Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis

Seroy, Justin; Grim, Shellee A.; Reid, Gail; Wellington, Trevor; Clark, Nina M.

doi:10.1093/jac/dkw178

Cited by 32 publications

(17 citation statements)

References 26 publications

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“…Overall, fosfomycin achieved microbiological cure within the first month in 71.4% (35 of 49) of the evaluable episodes due to MDR pathogens. A previous study including different patient populations demonstrated a cure rate of 55% for UTI produced by MDR bacteria . Various European surveillance studies have reported susceptibility rates for E. coli isolates exceeding 96%, which have remained stable over the previous 10 years .…”

Section: Discussionmentioning

confidence: 93%

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients—Results of a Spanish multicenter cohort

López‐Medrano

Silva

Fernández‐Ruiz

et al. 2020

American Journal of Transplantation

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Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram‐negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended‐spectrum β‐lactamase‐producing Enterobacteriaceae [14%] or carbapenem‐resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5‐2) was administered for a median of 7 days (IQR: 3‐10). Clinical cure (remission of UTI‐attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow‐up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98‐112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs.

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Section: Discussionmentioning

confidence: 93%

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients—Results of a Spanish multicenter cohort

López‐Medrano

Silva

Fernández‐Ruiz

et al. 2020

American Journal of Transplantation

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“…A recent large randomised trial found a lower clinical cure rate with fosfomycin compared with nitrofurantoin (58% vs 70%, p=0.004). 19 While some recent observational studies have demonstrated fosfomycin efficacy in uncomplicated urinary tract infection caused by resistant organisms, [52][53][54][55][56] including non-inferiority to carbapenems, 57,58 there are reports of treatment failures particularly with Klebsiella. 59 As low serum concentrations lead to treatment failures, fosfomycin is not appropriate for patients with bacteraemia or upper urinary tract infections such as pyelonephritis.…”

Section: Efficacy and Safetymentioning

confidence: 99%

Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems

Gardiner¹,

Stewardson²,

Abbott³

et al. 2019

Aust Prescr

110

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Uncomplicated urinary tract infection is one of the most common indications for antibiotic use in the community. However, the Gram-negative organisms that can cause the infection are becoming more resistant to antibiotics. Many multidrug resistant organisms retain susceptibility to two old antibiotics, nitrofurantoin and fosfomycin. Advantages over newer drugs include their high urinary concentrations and minimal toxicity. Fosfomycin is a potential treatment option for patients with uncomplicated urinary tract infection due to resistant organisms. Nitrofurantoin may be more effective and can be used for urinary infections in pregnant women. Nitrofurantoin Nitrofurantoin has been available since 1953, and in Australia since the 1970s. Its exact mechanism of action is not well understood and presumably multifactorial. Nitrofurantoin requires reduction by bacterial enzymes producing 'highly reactive electrophilic' metabolites. These then inhibit protein synthesis by interfering with bacterial ribosomal proteins. 11 Nitrofurantoin has 80% oral bioavailability, and approximately 25% is excreted unchanged in the urine, with only a small portion reaching the colon. 12 Like fosfomycin, therapeutic concentrations are only reached in the urinary tract, 13 so the clinical use of nitrofurantoin is limited to the treatment of uncomplicated urinary tract infection in women. Administration with food results in higher urinary concentrations and fewer gastrointestinal adverse effects. Antimicrobial activity Nitrofurantoin is active against common causes of urinary tract infection including E. coli, Citrobacter and Enterococcus. Klebsiella and Enterobacter are less reliably susceptible. Serratia, Acinetobacter, Morganella, Proteus and Pseudomonas are usually resistant. 14 Overall, resistance to nitrofurantoin is uncommon and many multidrug resistant organisms retain susceptibility. 15-17 Australian data are limited, but studies suggest resistance rates in E. coli of 1-2%. 4,6

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“…Our data suggest that baseline fosfomycin heteroresistance was more predictive of the treatment response in our bladder infection model, and if present, regrowth with resistant populations was almost universal irrespective of the modeled urinary concentrations or 3-dose frequency. This finding was supported by a clinical review of fosfomycin treatment in MDR UTIs, which found no association of treatment outcomes with the MIC of fosfomycin or the number of doses received (14).…”

Section: Figmentioning

confidence: 85%

Oral Fosfomycin Efficacy with Variable Urinary Exposures following Single and Multiple Doses against Enterobacterales : the Importance of Heteroresistance for Growth Outcome

Abbott

Gorp

Wijma

et al. 2020

Antimicrob Agents Chemother

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Oral fosfomycin trometamol is licensed as a single oral dose for the treatment of uncomplicated urinary tract infections, with activity against multidrug-resistant uropathogens. The impact of interindividual variability in urinary concentrations on antimicrobial efficacy, and any benefit of giving multiple doses, is uncertain. We therefore performed pharmacodynamic profiling of oral fosfomycin, using a dynamic bladder infection in vitro model, to assess high and low urinary exposures following a single oral dose and three repeat doses given every 72 h, 48 h, and 24 h against 16 clinical isolates with various MICs of fosfomycin (8 Escherichia coli, 4 Enterobacter cloacae, and 4 Klebsiella pneumoniae isolates). Baseline fosfomycin high-level-resistant (HLR) subpopulations were detected prior to drug exposure in half of the isolates (2 E. coli, 2 E. cloacae, and 4 K. pneumoniae isolates; proportion, 1 × 10−5 to 5 × 10−4% of the total population). Fosfomycin exposures were accurately reproduced compared to mathematical modeling (linear regression slope, 1.1; R2, 0.99), with a bias of 3.8% ± 5.7%. All 5/5 isolates with MICs of ≤1 μg/ml had no HLR and were killed, whereas 8/11 isolates with higher MICs regrew regardless of exposure to high or low urinary concentrations. A disk diffusion zone of <24 mm was a better predictor for baseline HLR and regrowth. Administering 3 doses with average exposures provided very limited additional kill. These results suggest that baseline heteroresistance is important for treatment response, while increased drug exposure and administering multiple doses may not be better than standard single-dose fosfomycin therapy.

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Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis

Abstract: This study supports the use of fosfomycin as an oral option for treating MDR UTIs. Additional studies are required to assess the optimal dosing and utility of combination therapy to decrease the incidence of treatment failure.

Cited by 32 publications

References 26 publications

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients—Results of a Spanish multicenter cohort

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients—Results of a Spanish multicenter cohort

Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems

Oral Fosfomycin Efficacy with Variable Urinary Exposures following Single and Multiple Doses against Enterobacterales : the Importance of Heteroresistance for Growth Outcome

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