Introduction
While many antimicrobial classes and compounds are potent in vitro, they may be accompanied with excessive toxicity or poor pharmacokinetics, limiting their clinical value in specific situations. As a result, the term “difficult-to-treat resistance” (DTR) was recently coined to define bacterial resistance to all first-line antimicrobials. DTR has been linked to unfavourable clinical outcomes in Gram-negative bacteria (GNB).
The in vitro efficacy of fosfomycin against DTR GNB, as well as its good safety profile, making it a potentially valuable drug for treating DTR GNB infections. Data on the clinical usage of the IV formulation for MDR and XDR GNB, on the other hand, is confined to research published more than 20 years ago, particularly from Europe and Japan. In this paper, we present our clinical experience with IV fosfomycin for the treatment of DTR GNB infections in Qatar.
Methods
Data were retrospectively retrieved for all hospitalized patients who received IV fosfomycin for ≥48 h for the treatment of a DTR GNB between September 27, 2017 and January 31, 2020. A total of 30 patients were included, of which 63.3% were males, and the median age was 63.5 years (IQR 46–73). For patients with an estimated creatinine clearance (CrCl) of >40 mL/min, a daily dose of 12–24 g/day divided into 2–4 daily doses was used.
The daily dose was reduced to 70%, 60%, 40% and 20% of the full dose in patients with CrCl of 31–40, 21–30, 11–20, and ≤10 mL/min, respectively. The primary outcome was clinical improvement at the end of IV fosfomycin therapy, defined as resolution of baseline signs and symptoms of infection. The median Charlson Comorbidity Score was 6 (IQR 3.8–9). Qualitative and quantitative data were presented as numbers (percentages) or medians, as appropriate. For patients with an estimated creatinine clearance (CrCl), the doses were reduced as below-
Results
Five (16.7%) of the 30 patients were in the intensive care unit at the time of starting IV fosfomycin therapy. The urinary tract (56.7%) was the most frequent site of infection, and the most frequent target organism was Klebsiella pneumoniae (17, 56.7%). IV Fosfomycin was started within a median of 4.5 days (1–10.3) from the onset of infection. The median daily IV fosfomycin dose was 18 g (IQR 6–24).
In the majority (23, 76.%), IV fosfomycin was used in combination with other antimicrobial agents. The primary outcome was achieved in 22 (73.3%) patients, including 20 (66.7%) with documented eradication of the baseline pathogens. However, seven (23.3%) patients died of any cause within 30 days from starting IV fosfomycin therapy. In the individuals who died within 30 days of starting IV fosfomycin therapy, the median age was 59 years (IQR 25–73), four had underlying malignant disease, and two were kidney transplant recipients. Four out of those seven patients died with uncontrolled infection.
The most frequently observed adverse events were hypokalemia (13, 43.3%) and hypernatremia (7, 23.3%). However, the majority of adverse events were classified as Grade 1–2.
In the individuals who died within 30 days of starting IV fosfomycin therapy, the median age was 59 years (IQR 25–73), four had underlying malignant disease, and two were kidney transplant recipients. Four out of those seven patients died with uncontrolled infection. Emergent in vitro resistance to fosfomycin within 90 days of initiation of fosfomycin therapy was documented in five (16.7%) individuals.
Conclusion
IV fosfomycin is a potentially efficacious and safe treatment option for the treatment of DTR GNB infections. Appropriately designed randomized clinical trials are urgently required to confirm the utility of IV fosfomycin as monotherapy and in combination with other agents.
Source: Tasneem A.K. Abdallah, Reem Elajez, Tawheeda B. Ibrahim, Abeir B. Alimam, Ali S. Omrani, Efficacy and safety of intravenous fosfomycin for the treatment of difficult-to-treat Gram-negative bacterial infections, Journal of Infection and Public Health, Volume 14, Issue 11, 2021, Pages 1620-1622, https://doi.org/10.1016/j.jiph.2021.09.025.
