Fosfomycin: the hottest drug in town!? News from ECCMID 2018

In our team Thijs ten Doesschate does a PhD in clinical epidemiology addressing some clinical aspects on fosfomycin; An old antibiotic, active against Enterobacteriaceae, and surfacing as promising alternative to beta-lactams and fluoroquinolones in times of antibiotic resistance. He is currently coordinating a multi-center double-blind placebo-controlled randomized trial to determine non-inferiority of fosfomycin (against ciprofloxaxin) in the step-down oral treatment of complicated Urinary Tract Infections (UTI). If non-inferior, we could reduce cipro usage. For himself (and now for us) he summarized fosfomycin news at ECCMID. Most presentations (O) and posters (P) can also be found on http://www.eccmidlive.org/ .

PK/PD studies:

  • After administration of a similar dosage of fosfomycin – intravenous or oral – fosfomycin concentrations in serum (after IV use) and urine (after oral use) vary considerably between patients, even in not critically ill patients. Urine and serum concentrations depend on the renal function, as 97% of fosfomycin is excreted non-metabolized in urine (Wijma O0728, Perez S0208 ).
  • Oral fosfomycin has in vitro bactericidal activity against coli, but hardly any against K. pneumoniae or P. mirabilis (Wijma O0728 , Wenzler P1626)
  • Based on in vitro models, the AUC/MIC ratio seems to predict fosfomycin effectivity best for both Enterobacteriaceae as P. aeruginosa (Perez S0208)
  • Oral fosfomycin 3 gram seems to be insufficient to kill E.coli strains with a MIC >4mg/L in urine, based on an in vitro bladder model. This probably results from hypermutators in the coli population (Abbott O0729)
  • Consequently, revision of EUCAST and CLSI breakpoints might be needed, yet in vivo data confirming these findings are lacking (Abott O0729, Wenzler P1626, Wijma O0728).
  • Due to rapid acquisition of fosfomycin resistance, especially within non-coli isolates, intravenous fosfomycin should be combined with other antibiotics, especially for the treatment of severe infections,  i.e. with meropenem or colistin (Perez S0208).

Resistance:

  • Resistance rates to fosfomycin were low (1-3%) both in ESBL-producing as in carbapenemase-producing coli isolates. Rates were much higher in non-E.coli Enterobacteriaceae (Perez SO208).
  • Multiple clinically used fosfomycin susceptibility testing methods were compared to the reference agar dilution for 976 clinical ESBL producing coli and K. pneumoniae  isolates. Despite a high level of categorical agreement, the very major error rate was high (VME=agar dilution says resistance and the other test says susceptible).  For E.coli the VME proportions were 12.9% for disk diffusion, 23.3% for Etest, 18.5% for MIC test strip, 18.8% for VITEK2 and 25% for PHOENIX. Based on this analysis, proposed epidemiological breakpoint were 2mg/L for E.coli and 64mg/L for K.pneumoniae (Bijllaardt P1628).
  • To take things even more complex: there are also doubts about the adequacy of the reference standard, agar dilution, as it has not been correlated yet with the clinical effectivity of intravenous or oral fosfomycin (Perez S0208).

Clinical studies:

  • In a prospective observational study of 22 patients oral fosfomycin (3gr/ day, on average 15 days) as a stepdown treatment after initial IV antibiotic treatment in complicated UTI microbiological cure after 30 days was achieved in 20 patients (91%). Yet, as the initial IV treatment was 7-14 days, it remains unknown to what extent the IV therapy or the stepdown treatment with fosfomycin contributed (Messiaen P2159).
  • In a retrospective study, the use and efficacy of oral fosfomycin was investigated in 56 UTI episodes in kidney transplant recipients. Fosfomycin had reasonable clinical efficacy when used as monotherapy for UTI with only local symptoms (clinical cure 14 days post-treatment: 22/34, 61%), but a microbiological cure rate within 90 days of only 21% (3/14). Poor microbiological cure (33%, 4/12) was also observed when fosfomycin monotherapy was used for asymptomatic bacteriuria. Fosfomycin as stepdown treatment after adequate IV antibiotics was associated with clinical and microbiological cure rates of 83% (5/6) and 100% (5/5). Fosfomycin was dosed very heterogeneously; optimizing the dose could improve efficacy (Doesschate P2151).
  • In an open-label RCT with 513 patients uncomplicated cystitis a single 3 gram dosage of oral fosfomycin was inferior to nitrofurantoin (5 days 100 mg / day) for clinical cure (resolution of symptoms) after 30 days. Striking was the low rates of clinical cure in both groups (fosfomycin 139/241, 58% versus nitrofurantoin 171/244 70%). The difference was larger for the population with coli infections (78% vs. 50%). Nitrofurantoin was also superior for microbiological cure. (Huttner O1127)
  • In an interim analysis of the FOREST RCT (comparing IV fosfomycin to meropenem or ceftriaxone for bacteriemic UTI caused by ESBL-producing-coli fosfomycin was not associated with an increased risk of reinfection or colonization with ESBL-E.coli. Final results are expected by the end of 2018. (Baño P1633)

 

Thijs_ten_Doesschate (HiRes Color)

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