Drug Res (Stuttg) 2024; 74(01): 24-31
DOI: 10.1055/a-2195-3032
Review

Parenteral Fosfomycin in Gastrointestinal Surgery: A Systematic Review

Siv Fonnes
1   Centre for Perioperative Optimisation, Department of Surgery, Herlev Hospital, University of Copenhagen, Herlev, Denmark
,
Masja Klindt Fonnes
1   Centre for Perioperative Optimisation, Department of Surgery, Herlev Hospital, University of Copenhagen, Herlev, Denmark
,
Barbara Juliane Holzknecht
2   Department of Clinical Microbiology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
3   Department of Clinical Medicine, University of Copenhagen, Copenhagen N, Denmark
,
Jacob Rosenberg
1   Centre for Perioperative Optimisation, Department of Surgery, Herlev Hospital, University of Copenhagen, Herlev, Denmark
3   Department of Clinical Medicine, University of Copenhagen, Copenhagen N, Denmark
› Author Affiliations

Abstract

Background To investigate if perioperative parenteral administration of fosfomycin given before or during gastrointestinal surgery could protect against postoperative infectious complications and characterise the administration of fosfomycin and its harms.

Methods This systematic review included original studies on gastrointestinal surgery where parental administration of fosfomycin was given before or during surgery to≥5 patients. We searched three databases on March 24 2023 and registered the protocol before data extraction (CRD42020201268). Risk of bias was assessed with Cochrane Handbook risk of bias assessment tool or the Newcastle-Ottawa Scale. A narrative description was undertaken. For infectious complications, results from emergency and elective surgery were presented separately.

Results We included 15 unique studies, reporting on 1,029 patients that received fosfomycin before or during gastrointestinal surgery. Almost half of the studies were conducted in the 1980s to early 1990s, and typically a dose of 4 g fosfomycin was given before surgery co-administered with metronidazole and often repeated postoperatively. The risk of bias across studies was moderate to high. The rates of infectious complications were low after fosfomycin; the surgical site infection rate was 0–1% in emergency surgery and 0–10% in elective surgery. If reported, harms were few and mild and typically related to the gastrointestinal system.

Conclusion There were few postoperative infectious complications after perioperative parenteral administration of one or more doses of 4 g fosfomycin supplemented with metronidazole in various gastrointestinal procedures. Fosfomycin was associated with few and mild harms.

