019 AR Threats Report) [homepage on the Internet]. Atlanta: Centers for Disease Control and Prevention (CDC); 2019 [cited 2024 Dec 1]. Available from: https://www.cdc.gov/drugresistance/Biggest-Threats.html
Kalanuria AA, Zai W, Mirski M. Ventilator-associated pneumonia in the ICU. Crit care 2014;18:1-8.
Karampatakis T, Antachopoulos C, Tsakris A, Roilides E. Molecular epidemiology of carbapenem-resistant Pseudomonas aeruginosa in an endemic area: comparison with global data. Eur J Clin Microbiol Infect Dis 2018;37:1211-20.
McCracken MG, Adam HJ, Blondeau JM, Walkty AJ, Karlowsky JA, Hoban DJ, et al. Characterization of carbapenem-resistant and XDR Pseudomonas aeruginosa in Canada: results of the CANWARD 2007–16 study. J Antimicrob Chemother 2019;74(Supplement_4):iv32-8.
Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clin Microbiol Rev 2016;29:321-47.
Albiero J, Mazucheli J, Barros JPdR, Szczerepa MMdA, Nishiyama SAB, Carrara-Marroni FE, et al. Pharmacodynamic attainment of the synergism of meropenem and fosfomycin combination against Pseudomonas aeruginosa producing metallo-β-lactamase. Antimicrob Agents Chemother 2019;63:e00126-19.
Falagas ME, Athanasaki F, Voulgaris GL, Triarides NA, Vardakas KZ. Resistance to fosfomycin: mechanisms, frequency and clinical consequences. Int J Antimicrob Agents 2019;53:22-8.
Aghamali M, Sedighi M, Zahedi bialvaei A, Mohammadzadeh N, Abbasian S, Ghafouri Z, et al. Fosfomycin: mechanisms and the increasing prevalence of resistance. J Med Microbiol 2019;68:11-25.
Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents 2009;34:111-20.
Kastoris AC, Rafailidis PI, Vouloumanou EK, Gkegkes ID, Falagas ME. Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria. Eur J Clin Pharmacol 2010;66:359-68.
Andrade FF, Silva D, Rodrigues A, Pina-Vaz C. Colistin update on its mechanism of action and resistance, present and future challenges. Microorganisms 2020;8:1716.
Bialvaei AZ, Samadi Kafil H. Colistin, mechanisms and prevalence of resistance. Curr Med Res Opin 2015;31:707-21.
Howard-Anderson J, Davis M, Page AM, Bower CW, Smith G, Jacob JT, et al. Prevalence of colistin heteroresistance in carbapenem-resistant Pseudomonas aeruginosa and association with clinical outcomes in patients: an observational study. J Antimicrob Chemother 2022;77:793-8.
Yau W, Owen RJ, Poudyal A, Bell JM, Turnidge JD, Heidi HY, et al. Colistin hetero-resistance in multidrug-resistant Acinetobacter baumannii clinical isolates from the Western Pacific region in the SENTRY antimicrobial surveillance programme. J Infect 2009;58:138-44.
Band VI, Satola SW, Smith RD, Hufnagel DA, Bower C, Conley AB, et al. Colistin heteroresistance is largely undetected among carbapenem-resistant Enterobacterales in the United States. MBio 2021;12:e02881-20.
Narimisa N, Keshtkar A, Dadgar-Zankbar L, Bostanghadiri N, Far YR, Shahroodian S, et al. Prevalence of colistin resistance in clinical isolates of Pseudomonas aeruginosa: a systematic review and meta-analysis. Front Microbiol 2024;15:1477836.
Lin J, Xu C, Fang R, Cao J, Zhang X, Zhao Y, et al. Resistance and heteroresistance to colistin in Pseudomonas aeruginosa isolates from Wenzhou, China. Antimicrob Agents Chemother 2019;63:e00556-19.
Mondal AH, Khare K, Saxena P, Debnath P, Mukhopadhyay K, Yadav D. A review on colistin resistance: an antibiotic of last resort. Microorganisms 2024;12:772.
Kon H, Hameir A, Nutman A, Temkin E, Keren Paz A, Lellouche J, et al. Prevalence and clinical consequences of colistin heteroresistance and evolution into full resistance in carbapenem-resistant Acinetobacter baumannii. Microbiol Spectr 2023;11:e05093-22.
Sanabria J, Garzón V, Pacheco T, Avila MP, Garcia JC, Jaimes D, et al. Estimation of the difference in colistin plasma levels in critically ill patients with favorable or unfavorable clinical outcomes. Pharmaceutics 2021;13:1630.
Di X, Wang R, Liu B, Zhang X, Ni W, Wang J, et al. In vitro activity of fosfomycin in combination with colistin against clinical isolates of carbapenem-resistant Pseudomonas aeruginosa. J Antibiot 2015;68:551-5.
