Fosfomycin efficacy and emergence of resistance among Enterobacteriaceae in an in vitro dynamic bladder infection model

Abbott, Iain J.; Meletiadis, Joseph; Belghanch, Imane; Wijma, Rixt A.; Kanioura, Lamprini; Roberts, Jason A.; Peleg, Anton Y.; Mouton, Johan W.

doi:10.1093/jac/dkx441

Cited by 31 publications

(22 citation statements)

References 39 publications

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“…In addition, emergence of resistance was often detected early, within the first 24 h, such that repeat doses of fosfomycin given after that time had very little impact on the overall bacterial density. This rapid emergence of resistance negated the benefit of giving multiple doses and particularly questions the role of delaying repeat doses by 48 or 72 h. Overall, the efficacy of fosfomycin against our K. pneumoniae isolates appeared limited, regardless of the baseline MIC or drug exposure, a finding supported by other studies (40)(41)(42).…”

Section: Figsupporting

confidence: 68%

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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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Section: Figsupporting

confidence: 68%

“…Fosfomycin exposure in the bladder infection in vitro model. We used an adaptation of a previously described in vitro model (40). Observed in vitro concentrations closely matched the target concentration of each of the single and multidose fosfomycin exposure simulations.…”

Section: Resultsmentioning

confidence: 99%

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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“…28 Urinary concentrations following a single 3 g dose are generally sufficient to treat patients infected with susceptible organisms, although some recent data suggest more variability in urinary concentrations than previously thought. 33,34 As fosfomycin has a unique structure there is minimal cross-resistance with other antibiotics. At present, many multidrug resistant isolates remain susceptible to fosfomycin, even in geographic regions where there has been widespread use of the drug.…”

Section: Antimicrobial Activitymentioning

confidence: 99%

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

Gardiner¹,

Stewardson²,

Abbott³

et al. 2019

Aust Prescr

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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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“…A fosfomycin exposure of an AUC0-24/MIC ≥ 3136 has been shown to suppress the emergence of resistance for E. coli and E. cloacae isolates with an MIC ≤8 mg/L. With a breakpoint of 8 mg/L, it may be possible to treat and prevent the emergence of resistance for systemic infections in most patients who receive a dose of 8 g administered thrice-daily (268), or to treat a urinary tract infection with a single 3 g oral dose (214). However, fosfomycin resistance may emerge during treatment for K. pneumoniae or non-fermenting Gram negative bacterial infections.…”

Section: Discussionmentioning

confidence: 99%

“…reported that continuous infusion of ceftazidime exhibited improved bacterial killing compared to an intermittent infusion against P. aeruginosa (30). In a separate study, an extended PTZ infusion, but not an intermittent infusion, suppressed the emergence of resistance of P. aeruginosa (214).…”

Section: Introductionmentioning

confidence: 95%

Optimisation of alternative antibiotic dosing regimens for maximal antibacterial activity and suppression of emergence of resistance

Sumi¹

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Infections caused by extended-spectrum beta-lactamase (ESBL)producing Enterobacterales, e.g., Escherichia coli and Klebsiella pneumoniae can be severe and often deadly in critically-ill patients in intensive care units (ICUs). Achieving target antibiotic concentrations to increase bacterial killing and suppress the emergence of resistance is a highly desirable aim of therapy. However, achieving these endpoints can be challenging in these patients with conventional dosing regimens because of variable pathophysiology affecting antibiotic dosing requirements and because the concentrations that suppress emergence of resistance are not well defined. Beta-lactams are the most commonly used to empirical agents in ICU patients. These antibiotics exhibit timedependent bacterial killing, therefore, prolonged infusion (i.e., extended/continuous infusion) I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from coauthors for any jointly authored works included in the thesis. v Publications included in this thesis Sumi CD, Heffernan AJ, Lipman J, Roberts JA, Sime FB. What antibiotic exposures are required to suppress the emergence of resistance for gram-negative bacteria? A systematic review. Clin Pharmacokinet. 2019.

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Fosfomycin efficacy and emergence of resistance among Enterobacteriaceae in an in vitro dynamic bladder infection model

Cited by 31 publications

References 39 publications

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

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

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

Optimisation of alternative antibiotic dosing regimens for maximal antibacterial activity and suppression of emergence of resistance

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