Supplementary Material



Publication History

Received: 30 June 2023

Accepted: 16 October 2023

Article published online:
28 November 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 WHO. Antimicrobial resistance. 2021. Available from https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance [Last accessed 29/06/2023]
  • 2 Falagas ME, Athanasaki F, Voulgaris GL, Triarides NA, Vardakas KZ. Resistance to fosfomycin: mechanisms, frequency and clinical consequences. Int J Antimicrob Agents 2019; 53: 22-28
  • 3 WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2023. Available from https://www.whocc.no/atc_ddd_index/ [Last accessed 29/06/2023]
  • 4 Kahan FM, Kahan JS, Cassidy PJ, Kropp H. The mechanism of action of fosfomycin (phosphonomycin). Ann N Y Acad Sci 1974; 235: 364-386
  • 5 Dijkmans AC, Zacarías NVO, Burggraaf J, Mouton JW, Wilms EB, van Nieuwkoop C, Touw DJ, Stevens J, Kamerling IMC. Fosfomycin: Pharmacological, Clinical and Future Perspectives. Antibiotics (Basel) 2017; 6: 24
  • 6 Michalopoulos AS, Livaditis IG, Gougoutas V. The revival of fosfomycin. International Journal of Infectious Diseases 2011; 15: e732-9
  • 7 Grabein B, Graninger W, Rodríguez Baño J, Dinh A, Liesenfeld DB. Intravenous fosfomycin—back to the future. Systematic review and meta-analysis of the clinical literature. Clinical Microbiology and Infection 2017; 23: 363-372
  • 8 Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clin Microbiol Rev 2016; 29: 321-347
  • 9 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. PLoS Med 2021; 18: e1003583
  • 10 Fonnes M, Fonnes S, Holzknecht BJ, Rosenberg J. Parenteral administration of fosfomycin prior to or during emergency or elective gastrointestinal surgery: a systematic review. PROSPERO. 2020 Available from https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020201268 [Last accessed 29/06/2023]
  • 11 Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016; 5: 210
  • 12 Cochrane Statistical Methods Group and the Cochrane Bias Methods Group. Assessing risk of bias in included studies. 2011. Available from https://handbook-5-1.cochrane.org/chapter_8/table_8_5_d_criteria_for_judging_risk_of_bias_in_the_risk_of.htm [Last accessed 29/06/2023]
  • 13 Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2021 Available from http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp [Last accessed 29/06/2023]
  • 14 Deeks J, Higgins J, Altman D. Chapter 10: Analysing data and undertaking meta-analyses. In: Cochrane Handbook for Systematic Reviews of Interventions version 6.3. (updated February 2022). Cochrane. 2022. Available from https://training.cochrane.org/handbook [Last accessed 29/06/2023]
  • 15 Wallace BC, Schmid CH, Lau J, Trikalinos TA. Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol 2009; 9: 80
  • 16 Fonnes S, Roepstorff S, Holzknecht BJ, Olesen CS, Olsen JHH, Schmidt L, Alder R, Gamborg S, Rasmussen T, Arpi M, Jørgensen LN, Rosenberg J. Shorter total length of stay after intraperitoneal fosfomycin, metronidazole, and molgramostim for complicated appendicitis: a pivotal quasi-randomized controlled trial. Front Surg 2020; 7: 25
  • 17 Dorn C, Petroff D, Neumann N, Kratzer A, El-Najjar N, Dietrich A, Kloft C, Zeitlinger M, Kees MG, Kees F, Wrigge H, Simon P. Plasma and tissue pharmacokinetics of fosfomycin in morbidly obese and non-obese surgical patients: a controlled clinical trial. J Antimicrob Chemother 2019; 74: 2335-2340
  • 18 Fonnes S, Holzknecht BJ, Arpi M, Rosenberg J. Intraperitoneal administration of fosfomycin, metronidazole, and granulocyte-macrophage colony-stimulating factor in patients undergoing appendectomy is safe: a phase II clinical trial. Sci Rep 2019; 9: 6727
  • 19 Shinagawa N, Mizuno I, Fukui T, Takeyama H, Yasuda A, Matsumoto K, Ueda N, Mouri N, Nagasaki T, Yokoyama T, Shinbara K, Isaka M, Kurisu Y, Akagi S, Tagawa K, Kano M, Niitani N, Watatani Y. [Prophylactic effect of fosfomycin on postoperative infection in gastroenterological surgery]. Jpn J Antibiot 2006; 59: 417-427
  • 20 Unemura Y, Ishida Y, Nakabayashi Y, Yamadera H, Ohtsuka M, Nakono S, Misawa T, Hashimoto K, Kobayashi S, Yamazaki Y. [Prevention of postoperative infection following laparoscopic cholecystectomy – comparison between single dose and 2-day dose administration of antibiotic prophylaxis]. Japanese J Gastroenterol Surg 2000; 33: 1880-1884
  • 21 Andåker L, Burman LG, Eklund A, Graffner H, Hansson J, Hellberg R, Höjer H, Ljungqvist U, Kjellgren K, Kling PA. Fosfomycin/metronidazole compared with doxycycline/metronidazole for the prophylaxis of infection after elective colorectal surgery. A randomised double-blind multicentre trial in 517 patients. Eur J Surg 1992; 158: 181-185
  • 22 Nøhr M, Andersen JC, Juul-Jensen KE. Prophylactic single-dose fosfomycin and metronidazole compared with neomycin, bacitracin, metronidazole and ampicillin in elective colorectal operations. Acta Chir Scand 1990; 156: 223-230
  • 23 Andåker L, Hojer H, Kihlstrom E, Lindhagen J. Stratified duration of prophylactic antimicrobial treatment in emergency abdominal surgery. Metronidazole-fosfomycin vs. metronidazole-gentamicin in 381 patients. Acta Chir Scand 1987; 153: 185-192
  • 24 Lindhagen J, Andåker L, Höjer H. Comparison of systemic prophylaxis with metronidazole/placebo and metronidazole/fosfomycin in colorectal surgery. A clinical study demonstrating the need for additional anti-aerobic prophylactic cover. Acta Chir Scand 1984; 150: 317-323
