Comment on: Efficacy of temocillin against MDR Enterobacterales: a retrospective cohort study Free

Sir,

A recently published paper by Alexandre et al.¹ demonstrated good clinical efficacy of temocillin in the treatment of infections originating from the urinary tract. Lower treatment efficacy was observed in severe sepsis, septic shock and in infections originating outside the urinary tract. Most of the patients received 2 g × 2, while less than 20% received 2 g × 3. The authors used a breakpoint of 8 mg/L with automated antimicrobial susceptibility testing (VITEK2) and 20 mm when using disc diffusion and did not report any quality control efforts.

EUCAST agrees with the overall conclusion that temocillin has proven clinical efficacy in infections originating from the urinary tract. However, there are several conclusions in the paper that need further discussion.

First of all, the authors cite that they use French clinical breakpoint recommendations (CA-SFM), but it should be noted that EUCAST is a joint effort where CA-SFM together with other European countries unite behind one recommendation. The current French recommendation for all antimicrobials including temocillin is to use EUCAST methodology and breakpoints. In early 2020, EUCAST published temocillin breakpoints (susceptible ≤0.001 mg/L and resistant >16 mg/L),² which categorized the WT distributions of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca and Proteus mirabilis in the category ‘susceptible, increased exposure’ (I). Since temocillin will concentrate in the urinary tract, the criteria for ‘susceptible, increased exposure’ are fulfilled with the standard dose as long as the infection is confined to the urinary tract (complicated bacteria in uncomplicated infections). For infections originating from but not confined to the urinary tract, the increased dose of 2 g × 3 corresponds to the EUCAST breakpoints.

Secondly, the authors propose a susceptibility breakpoint of 8 mg/L. This breakpoint bisects the WT of several of the target species, thus leading to unacceptable categorical errors with all antimicrobial susceptibility testing methods. These errors apply to both MIC testing and disc diffusion. A subgroup analysis relating outcome to MIC in the 86 patients with isolates tested by gradient test (Supplementary data¹) is lacking and might have been informative. The lack of quality control data for VITEK2 results, for gradient test results and for disc diffusion is a major challenge when interpreting data. There is no indication that isolates were tested with any reference methodology.

Thirdly, 60/153 patients were reported as having chronic renal disease (no measure of renal function stated) but only 3.9% were given a reduced temocillin dose. This implies that many of the patients may have received ‘increased exposure’ to the drug related to reduced renal function, which may partly account for the successes in this treatment group.

Finally, severe infections responded less well to the dosing regimen 2 g × 2 mainly used in the study. In fact, it is not known whether many of the patients with more severe illness would have benefited from receiving the dosing regimen 2 g × 3, a regimen only used in 17.6% of patients. From a pharmacokinetic-pharmacodynamic perspective there is no doubt that the 2 g × 3 dosing regimen is preferable. However, the study was not powered to determine whether the 8-hourly dosing regimen would have been superior.

In non-severe infections originating from the urinary tract and with no concomitant bacteraemia, 2 g × 2 could be an adequate dosing regimen since these patients will have high urinary concentrations, to cover uncomplicated infections with ‘complicated’ pathogens.³ However, the EUCAST breakpoint supports the use of temocillin 2 g × 3 in all infections originating from the urinary tract, including more severe infections.

After a long review process and public consultation, EUCAST concluded that 2 g × 3 will ensure successful outcomes in all patients with infections originating in the urinary tract. The breakpoints susceptible ≤0.001 mg/L and resistant >16 mg/L avoid dividing the WT of relevant organisms and increase the chance of reproducible susceptibility results. These conclusions are in line with official recommendations both in France and other EU countries where the drug is available.

Transparency declarations

All authors are members of the EUCAST Steering Committee. There are no financial conflicts of interest to declare.

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