Samonis G, Maraki S, Karageorgopoulos D, Vouloumanou E, Falagas M. Synergy of fosfomycin with carbapenems, colistin, netilmicin, and tigecycline against multidrug-resistant Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa clinical isolates. Eur J Clin Microbiol Infect Dis 2012;31:695-701.
MarÝ-Almirall M, Cosgaya C, Higgins PG, Van Assche A, Telli M, Huys G, et al. MALDI-TOF/MS identification of species from the Acinetobacter baumannii (Ab) group revisited: inclusion of the novel A. áseifertii and A. ádijkshoorniae species. Clin Microbiol Infect 2017;23:210e1-9.
Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing. 33rd ed. Wayne: CLSI; 2023.
European Committee on Antimicrobial Susceptibility Testing (EUCAST). Breakpoint tables for interpretation of MICs and zone diameters. Version 9.0, 2019. Växjö: EUCAST; 2019.
Chukamnerd A, Pomwised R, Phoo MTP, Terbtothakun P, Hortiwakul T, Charoenmak B, et al. In vitro synergistic activity of fosfomycin in combination with other antimicrobial agents against carbapenem-resistant Klebsiella pneumoniae isolated from patients in a hospital in Thailand. J Infect Chemother 2021;27:507-14.
Nwabor LC, Chukamnerd A, Nwabor OF, Surachat K, Pomwised R, Jeenkeawpiam K, et al. Genotypic and phenotypic mechanisms underlying antimicrobial resistance and synergistic efficacy of rifampicin-based combinations against carbapenem-resistant Acinetobacter baumannii. Heliyon 2024;10:e27326.
National Antimicrobial Resistance Surveillance, Thailand. Antimicrobial resistance 2000-2022 (12M) [homepage on the Internet]. Nonthaburi: National Antimicrobial Resistance Surveillance, National Institute of Health (NIH), Department of Medical Sciences, Thailand; 2022 [cited 2024 Dec 1]. Available from: http://narst.dmsc.moph.go.th/
Barron MA, Richardson K, Jeffres M, McCollister B. Risk factors and influence of carbapenem exposure on the development of carbapenem resistant Pseudomonas aeruginosa bloodstream infections and infections at sterile sites. Springerplus 2016;5:1-6.
Liu Y, Xu Y, Wang S, Zeng Z, Li Z, Din Y, et al. Antibiotic susceptibility pattern, risk factors, and prediction of carbapenem-resistant Pseudomonas aeruginosa in patients with nosocomial pneumonia. Heliyon 2023;9:e15724.
Djordjevic ZM, Folic MM, Jankovic SM. Distribution and antibiotic susceptibility of pathogens isolated from adults with hospital-acquired and ventilator-associated pneumonia in intensive care unit. J Infect Public Heal 2017;10:740-4.
Heidari R, Farajzadeh Sheikh A, Hashemzadeh M, Farshadzadeh Z, Salmanzadeh S, Saki M. Antibiotic resistance, biofilm production ability and genetic diversity of carbapenem-resistant Pseudomonas aeruginosa strains isolated from nosocomial infections in southwestern Iran. Mol Biol Rep 2022;49:3811-22.
Slimene K, El Salabi AA, Dziri O, Mabrouk A, Miniaoui D, Gharsa H, et al. High carbapenem resistance caused by VIM and NDM enzymes and OprD alteration in nonfermenter bacteria isolated from a Libyan hospital. Microb Drug Resist 2021;27:1546-54.
Asuphon O, Montakantikul P, Houngsaitong J, Kiratisin P, Sonthisombat P. Optimizing intravenous fosfomycin dosing in combination with carbapenems for treatment of Pseudomonas aeruginosa infections in critically ill patients based on pharmacokinetic/pharmacodynamic (PK/PD) simulation. Int J Infect Dis 2016;50:23-9.
Rostami S, Sheikh AF, Shoja S, Farahani A, Tabatabaiefar MA, Jolodar A, et al. Investigating of four main carbapenem-resistance mechanisms in high-level carbapenem resistant Pseudomonas aeruginosa isolated from burn patients. J Chin Med Assoc 2018;81:127-32.
Pai H, Kim JW, Kim J, Lee JH, Choe KW, Gotoh N. Carbapenem resistance mechanisms in Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother 2001;45:480-4.
Hao M, Yang Y, Guo Y, Wu S, Hu F, Qin X. Combination regimens with colistin sulfate versus colistin sulfate monotherapy in the treatment of infections caused by carbapenem-resistant gram-negative bacilli. Antibiotics 2022;11:1440.
Moore NM, Flaws ML. Antimicrobial resistance mechanisms in Pseudomonas aeruginosa. Clin Lab Sci 2011;24:47.
Mah T-FC, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol 2001;9:34-9.
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.