  • 25 Müller O, Rückert U, Walter W, Haag R, Sauer W. [Fosfomycin concentrations in serum and bile]. Infection 1982; 10: 18-20
  • 26 Lindhagen J, Hadziomerovic A, Nordlung S, Zbornik J. Comparison of systemic prophylaxis with metronidazole-fosfomycin and metronidazole-cephalothin in elective colorectal surgery. Acta Chir Scand 1981; 147: 277-283
  • 27 Cardia G, Palasciano N, Catalano G, Chetta G. [Phosphomycin in postoperative infectious prophylaxis]. Policlin Sez Chir 1980; 87: 841-843
  • 28 Bianca T, Rinella P, Ciuni S, Barbagallo G, Caragliano V. [Prevention of postoperative infections with phosphomycin: a controlled study]. G Ital Chir 1979; 35: 139-150
  • 29 Germiniani R, Longoni F, Maltempi P, Orio A. [Short term antibiotic prophylaxis of surgical infections using fosfomycin]. Farm Prat 1979; 34: 440-448
  • 30 Gallardo A, Sáez JM, Enriquez G, Cobacho AR, Torronteras R, Recordan C, Del Moral A, Arroyo A, Curiel AG. Surgical suppurating infections and surgical abdominal infections treated with fosfomycin. Chemotherapy 1977; 23 (Suppl. 01) 392-398
  • 31 Busse D, Simon P, Petroff D, El-Najjar N, Schmitt L, Bindellini D, Dietrich A, Zeitlinger M, Huisinga W, Michelet R, Wrigge H, Kloft C. High-dosage fosfomycin results in adequate plasma and target-site exposure in morbidly obese and nonobese nonhyperfiltration patients. Antimicrob Agents Chemother 2022; 66: e0230221
  • 32 Simon P, Petroff D, Dorn C, Ehmann L, Kloft C, Prettin C, Dietrich A, Zeitlinger M, Kees F, Wrigge H. Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – a prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial. Contemp Clin Trials Commun 2019; 15: 100375
  • 33 Olsson-Liljequist B, Burman LG. Introducing fosfomycin for surgical prophylaxis--emergence of resistance in aerobic faecal gram-negative bacteria of in-patients, but not among strains causing infection after elective colorectal procedures. Scand J Infect Dis 1993; 25: 725-733
  • 34 Germiniani R, Colombo F, Lavorato F. [Prevention of surgical infections with fosfomycin]. G Ital Chemioter 1978; 25: 115-122
  • 35 Fonnes S, Weisser JJ, Holzknecht BJ, Arpi M, Rosenberg J. The plasma pharmacokinetics of fosfomycin and metronidazole after intraperitoneal administration in patients undergoing appendectomy for uncomplicated appendicitis. Fundam Clin Pharmacol 2020; 34: 504-512
  • 36 Andåker L, Hojer H, Kihlstrom E, Lindhagen J. Stratified duration of prophylactic antimicrobial treatment in emergency abdominal surgery. Metronidazole-fosfomycin vs. metronidazole-gentamicin in 381 patients. Acta Chir Scand 1987; 153: 185-192
  • 37 Germiniani R, Longoni F, Maltempi P, Orio A. [Short term antibiotic prophylaxis of surgical infections using fosfomycin]. Farmaco Prat 1979; 34: 440-448
  • 38 Lindhagen J, Hadziomerovic A, Nordlung S, Zbornik J. Comparison of systemic prophylaxis with metronidazole-fosfomycin and metronidazole-cephalothin in elective colorectal surgery. Acta Chir Scand 1981; 147: 277-283
  • 39 Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992; 111: 518-526
  • 40 Miettinen P, Lahtinen J, Ristkari S, Alhava EM, Antila S, Härkönen N, Päkkönen M, Mokka R. Fosfomycin-metronidazole vs cefuroxime-metronidazole in 371 patients. Gastroenterology International 1988; Abstract no .: 794
  • 41 Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Ann Intern Med 2007; 147: 573-577
  • 42 Schulz KF, Altman DG, Moher D. CONSORT Group CONSORT 2010 statement: Updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010; 152: 726-732
  • 43 Kanji S, Hayes M, Ling A, Shamseer L, Chant C, Edwards DJ, Edwards S, Ensom MH, Foster DR, Hardy B, Kiser TH, la Porte C, Roberts JA, Shulman R, Walker S, Zelenitsky S, Moher D. Reporting guidelines for clinical pharmacokinetic studies: The ClinPK statement. Clin Pharmacokinet 2015; 54: 783-795
  • 44 European Medicines Agency. Guideline for good clinical practice E6(R2). 2016. Available from https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-good-clinical-practice-e6r2-step-5_en.pdf [Last accessed 29/06/2023]
  • 45 Pilatz A, Dimitropoulos K, Veeratterapillay R, Yuan Y, Omar MI, MacLennan S, Cai T, Bruyère F, Bartoletti R, Köves B, Wagenlehner F, Bonkat G, Pradere B. Antibiotic prophylaxis for the prevention of infectious complications following prostate biopsy: a systematic review and meta-analysis. J Urol 2020; 204: 224-230
  • 46 Bonkat G, Pilatz A, Wagenlehner F. Time to adapt our practice? The European Commission has restricted the use of fluoroquinolones since March 2019. Eur Urol 2019; 76: 273-275
  • 47 European Medicines Agency. Fosfomycin-containing medicinal products. 2020. Available from https://www.ema.europa.eu/en/medicines/human/referrals/fosfomycin-containing-medicinal-products [Last accessed 29/06/2023]
  • 48 Cai T, Tamanini I, Tascini C, Köves B, Bonkat G, Gacci M, Novelli A, Horcajada JP, Bjerklund Johansen TE, Zanel G. Fosfomycin trometamol versus comparator antibiotics for the treatment of acute uncomplicated urinary tract infections in women: a systematic review and meta-analysis. J Urol 2020; 203: 570-578
  • 49 Benevent J, Araujo M, Beau AB, Sicard D, Sommet A, Hurault-Delarue C, Lacroix I, Damase-Michel C. First trimester pregnancy exposure to fosfomycin and risk of major congenital anomaly: a comparative study in the EFEMERIS database. Infection 2023; 51: 137-146